Compositions and methods for treating metabolic disorders

Abstract

Provided herein, inter alia, are methods, compositions, and kits effective for treating metabolic disorders. The method, kits and compositions provided herein include a Krüppel-like factor 15 (KLF15) inhibitor, a beta-1 adrenergic receptor (ADRB1) agonist, a nucleic acid encoding ADRB1, or a combination thereof.

Description

COMPOSITIONS AND METHODS FOR TREATING METABOLIC DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 662,403, filed June 20, 2024, which is hereby incorporated by reference in its entirety and for all purposes.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (048536- 767001WO_Sequence_Listing_ST26.xml; Size: 57,710 bytes; and Date of Creation: June 19, 2025) are hereby incorporated by reference in their entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0003] This invention was made with government support under R01 DK132404 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0004] Healthy adipose tissue is essential for normal physiology. There are two broad types of adipose tissue depots: brown (BAT), that contain adipocytes poised to burn energy through thermogenesis and white (WAT), which contain adipocytes that store lipids. However, within those types of adipose, adipocytes possess depot and cell specific properties which have important implications. For example, the subcutaneous and visceral WAT confer divergent risk for metabolic disease. Furthermore, within a depot, different adipocytes can have distinct properties; subcutaneous WAT can contain adipocytes with either white or brown-like (beige) adipocyte properties. However, the pathways that regulate and maintain this cell and depot-specificity are incompletely understood.BRIEF SUMMARY

[0005] In an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject an effective amount of Kriippel-like factor 15 (KLF15) inhibitor.

[0006] In an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

[0007] In an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject an effective amount of a nucleic acid encoding beta-1 adrenergic receptor (ADRB1) protein.

[0008] In an aspect is provided a method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method including contacting a cell with a Kriippel-like factor 15 (KLF15) inhibitor.

[0009] In an aspect is provided a method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method including contacting a cell with a nucleic acid encoding beta-1 adrenergic receptor (ADRB1).

[0010] In an aspect is provided a method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method including contacting a cell with a beta-1 adrenergic receptor (ADRB1) agonist.

[0011] In an aspect is provided a pharmaceutical composition including a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0012] In an aspect is provided a pharmaceutical composition including a nucleic acid encoding beta-1 adrenergic receptor (ADRB1).

[0013] In another aspect is provided a kit including a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0014] In another aspect is provided a kit including a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein and a Kriippel-like factor 15 (KLF15) inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG.s 1A-1K. Acute modulation of Klfl5 expression in white adipocytes induces a beige fat expression profile. (FIG. 1A) RT-qPCR quantifying the expression levels of Ktfl5 in adipocytes isolated from distinct fat pads. One-way ANOVA, n=3. (FIG. IB) RT-qPCR quantifying the expression levels of Klfl5 in adipocytes after isoproterenol (Iso) treatment for 4h. Student’s t test, n=6. (FIG. 1C) RT-qPCR quantifying the expression levels of Klfl5 in iWAT isolated from miceafter they were injected with CL316243 (CL) (1 mg / kg / day) for 7 days. Student’s t test, n=4. (FIG.ID) RT-qPCR quantifying the relative expression levels o Adrbl, Adrb2 andAdrb3 in iWAT, gWAT and BAT with iWAT set to one for each litter. For the Adrbl, Adrb2 andAdrb3 data sets, the bars from left to right represent: iWAT, gWAT, and BAT. One-way ANOVA, n=5. (FIG. IE) Light phase microscopy images of adipocytes from differentiated SVF harvested from the iWAT of Klfl 5- fl / fl mice and infected with adenovirus expressing Cre (Ad-Cre) or adenovirus control (Ad-Control). Scale bar: 25 pm. (FIG. IF) RT-qPCR quantifying the expression levels of thermogenic genes and pan-adipocyte marker Adipoq. Student’s test, n = 4. (FIG. 1G) RT-qPCR quantifying the expression levels. Student’s t tests followed by Holm-Sidak correction, n = 7. (FIG. 1H) Immunoblots detecting and quantifying the relative levels of [31 AR following acute Klfl5 deletion in adipocytes. Student’s t test, n = 3. (FIG. II) Immunoblots detecting and quantifying the relative levels of phosphorylation of p38 MAPK following acute Klfl 5 deletion in adipocytes. Student’s t test, n = 3. (FIG. 1 J) RT-qPCR quantifying the change in Ucpl expression levels with SB202190 pre-treatment. Student’s t test, n = 3-4. (FIG. IK) RT-qPCR quantifying the expression levels of Ucpl following acute Klfl5 deletion in adipocytes treated with Isoproterenol. Two-way ANOVA, n = 3. *P < 0.05, **P < 0.01, ***P < 0.001. For FIG.s 1F-1K, dark gray bars represent Ad-Cre and light gray bars represent Ad-Control.

[0016] FIG.s 2A-2K. Adipocyte-specific Klfl5 knockout promotes beige adipocyte formation in iWAT. (FIG. 2A) RT-qPCR quantifying the expression levels of Klfl 5 in iWAT, gWAT, BAT and liver from WT and Adipo-Klfl5 mice. Student’s t tests followed by Holm-Sidak correction, n = 3. (FIG. 2B) RT-qPCR quantifying the expression levels of Klfl 5 in the SVF and adipocyte fraction of iWAT from WT and Adipo-Klfl5 mice. Student’s t test followed by Holm-Sidak correction, n = 3. (FIG. 2C) Representative images of in situ iWAT in WT and Adipo-Klfl 5 mice. Scale bar: 5 mm. (FIG. 2D) Quantification of iWAT mass as a percent of body weight in WT and Adipo-Klfl 5 littermates. Ratio paired t test, n = 5. (FIG. 2E) RT-qPCR quantifying the expression levels of thermogenic genes in iWAT of WT and Adipo-Klfl 5 littermates. Student’s t test, n = 5. (FIG. 2F- 2H) RT-qPCR quantifying the expression levels of adrenergic receptors in iWAT, gWAT and BAT from WT and Adipo-Klfl 5 mice. Student’s t test followed by Holm-Sidak correction, n = 5. (FIG.21) RT-qPCR quantifying the expression levels of Adrbl vs Adrb3 in iWAT in littermates of WT and Adipo-Klfl 5 mice. One-tailed ratio paired t test, n = 4. (FIG. 2J) Immunoblots detecting the levels of pi AR protein in iWAT from WT and Adipo-Klfl 5 mice compared to the levels of Pactincontrols. (FIG. 2K) Quantifying the relative protein level of 01AR. Student’s t test, n = 4. *P < 0.05, **P < 0.01, ***P < 0.001. For FIG.s 2A, 2B, 2D-2H, and 2K, light gray bar or data point represents WT and dark gray bar or data point represents Adipo-Klfl5 cKO.

[0017] FIG.s 3A-3N. Enhanced beiging occurs in the iWAT of Prxl-Klfl5 cKO mice. (FIG. 3A) RT-qPCR quantifying the expression levels of Klfl5 in iWAT, gWAT, BAT and liver from WT and Prxl-Klfl5 mice. Student’s t tests followed by Holm-Sidak correction, n = 3. (FIG. 3B) RT-qPCR quantifying the expression levels of Klfl5 in the SVF and adipocyte fractions of iWAT from WT and Prxl-Klfl5 mice. Student’s t tests followed by Holm-Sidak correction, n = 3. (FIG. 3C) Quantification of iWAT mass as a percent of body weight in WT and Prxl-Klfl5 mice. Student’s t test, n = 9. (FIG. 3D) Representative images of in situ iWAT from female WT and Prxl-Klfl5 mice. Scale bar: 5 mm. (FIG. 3E) Representative images of H&E stained histological sections of iWAT from female WT and Prxl-Klfl5 mice. Scale bar: 100 pm. (FIG.s 3F-3H) RT-qPCR quantifying the expression levels of (FIG. 3F) pan-adipocyte markers, n = 4 (FIG. 3G) white adipocyte markers, n = 3-8 and (FIG. 3H) thermogenic genes in iWAT, n = 6-11. Student’s t test followed by Holm-Sidak correction (FIG. 31) RT-qPCR quantifying the expression levels of adrenergic receptors in iWAT from WT and Prxl-Klfl5 mice. Student’s t test followed by Holm-Sidak correction, n = 4. (FIG. 3 J) RT-qPCR quantifying the expression levels oi Adrbl vs Adrb3 in iWAT from littermates of WT and Prxl-Klfl5 mice. One-tailed ratio paired t test, n = 4. (FIG. 3K) Immunoblot detecting UCP1 and GAPDH protein levels in the iWAT of WT and Prxl-Klfl5 mice. (FIG. 3L) Time course quantification of OCRs of iWAT isolated from WT and Prxl-Klfl5 littermates after exposure to Xamoterol using a Seahorse Bioanalyzer. Two-way ANOVA, n = 5. (FIG.s 3M, 3N) Whole-body heat generation (kcal) of mice undergoing cold exposure. (FIG. 3M) Two-way ANOVA, (FIG. 3N) ANCOVA, n = 5. *P < 0.05, **P < 0.01, ***p < 0.001. In FIG.s 3A-3C and 3F-3I, for each set of two data bars, the left bar represents WT and the right bar represents Prxl-Klfl5 cKO.

[0018] FIG.s 4A-4N. KLF15 regulates the expression of Adrbl in a pathway conserved in humans. (FIG. 4A, FIG. 4B) RT-qPCR quantifying the expression levels of Adrbl and Ucpl in adipocytes with or without Xamoterol treatment. Student’s t test, n = 5. (FIG. 4C) Quantifying of unstimulated intracellular cAMP levels in adipocytes with deletion of Klfl5. Student’s t test, n = 5. For FIG.s 4A-4C, circle data points represent Ad-Control and square data points represent Ad-Cre. (FIG. 4D) Conservation of a canonical KLF15 binding site sequence (underlined) identified in themouse Adrbl gene. (FIG. 4E) Quantification of dual-luciferase assays on adipocytes transfected with the Adrbl promoter-driven Firefly luciferase reporter construct and pCMV-Klfl5 or control plasmid and normalized by Renilla bioluminescence, facilitated by co-transfected pRL-TK plasmid. Student’s t test, n = 3. (FIG. 4F) RT-qPCR quantifying the amount of immunoprecipitated DNA containing the putative KLF15 binding site located in Adrbl using a KLF15 antibody in iWAT adipocytes from WT and Prxl-Klfl5 cKO mice. Student’s t test, n = 3. (FIG. 4G) RT-qPCR quantifying the amount of immunoprecipitated DNA containing the putative KLF15 binding site located in the Adrbl using the FLAG compared to IgG antibody in iWAT adipocytes isolated from Klfl53 V[ AGmice. Student’s t test, n = 3. (FIG. 4H) Image of PCR amplicons in an agarose gel of the putative KLF15 binding site (Target region) compared to amplification of the Control region from the ChIP of adipocytes from WT and Prxl-Klfl5 cKO mice with the KLF15 antibody. (FIG. 41) RT- qPCR quantifying the expression levels of Ucpl in iWAT from mice injected with saline, Denopamine (10 pg / g / day), Xamoterol (8 ng / g / day) or Dobutamine (10 pg / g / day) for 7 days. Oneway ANOVA, n = 4-5. (FIG. 4J) Light phase microscopy images of human adipocytes. Scale bar: 25 pm. (FIG. 4K) RT-qPCR quantifying the expression levels of hKLF15, hADRBl and hUCPl in human adipocytes infected by Ad-shCtrl or Ad-shKLF15. Student’s t test followed by Holm-Sidak correction, n = 4. (FIG. 4L) OCRs and (FIG. 4M) respiratory profile in Ad-shKLF15 and Ad-shCtrl infected human adipocytes quantified using a Seahorse Bioanalyzer, 2-way ANOVA n = 8. (FIG. 4N) Time-course of OCRs of human adipocytes after exposure to Xamoterol. 2-way ANOVA, n = 8-9. *P < 0.05, **P < 0.01, ***P < 0.001. For FIG.s 4K-4N, circle data points represent Ad-shCtrl and square data points represent Ad-shKLF15.

[0019] FIG.s 5A-5H. Adipocyte-specific deletion of Klfl5 induces a thermogenic gene expression in the adipocyte fraction of iWAT. (FIG. 5A) RT-qPCR quantifying the relative expression level of Adrb\-3 in different adipose tissue depots, t tests followed Fisher’s LSD test, n = 6. (FIG. 5B) RT- qPCR quantifying the expression levels of Ucpl after acute Klfl5 deletion (dark gray bar) in adipocytes treated with vehicle or propranolol for 24h. One-way ANOVA, n = 4. (FIG. 5C) RT- qPCR quantifying the expression levels of Ucpl and Ppargcla in the adipocyte fraction of iWAT isolated from WT and Adipo-Klfl5 mice. Student’s t test followed by Holm-Sidak correction, n = 3. (FIG.s 5D, 5E) RT-qPCR quantifying the expression levels of thermogenic genes. Student’s t test, n = 4. (FIG.s 5F, 5G) Ratios of Adrbl xs Adrb3 expression levels in BAT (FIG. 5F) and gWAT (FIG.5G) from WT and Adipo-Klfl5 littermates, quantified by RT-qPCR. Ratio paired t test, n = 4-5. (FIG. 5H) RT-qPCR quantifying the expression levels of factors relevant to Ucpl and PAR independent thermogenic pathways. Student’s t test, n = 3-6. *p < 0.05, **p < 0.01, ***p < 0.001. For FIG.s 5C-5H, light gray bar represents WT and dark gray bar represents Adipo-Klfl5 cKO.

[0020] FIG.s 6A-6G. Analysis of Prx l -A7 / 75 mice. (FIG. 6A) Representative images of in situ iWAT from 6-weeks old male WT and Prxl-Klfl5 mice. Scale bar: 5 mm. (FIG. 6B) Representative images of H&E stained histological sections of iWAT from male WT w Prxl-Klfl5 mice. Scale bar: 1 mm. (FIG.s 6C, 6D) Body weights of female fed standard diets and HDFs. Two-way ANOVA n= 4-5. (FIG. 6E) Average weekly food intake of mice; each point represents the total food intake for one-week. Student’s t test, n = 8. (FIG. 6F) Immunoblots detecting iAR and Pactin protein levels in the iWAT. (FIG. 6G) Time course quantification of OCRs of iWAT isolated from WT and Prx-Klfl5 cKO littermates after exposure to isoproterenol stimulation. Two-way ANOVA, n = 3-4. *p < 0.05, **p < 0.01, ***p < 0.001. For FIG.s 6C-6E and 6G circle data points represent WT and square data points represent Prxl-Klfl5 cKO.

[0021] FIG.s 7A-7G. Deletion of Klfl5 in iWAT increases systemic energy expenditure. (FIG. 7A) Rectal core body temperature of male WT and Prxl-Klfl5 cKO mice maintained at 10 °C. One- tailed, t test, n = 3. (FIG. 7B) Quantification of the locomotor activity of mice during acute cold exposure. (FIG. 7C) Real-time monitoring of energy expenditure of singly housed WT and / T AT ' / 5 cKO mice in thermoneutral (30°C) cages and after agonist administration. (FIG. 7D) Quantification of the average change in energy expenditure during the 5h after injection of agonists. Two-way ANOVA, n = 5. (FIG.s 7E, 7F) Energy expenditure versus body weight in mice before (FIG. 7E) and after (FIG. 7F) agonist injection. ANCOVA, n = 5. (FIG. 7G) Quantification of the locomotor activity of mice in thermoneutral cages after agonist injection (time window: 30-64 in (FIG. 7C)). *p < 0.05. ***p < 0.001. For FIG.s 7A, 7B, 7G, left bar represents WT and right bar represents Prxl-Klfl5 cKO.

[0022] FIG.s 8A-8L. KLF15 regulates Adrbl expression. (FIG. 8A) Position weight matrix of canonical KLF15 DNA binding motif. (FIG. 8B) RT-qPCR quantifying the expression levels of Adrbl from Ad-GFP and Ad-KLF15 infected adipocytes. Student’s t test, n = 4. (FIG. 8C) DNA sequence of the wild-type (SEQ ID NO:26) and mutated (SEQ ID NO:27) KLF15 DNA bindingmotif within the Adrbl luciferase reporter constructs. Nucleotides mutated using site-directed mutagenesis are underlined. (FIG. 8D) Quantification of luciferase assays performed on adipocytes transfected with the Adrbl -\\!" or Adrbl -Wu\. promoter-driven luciferase reporter construct normalized using dual -luciferase with Renilla from the pRL-TK co-transfected plasmid. Student’s t test, n = 4. (FIG. 8E) RT-qPCR quantifying expression levels in Ad-shRNA and Lenti-shRNA transduced human adipocytes. Student’s t tests followed by Holm-Sidak correction, n= 3-5. (FIG. 8F) Immunoblots detecting pHSL protein from Ad-shRNA transduced human adipocytes. (FIG. 8G) Quantification of relative protein level of pHSL in human-derived adipocytes. One-way ANOVA, n= 4-6. (FIG. 8H) Quantification of glycerol released into the media from human adipocytes. Student’s t test, n = 6. (FIG. 81) Relative mitochondrial (hMito) DNA content in transduced human adipocytes by RT-qPCR. Student’s t test, n = 3-4. (FIG. 8 J) Time course monitoring OCRs of human-derived adipocytes after exposure to Dobutamine. Two-way ANOVA, n = 4. (FIG. 8K) Quantification of the increased OCR after dobutamine (IM) stimulation. Student’s t test, n = 4. (FIG. 8L) H3K4mel and H3K27ac ChlP-seq peaks at the Adrbl loci in different adipocyte contexts. *p < 0.05, **p < 0.01, ***p < 0.001. For FIG.s 8E and 8G-8K, white circle data points represent Ad-shCtrl, gray square data points represent Ad-shKLF15, white triangle data points represent Ad- shCtrl+shADRB 1 and gray triangle data points represent Ad-shKLF15+shADRBl.DETAILED DESCRIPTION

[0023] While various embodiments and aspects of the present invention are shown and described herein, it will be obvious to those skilled in the art that such embodiments and aspects are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.

[0024] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, without limitation, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0025] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0026] As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to + / - 10% of the specified value. In embodiments, about includes the specified value.

[0027] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. See, e.g., Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of this invention. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.

[0028] "Nucleic acid" refers to nucleotides (e.g., deoxyribonucleotides or ribonucleotides) and polymers thereof in either single-, double- or multiple-stranded form, or complements thereof; or nucleosides (e.g., deoxyribonucleosides or ribonucleosides). In embodiments, “nucleic acid” does not include nucleosides. The terms “polynucleotide,” “oligonucleotide,” “oligo” or the like refer, in the usual and customary sense, to a linear sequence of nucleotides. The term “nucleoside” refers, in the usual and customary sense, to a glycosylamine including a nucleobase and a five-carbon sugar (ribose or deoxyribose). Non limiting examples, of nucleosides include, cytidine, uridine, adenosine, guanosine, thymidine and inosine. The term “nucleotide” refers, in the usual and customary sense, to a single unit of a polynucleotide, i.e., a monomer. Nucleotides can be ribonucleotides, deoxyribonucleotides, or modified versions thereof. Examples of polynucleotides contemplated herein include single and double stranded DNA, single and double stranded RNA, and hybrid molecules having mixtures of single and double stranded DNA and RNA. Examples of nucleic acid, e.g. polynucleotides contemplated herein include any types of RNA, e.g. mRNA, siRNA, miRNA,and guide RNA and any types of DNA, genomic DNA, plasmid DNA, and mini circle DNA, and any fragments thereof. The term “duplex” in the context of polynucleotides refers, in the usual and customary sense, to double strandedness. Nucleic acids can be linear or branched. For example, nucleic acids can be a linear chain of nucleotides or the nucleic acids can be branched, e.g., such that the nucleic acids comprise one or more arms or branches of nucleotides. Optionally, the branched nucleic acids are repetitively branched to form higher ordered structures such as dendrimers and the like.

[0029] As may be used herein, the terms “nucleic acid,” “nucleic acid molecule,” “nucleic acid oligomer,” “oligonucleotide,” “nucleic acid sequence,” “nucleic acid fragment” and “polynucleotide” are used interchangeably and are intended to include, but are not limited to, a polymeric form of nucleotides covalently linked together that may have various lengths, either deoxyribonucleotides or ribonucleotides, or analogs, derivatives or modifications thereof. Different polynucleotides may have different three-dimensional structures, and may perform various functions, known or unknown. Non-limiting examples of polynucleotides include a gene, a gene fragment, an exon, an intron, intergenic DNA (including, without limitation, heterochromatic DNA), messenger RNA (mRNA), transfer RNA, ribosomal RNA, a ribozyme, cDNA, a recombinant polynucleotide, a branched polynucleotide, a plasmid, a vector, isolated DNA of a sequence, isolated RNA of a sequence, a nucleic acid probe, and a primer. For example, the nucleic acid provided herein may be part of a vector. In embodiments, the nucleic acid provided herein may be part of a bacterial vector or a viral vector (e.g. lentiviral vector, adenovirus vector) which may be transduced into a cell. Polynucleotides useful in the methods of the disclosure may comprise natural nucleic acid sequences and variants thereof, artificial nucleic acid sequences, or a combination of such sequences.

[0030] The terms also encompass nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphodiester derivatives including, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate (also known as phosphothioate having double bonded sulfur replacing oxygen in the phosphate), phosphorodi thioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite linkages (see Eckstein, OLIGONUCLEOTIDES AND ANALOGUES: A PRACTICAL APPROACH, Oxford University Press) as well as modifications to the nucleotide bases such as in 5-methyl cytidine or pseudouridine.; and peptide nucleic acid backbones and linkages. Other analog nucleic acids include those with positive backbones; non-ionic backbones, modified sugars, and non-ribose backbones (e.g. phosphorodiamidate morpholino oligos or locked nucleic acids (LNA) as known in the art), including those described in U.S. Patent Nos. 5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CARBOHYDRATE MODIFICATIONS IN ANTISENSE RESEARCH, Sanghui & Cook, eds. Nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made. In embodiments, the internucleotide linkages in DNA are phosphodiester, phosphodiester derivatives, or a combination of both.

[0031] Nucleic acids, including e.g., nucleic acids with a phosphothioate backbone, can include one or more reactive moieties. As used herein, the term reactive moiety includes any group capable of reacting with another molecule, e.g., a nucleic acid or polypeptide through covalent, non-covalent or other interactions. By way of example, the nucleic acid can include an amino acid reactive moiety that reacts with an amio acid on a protein or polypeptide through a covalent, non-covalent or other interaction.

[0032] Nucleic acids can include nonspecific sequences. As used herein, the term "nonspecific sequence" refers to a nucleic acid sequence that contains a series of residues that are not designed to be complementary to or are only partially complementary to any other nucleic acid sequence. By way of example, a nonspecific nucleic acid sequence is a sequence of nucleic acid residues that does not function as an inhibitory nucleic acid when contacted with a cell or organism.

[0033] A polynucleotide is typically composed of a specific sequence of four nucleotide bases: adenine (A); cytosine (C); guanine (G); and thymine (T) (uracil (U) for thymine (T) when thepolynucleotide is RNA). Thus, the term “polynucleotide sequence” is the alphabetical representation of a polynucleotide molecule; alternatively, the term may be applied to the polynucleotide molecule itself. This alphabetical representation can be input into databases in a computer having a central processing unit and used for bioinformatics applications such as functional genomics and homology searching. Polynucleotides may optionally include one or more non-standard nucleotide(s), nucleotide analog(s) and / or modified nucleotides.

[0034] An "antisense nucleic acid" as referred to herein is a nucleic acid (e.g., DNA or RNA molecule) that is complementary to at least a portion of a specific target nucleic acid and is capable of reducing transcription of the target nucleic acid (e.g. mRNA from DNA), reducing the translation of the target nucleic acid (e.g. mRNA), altering transcript splicing (e.g. pre-mRNA), or interfering with the endogenous activity of the target nucleic acid. See, e.g., Weintraub, Scientific American, 262:40 (1990). In embodiments, an antisense nucleic acid hybridizes to DNA. In embodiments, an antisense nucleic acid hybridizes to a target DNA, thereby reducing transcription of the target DNA. In embodiments, an antisense nucleic acid hybridizes to a target RNA (e.g. mRNA) forming a double-stranded RNA molecule. In embodiments, the antisense nucleic acid hybridizes to a target RNA (e.g. mRNA), thereby reducing translation of the target RNA. In embodiments, the antisense nucleic acid hybridizes to a target RNA (e.g. pre-mRNA), thereby reducing transcript splicing of the target RNA. In embodiments, an antisense nucleic acid hybridizes to a corresponding RNA, and the double-stranded molecule may be degraded via the RNAi pathway. In embodiments, an antisense nucleic acid interferes with the endogenous behavior of a DNA or RNA and inhibits its function relative to the absence of the antisense nucleic acid. The use of antisense methods for inhibiting transcription or translation of genes is well known in the art (Marcus-Sakura, Anal. Biochem., 172:289, (1988)).

[0035] Typically, synthetic antisense nucleic acids are generally between 6 and 90 bases in length. In embodiments, a synthetic antisense nucleic acid is between 8 and 70 bases in length. As described above, antisense nucleic acids are capable of hybridizing to (e.g. selectively hybridizing to) a target nucleic acid. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in vitro. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in a cell. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid in an organism. In aspects, the antisense nucleic acid hybridizes to the target nucleic acid under physiological conditions. Antisense nucleicacids may comprise naturally occurring nucleotides or modified nucleotides such as, e.g., phosphorothioate, methylphosphonate, and anomeric sugar-phosphate, backbone-modified nucleotides. Methods for making antisense nucleic acids are described in more detail in US Patent No.s 12,152,244, 12,234,447, 6,346,614, and 6,395,474, which are incorporated herein by reference in their entirety and for all purposes.

[0036] Antisense nucleic acids may be single or double stranded nucleic acids. Non-limiting examples of antisense nucleic acids include small interfering RNAs (siRNAs), short hairpin RNAs (shRNA), antisense oligonucleotides (ASO), micro RNAs (miRNA), saRNAs (small activating RNAs) and small nucleolar RNAs (snoRNA).

[0037] “Antisense oligonucleotide” and “ASO” as provided herein refer to a synthetic singlestranded DNA or RNA molecule that hybridizes to a target RNA (e.g. mRNA, pre-mRNA) to inhibit or decrease translation to a protein, or to alter transcript splicing. In embodiments, the ASO is DNA. In embodiments, the ASO is RNA. Typically, an ASO includes modified nucleotides, that may contribute to enhancing distribution, increasing cell penetration, increasing stability, and / or reducing degradation of the ASO. An ASO may include phosphorodiamidate morpholino oligos, locked nucleic acids (LNA), peptide nucleic acid backbones and linkages, or a combination thereof. Typically, an ASO is between 8 and 50 nucleotides in length. In embodiments, an ASO is between 10 and 30 nucleotides in length. In embodiments, an ASO hybridizes to a target RNA, and the target RNA is degraded by cleavage by RNase H. In embodiments, an ASO decreases or inhibits translation of an mRNA into a protein by blocking ribosome binding to the mRNA.

[0038] “siRNA” and “small interfering RNA” as provided herein refers to a double-stranded RNA formed from 2 RNA molecules, or a single-stranded ribonucleic acid (RNA) that has the ability to reduce or inhibit expression of a gene or the activity of a target nucleic acid (e.g., mRNA, pre- mRNA). Where the siRNA is a double-stranded RNA, the complementary portions of the ribonucleic acid that hybridize to form the double stranded RNA molecule typically have substantial or complete identity. In embodiments, the siRNA is a double-stranded RNA. In embodiments, the double-stranded siRNA is generated by processing a long dsRNA or a short hairpin RNA (e.g. small hairpin RNA, shRNA) by a Dicer enzyme. In embodiments, siRNA refers to a single-stranded RNA. In embodiments, the single-stranded siRNA is generated by unwinding a double-strandedsiRNA by the RISC complex (e.g. RNA-induced silencing complex), thereby generating a singlestranded siRNA capable of hybridizing to a target RNA. In embodiments, the single-stranded siRNA capable of hybridizing to a target RNA is referred to as the “guide strand”. In embodiments, the nontargeting strand of a double-stranded siRNA is referred to as the “passenger strand”. In embodiments, the passenger strand is degraded by RISC. In embodiments, the siRNA inhibits gene expression by triggering RNA interference (RNAi), wherein the target nucleic acid is degratded.

[0039] As described above, an siRNA includes a targeting nucleic acid sequence that has substantial or complete identity to a target RNA and forms a double stranded RNA with the target RNA. In aspects, the siRNA inhibits gene expression by interacting with a complementary cellular RNA thereby interfering with the endogenous behavior of the complementary cellular RNA. In embodiments, the siRNAs provided herein regulate expression of a target gene or activity of a target nucleic acid by hybridizing to the mRNA of the gene or by hybridizing to the promoter of the target nucleic or the target nucleic acid itself. Where the siRNA hybridizes to a promoter of a gene thereby modulating the expression of said gene, the siRNA may be referred to as "antigen RNA" or "agRNA.” In aspects, the nucleic acid sequences provided herein are siRNA. Typically, the siRNA is about 6-50 nucleotides in length (e.g., each complementary sequence of a double stranded siRNA is 6-50 nucleotides in length, and the double stranded siRNA is about 6-50 base pairs in length). In other embodiments, the length is 20-30 base nucleotides, preferably about 20-25 or about 24-29 nucleotides in length, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides in length.

[0048] The terms “short hairpin RNA” or “shRNA” refer to an anti-sense ribonucleic acid sequence as defined above, which is capable of binding (hybridizing) and inhibiting activity of a target RNA (e.g., mRNA, pre-mRNA), to which it is partially or entirely complementary. An shRNA is a single-stranded RNA sequence that is capable of folding into a double-stranded RNA structure, also referred to an RNA hairpin or RNA stem-loop structure. In embodiments, the RNA stem loop structure of an shRNA includes a stem typically 10-30 base pairs in length and a loop typically 1 to 10 nt in length. In embodiments, in a cell, the shRNA is cleaved by Dicer enzyme to generate a double-stranded siRNA.

[0040] “Dicer-substrate small interfering RNA” or “dsiRNA” are siRNA that are generated through Dicer cleavage activity. In embodiments, Dicer cleaves long double-stranded RNA(dsRNA) into siRNA about 20 to 30 nucleotides in length, In embodiments, the dsiRNA are capable of triggering RNA interference.

[0041] “Dicer-dependent short hairpin RNA” or “dicer-dependent shRNA” refers to an shRNA that is processed by the Dicer enzyme into an siRNA of limited length (e.g. about 20 to 30 nucleotides in length, or about 20 to 30 base pairs in length). In embodiments, the processed RNA is an effector of RNA interference.

[0042] “Hybridize” and “hybridization” refer to the pairing of complementary (including partially complementary) nucleic acid strands. Hybridization and the strength of hybridization (e.g., the strength of the association between nucleic acid strands) is impacted by factors known in the art including the degree of complementarity between the nucleic acid, stringency of the conditions involved affected by such conditions as the concentration of salts, the melting temperature (Tm) of the formed hybrid, the presence of other components, the molarity of the hybridizing strands and the G:C content of the nucleic acid strands. When one nucleic acid is said to “hybridize” to another nucleic acid, it means that there is some complementarity between the two nucleic acids or that the two nucleic acids form a hybrid under high or low stringency conditions.

[0043] The term “complement,” as used herein, refers to a nucleotide (e.g., RNA or DNA) or a sequence of nucleotides capable of base pairing with a complementary nucleotide or sequence of nucleotides. As described herein and commonly known in the art the complementary (matching) nucleotide of adenosine is thymidine and the complementary (matching) nucleotide of guanosine is cytosine. Thus, a complement may include a sequence of nucleotides that base pair with corresponding complementary nucleotides of a second nucleic acid sequence. The nucleotides of a complement may partially or completely match the nucleotides of the second nucleic acid sequence. Where the nucleotides of the complement completely match each nucleotide of the second nucleic acid sequence, the complement forms base pairs with each nucleotide of the second nucleic acid sequence. Where the nucleotides of the complement partially match the nucleotides of the second nucleic acid sequence only some of the nucleotides of the complement form base pairs with nucleotides of the second nucleic acid sequence. Examples of complementary sequences include coding and a non-coding sequences, wherein the non-coding sequence contains complementary nucleotides to the coding sequence and thus forms the complement of the codingsequence. A further example of complementary sequences are sense and antisense sequences, wherein the sense sequence contains complementary nucleotides to the antisense sequence and thus forms the complement of the antisense sequence.

[0044] As described herein the complementarity of sequences may be partial, in which only some of the nucleic acids match according to base pairing, or complete, where all the nucleic acids match according to base pairing. Thus, two sequences that are complementary to each other, may have a specified percentage of nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region).

[0045] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and O- phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. The terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.

[0046] Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.

[0047] The terms "polypeptide," "peptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may In embodiments be conjugated to amoiety that does not consist of amino acids. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0048] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0049] The terms "numbered with reference to" or "corresponding to," when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. An amino acid residue in a protein "corresponds" to a given residue when it occupies the same essential structural position within the protein as the given residue. One skilled in the art will immediately recognize the identity and location of residues corresponding to a specific position in a protein in other proteins with different numbering systems. For example, by performing a simple sequence alignment with a protein the identity and location of residues corresponding to specific positions of the protein are identified in other protein sequences aligning to the protein. For example, a selected residue in a selected protein corresponds to glutamic acid at position 138 when the selected residue occupies the same essential spatial or other structural relationship as a glutamic acid at position 138. In some embodiments, where a selected protein is aligned for maximum homology with a protein, the position in the aligned selected protein aligning with glutamic acid 138 is the to correspond to glutamic acid 138. Instead of a primary sequencealignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the glutamic acid at position 138, and the overall structures compared. In this case, an amino acid that occupies the same essential position as glutamic acid 138 in the structural model is the to correspond to the glutamic acid 138 residue.

[0050] "Conservatively modified variants" applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, "conservatively modified variants" refers to those nucleic acids that encode identical or essentially identical amino acid sequences. Because of the degeneracy of the genetic code, a number of nucleic acid sequences will encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are "silent variations," which are one species of conservatively modified variations.Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid which encodes a polypeptide is implicit in each described sequence.

[0051] As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the disclosure.

[0052] The following eight groups each contain amino acids that are conservative substitutions for one another:1) Alanine (A), Glycine (G);2) Aspartic acid (D), Glutamic acid (E);3) Asparagine (N), Glutamine (Q);4) Arginine (R), Lysine (K);5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V);6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W);7) Serine (S), Threonine (T); and8) Cysteine (C), Methionine (M)(see, e.g., Creighton, Proteins (1984)).

[0053] The terms "identical" or percent "identity," in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., about 60% identity, preferably 65%, 70%, 75%, 75%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or higher identity over a specified region, when compared and aligned for maximum correspondence over a comparison window or designated region) as measured using a BLAST or BLAST 2.0 sequence comparison algorithms with default parameters described below, or by manual alignment and visual inspection (see, e.g., NCBI web site http: / / www.ncbi.nlm.nih.gov / BLAST / or the like). Such sequences are then said to be "substantially identical." This definition also refers to, or may be applied to, the compliment of a test sequence. The definition also includes sequences that have deletions and / or additions, as well as those that have substitutions. The preferred algorithms can account for gaps and the like. Preferably, identity exists over a region that is at least about 25 amino acids or nucleotides in length, or more preferably over a region that is 50-100 amino acids or nucleotides in length.

[0054] "Percentage of sequence identity" is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide or polypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number ofmatched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity.

[0055] An amino acid or nucleotide base "position" is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence.

[0056] A "comparison window", as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of, e.g., a full length sequence or from 20 to 600, about 50 to about 200, or about 100 to about 150 amino acids or nucleotides in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well-known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat’L Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)).

[0057] An example of an algorithm that is suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always > 0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, an expectation (E) or 10, M=5, N=-4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a word length of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) alignments (B) of 50, expectation (E) of 10, M=5, N=-4, and a comparison of both strands.

[0058] The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to thereference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001.

[0059] For specific proteins described herein, the named protein includes any of the protein’s naturally occurring forms, variants or homologs that maintain activity of the protein (e.g., within at least 50%, 75%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein). In some embodiments, variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form. In other embodiments, the protein is the protein as identified by its NCBI sequence reference. In other embodiments, the protein is the protein as identified by its NCBI sequence reference, homolog or functional fragment thereof.

[0060] The term “KLF15 protein” or “KLF15” as used herein includes any of the recombinant or naturally-occurring forms of Krtippel-like factor 15 (KLF15), also referred to as Kidney-enriched krueppel-like factor, or variants or homologs thereof that maintain KLF15 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to KLF15). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring KLF15 protein. In embodiments, the KLF15 protein is substantially identical to the protein identified by the UniProt reference number Q9UIH9 or a variant or homolog having substantial identity thereto. In embodiments, the KLF15 is a mammalian KLF15. In embodiments, the KLF15 is a human KLF15, a mouse KLF15, a rat KLF15, a rabbit KLF15, or a dog KLF15. In embodiments, the KLF15 is a primate KLF15. In embodiments, the KLF15 is a human KLF15. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NON, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the KLF15 is substantially identical to the protein encoded by the nucleic acid sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NON, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NON. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NO:2. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NON. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NON. In embodiments, the KLF15 is encoded by thesequence of SEQ ID NO:5. In embodiments, the KLF15 is encoded by the sequence of SEQ ID NO:6.

[0061] The term “ADRB1 protein” or “ADRB1” as used herein includes any of the recombinant or naturally-occurring forms of beta-1 adrenergic receptor (ADRB1), also referred to as Beta-1 adrenoreceptor, Beta-1 adrenoceptor, or variants or homologs thereof that maintain ADRB1 activity (e.g. within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to ADRB1). In some aspects, the variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g. a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring ADRB1 protein. In embodiments, the ADRB1 protein is substantially identical to the protein identified by the UniProt reference number P08588 or a variant or homolog having substantial identity thereto. In embodiments, the ADRB1 is a mammalian ADRB1. In embodiments, the ADRB1 is a human ADRB1, a mouse ADRB1, a rat ADRB1, a rabbit ADRB1, or a dog ADRB1. In embodiments, the ADRB1 is a primate ADRB I In embodiments, the ADRB1 is a human ADRB1.

[0062] The term "gene" means the segment of DNA involved in producing a protein; it includes regions preceding and following the coding region (leader and trailer) as well as intervening sequences (introns) between individual coding segments (exons). The leader, the trailer as well as the introns include regulatory elements that are necessary during the transcription and the translation of a gene. Further, a "protein gene product" is a protein expressed from a particular gene.

[0063] 1 'he term "‘target gene” refers to any nucleic acid sequence which contains an identified genes or a target region within a gene, including intergenic regions, non-coding regions, untranscribed regions, introns, exons, and transgenes. The target gene (or a target site within the gene) can be a gene derived from a cell, an endogenous gene, a transgene, or exogenous genes such as genes of a pathogen, for example a virus, which is present in the cell after infection thereof. The cell containing the target gene can be derived from or contained in any organism.

[0064] The terms "plasmid", "vector" or "expression vector" refer to a nucleic acid molecule that encodes for genes and / or regulatory elements necessary for the expression of genes. Expression of a gene from a plasmid can occur in cis or in trans. If a gene is expressed in cis, the gene and theregulatory elements are encoded by the same plasmid. Expression in trans refers to the instance where the gene and the regulatory elements are encoded by separate plasmids.

[0065] The terms "transfection", "transduction", "transfecting" or "transducing" can be used interchangeably and are defined as a process of introducing a nucleic acid molecule or a protein to a cell. Nucleic acids are introduced to a cell using non-viral or viral-based methods. The nucleic acid molecules may be gene sequences encoding complete proteins or functional portions thereof. Non- viral methods of transfection include any appropriate transfection method that does not use viral DNA or viral particles as a delivery system to introduce the nucleic acid molecule into the cell. Exemplary non-viral transfection methods include calcium phosphate transfection, liposomal transfection, nucleofection, sonoporation, transfection through heat shock, magnetifection and electroporation. In some embodiments, the nucleic acid molecules are introduced into a cell using electroporation following standard procedures well known in the art. For viral -based methods of transfection any useful viral vector may be used in the methods described herein. Examples for viral vectors include, but are not limited to retroviral, adenoviral, lentiviral and adeno-associated viral vectors. In some embodiments, the nucleic acid molecules are introduced into a cell using a adenoviral or lentiviral vector following standard procedures well known in the art. The terms "transfection" or "transduction" also refer to introducing proteins into a cell from the external environment. Typically, transduction or transfection of a protein relies on attachment of a peptide or protein capable of crossing the cell membrane to the protein of interest. See, e.g., Ford et al. (2001) Gene Therapy 8: 1-4 and Prochiantz (2007) Nat. Methods 4: 119-20.

[0066] As used herein, the term “construct” is intended to mean any recombinant nucleic acid molecule. In embodiments, a construct includes an expression cassette, plasmid, cosmid, virus, autonomously replicating polynucleotide molecule, phage, or linear or circular, single-stranded or double-stranded, DNA or RNA polynucleotide molecule. In embodiments, a nucleic acid encoding the anti-KLF15 antisense nucleic acid provided herein including embodiments thereof is delivered into a cell as part of an expression construct, and the anti-KLF15 antisense nucleic acid is expressed in the cell. In embodiments, the nucleic acid encoding ADRB1 is delivered into a cell as part of an expression vector and the ADRB1 protein is expressed in the cell. A construct may be derived from any source, capable of genomic integration or autonomous replication, including a nucleic acidmolecule where one or more nucleic acid sequences has been linked in a functionally operative manner, e.g., operably linked.

[0067] “Contacting” is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g. chemical compounds including biomolecules or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents that can be produced in the reaction mixture.

[0068] The term "contacting" may include allowing two species to react, interact, or physically touch, wherein the two species may be, for example, a nucleic acid (e.g. an antisense nucleic acid, a nucleic acid encoding ADRB1, an ADRB1 agonist) as provided herein and a cell. In embodiments contacting includes, for example, allowing a nucleic acid as described herein to interact with a cell. Thus, in embodiments, contacting includes allowing a nucleic acid to interact with a cell, thereby resulting in a transduced or transfected cell. In embodiments contacting includes, for example, allowing a composition (e g. pharmaceutical composition) as described herein to interact with a cell. In embodiments, contacting includes, for example, allowing a composition provided herein to be delivered into the cell. Thus, in embodiments, contacting includes intracellular delivery of a composition acid (e.g. an antisense nucleic acid, a nucleic acid encoding ADRB1, an ADRB1 agonist) provided herein into a cell.

[0069] A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. In embodiments, the cell is a primate cell. In embodiments, the cell is a human cell. In embodiments, the cell is an adipocyte. In embodiments, the cell is a white adipocyte, a brown adipocyte, or a beigeadipocyte. In embodiments, the cell is obtained from a subject, for example, a subject having a metabolic disorder.

[0070] The term "recombinant" when used with reference, e.g., to a cell, nucleic acid, protein, or vector, indicates that the cell, nucleic acid, protein or vector, has been modified by the introduction of a heterologous nucleic acid or protein or the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, recombinant cells express proteins that are not found within the native (non-recombinant) form of the cell.

[0071] The term "isolated", when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.

[0072] The term "heterologous" when used with reference to portions of a nucleic acid indicates that the nucleic acid comprises two or more subsequences that are not found in the same relationship to each other in nature. For instance, the nucleic acid is typically recombinantly produced, having two or more sequences from unrelated genes arranged to make a new functional nucleic acid, e.g., a promoter from one source and a coding region from another source. Similarly, a heterologous protein indicates that the protein comprises two or more subsequences that are not found in the same relationship to each other in nature (e.g., a fusion protein).

[0073] The term "exogenous" refers to a molecule or substance e.g., a compound, nucleic acid or protein) that originates from outside a given cell or organism. For example, an "exogenous antisense nucleic acid" as referred to herein is an antisense nucleic acid that does not originate from the cell or organism it is expressed by. Conversely, the term "endogenous" or "endogenous antisense nucleic acid" refers to an antisense nucleic acid that is native to, or originates within, a given cell or organism.

[0074] The term “inhibition”, “inhibit”, “inhibiting” and the like in reference to a protein-inhibitor interaction means negatively affecting (e.g. decreasing) the activity or function of the protein relative to the activity or function of the protein in the absence of the inhibitor. In aspects inhibitionmeans negatively affecting (e.g. decreasing) the concentration or levels of the protein relative to the concentration or level of the protein in the absence of the inhibitor. In aspects inhibition refers to reduction of a disease or symptoms of disease. In aspects, inhibition refers to a reduction in the activity of a particular protein target. Thus, inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating signal transduction or enzymatic activity or the amount of a protein. In aspects, inhibition refers to a reduction of activity of a target protein resulting from a direct interaction (e.g. an inhibitor binds to the target protein). In aspects, inhibition refers to a reduction of activity of a target protein from an indirect interaction (e.g. an inhibitor binds to a protein that activates the target protein, thereby preventing target protein activation).

[0075] The terms “inhibitor,” “repressor” or “antagonist” or “downregulator” interchangeably refer to a substance capable of detectably decreasing the expression or activity of a given gene or protein. The antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.

[0076] The term "expression" includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post- translational modification, and secretion. In embodiments, protein expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.). In embodiments, a transcript (e.g mRNA) can be detected using conventional techniques for detecting gene expression (e. RT-PCR (Reverse Transcription Polymerase Chain Reaction), Northern blotting, and in situ hybridization).

[0077] “Biological sample” or “sample” refer to materials obtained from or derived from a subject or patient. A biological sample includes sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include bodily fluids such as blood and blood fractions or products (e.g., serum, plasma, platelets, red blood cells, and the like), sputum, tissue, cultured cells (e.g., primary cultures, explants, and transformed cells) stool, urine, synovial fluidjoint tissue, immune cells, hematopoietic cells, fibroblasts, macrophages, Tcells, etc. A biological sample is typically obtained from a eukaryotic organism, such as a mammal such as a primate e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish. In embodiments, the biological sample is derived from a healthy subject. In embodiments, the biological sample is derived from a subject having a metabolic disorder. In embodiments, the biological sample is adipose tissue. In embodiments, the biological sample is white adipose tissue. In embodiments, the biological sample includes an adipocyte (e.g. a white, brown or beige adipocyte).

[0078] “ Control” or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, a control is the measurement of the activity of a protein in the absence of a compound as described herein (including embodiments and examples).

[0079] A “control” or “standard control” refers to a sample, measurement, or value that serves as a reference, usually a known reference, for comparison to a test sample, measurement, or value. For example, a test sample can be taken from a patient suspected of having a given disease (e.g. a metabolic disorder) and compared to a known normal (non-diseased) individual (e.g. a standard control subject). A standard control can also represent an average measurement or value gathered from a population of similar individuals (e.g. standard control subjects) that do not have a given disease (i.e. standard control population), e.g., healthy individuals with a similar medical background, same age, weight, etc. A standard control value can also be obtained from the same individual, e.g. from an earlier-obtained sample from the patient prior to disease onset. For example, a control can be devised to compare therapeutic benefit based on pharmacological data {e.g., half-life) or therapeutic measures {e.g., comparison of side effects). Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant. One of skill will recognize that standard controls can be designed for assessment of any number of parameters (e.g. RNA levels, protein levels, specific cell types, specific bodily fluids, specific tissues, etc). In embodiments, the control is a healthy subject. In embodiments, the control is a subject who does not have a metabolic disorder. In embodiments, the control is a subject who is not administered ancompound (e.g. anti-KLF15 antisense nucleic acid, nucleic acid encoding ADRB1, ADRB1 agonist) or composition (e g. pharmaceutical composition) provided herein including embodiments thereof.

[0080] One of skill in the art will understand which standard controls are most appropriate in a given situation and be able to analyze data based on comparisons to standard control values. Standard controls are also valuable for determining the significance (e.g. statistical significance) of data. For example, if values for a given parameter are widely variant in standard controls, variation in test samples will not be considered as significant.

[0081] “Patient”, “subject” or “subject in need thereof’ refers to a living organism suffering from or prone to a disease or condition (e.g. a metabolic disorder) that can be treated by administration of a compound or composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In embodiments, the subject is a primate. In embodiments, the subject is a human. In embodiments, the subject is a mouse. In embodiments, the subject is a rabbit. In embodiments, the subject is a dog.

[0082] The terms “disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein. The disease may be a metabolic disorder. As used herein, “metabolic disorder” refers to a disease or condition that occurs when a chemical process in the body is dysregulated and disrupts processing, conversion, or storage of a biomolecule (e.g. lipid, protein, carbohydrate). Thus, in embodiments, a metabolic disorder is a disease or condition that negatively affects a metabolic process, including processing of a biomolecule (e.g. protein, lipid and / or carbohydrate), storage of a biomolecule (e.g. protein, lipid and / or carbohydrate), conversion of a biomolecule (e.g. protein, lipid and / or carbohydrate) to another biomolecule (e.g. nucleic acid, protein, carbohydrate, lipid, etc.), elimination of metabolic waste products, or a combination thereof. A metabolic disorder may be characterized by one or more of dysregulated or impaired lipid metabolism, increased blood cholesterol (e.g. LDL) level, increased blood triglyceride level, decreased blood High-density lipoprotein (HDL) level, mitochondrial dysfunction, dysregulated blood glucose level, insulin resistance, insulin deficiency, and high blood pressure. In embodiments, a metabolic disorder causes aberrant or dysregulated processing of proteins, fats, and / or and carbohydrates. In embodiments, a metabolic disorder causesaberrant or dysregulated energy (e.g. triglyceride, glycogen) storage in the body. In embodiments, a metabolic disorder causes obesity and / or an increased risk of cardiovascular disease in a subject. In embodiments, the metabolic disorder is caused by or is a symptom of a primary condition. For example, a metabolic disorder may be caused by or is a symptom of a hormonal disorder (e.g. Cushing’s syndrome). In embodiments, the metabolic disorder is caused by or is a symptom of a genetic disorder (e.g. Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, Inborn Errors of Metabolism, Gaucher disease, Glycogen storage diseases, Mitochondrial disorders). In embodiments, the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, Inborn Errors of Metabolism, Gaucher disease, Glycogen Storage Diseases, Mitochondrial disorders, or a combination thereof.

[0083] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease (e.g. metabolic disorder) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function. As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease.

[0084] The term “aberrant” as used herein refers to different from normal. When used to describe enzymatic activity or protein function, aberrant refers to activity or function that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g. by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.

[0085] The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters;including the results of a physical examination, neuropsychiatric exams, and / or a psychiatric evaluation. The term "treating" and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0086] “Treating” or “treatment” as used herein (and as well -understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject’s condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (z.e., not worsening) the state of disease, prevention of a disease’s transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease’s spread; relieve the disease’s symptoms, fully or partially remove the disease’s underlying cause, shorten a disease’s duration, or do a combination of these things. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, or 100% reduction in the severity of an established disease, condition, or symptom of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms of the disease in a subject as compared to a control. Thus, the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition. Further, as used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90% or greater as compared to a control level and such terms can include but do not necessarily include complete elimination. In embodiments, treatment includes generation of beige adipocyte cells (beiging) from white adipocyte cells in white adipose tissue (e g. WAT depots) or adjacent to white adipose tissue. In embodiments, the white adipose tissue is subcutaneous white adipose tissue. In embodiments, treatment includes inducing expression of one or more brown adipocyte markers (e.g Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, Fabp3) in an adipocyte cell. In embodiments, treatment includes increasing the levelone or more brown adipocyte markers (e.g Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, Fabp ) in an adipocyte cell relative to the level of the one or more brown adipocyte markers in the absence of a compound (e.g. anti-KLF15 antisense nucleic acid, ADRB1 agonist, nucleic acid encoding ADRB1) or composition provided herein including embodiments thereof. In embodiments, treatment includes inducing thermogenesis in an adipocyte cell. In embodiments, treatment includes increasing thermogenesis in an adipocyte cell relative to the level of thermogenesis in the absence of a compound or composition provided herein including embodiments thereof. In embodiments, thermogenesis is measured by oxygen consumption, heat release, imaging (e.g. PET / CT imaging). In embodiments, treatment includes decreasing the level of one or more white adipocyte markers (e.g. Retn, Tle3, Afp423,~) in a white adipocyte cell. In embodiments, treatment includes decreasing the weight of a white adipocyte tissue depot in a subject relative to the weight of the white adipose tissue depot in the subject in the absence of a compound or composition provided herein including embodiments thereof. In embodiments, treatment includes decreasing the body weight of a subject relative to the body weight of the subject in the absence of a compound or composition provided herein including embodiments thereof.

[0087] "Treating" and "treatment" as used herein include prophylactic treatment. Treatment methods include administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof. It will also be appreciated that the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient. In embodiments, the treating or treatment is not prophylactic treatment.

[0088] The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.

[0089] A “effective amount,” as used herein, is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). In these methods, the effective amount of the nucleic acid (antisense nucleic acid (e.g. ASO, shRNA, siRNA), nucleic acid encoding ADRB1) described herein is an amount effective to accomplish the stated purpose of the method. In these methods, the effective amount of the compound (ADRB1 agonist) described herein is an amount effective to accomplish the stated purpose of the method. An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0090] The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control. For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art. As is in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals.

[0091] As used herein, the term "administering" is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent.

[0092] A variety of suitable methods administering a compound (e.g. anti-KLF15 antisense nucleic acid, ADRB1 agonist, nucleic acid encoding ADRB1) of the present disclosure are available. In embodiments, the administering a compound includes delivering the compound into a cell. In embodiments, the compound is in or complexed with a carrier, such as in a liposome, nanoparticle (lipid nanoparticle, polymer nanoparticle), in a virus, or complexed with a transfection reagent (e.g., a cationic polymer). For example, in embodiments, the siRNA or ASO provided herein including embodiments thereof may delivered via a carrier, such as in a liposome or nanoparticle. In embodiments, a compound provided herein is delivered into a cell via electroporation. In embodiments, a compound provided herein is delivered into a cell via a process comprising temporarily deforming a cell as it passes through a small opening to disrupt the cell membrane thereof, and allowing the compound or complex to be inserted into the cell. In embodiments, a compound provided herein is delivered into a cell with a liposome. In embodiments, a compound provided herein is delivered into a cell (e.g., via electroporation, temporary cell deformation) and an anti-sense nucleic acid (e.g. anti-KLF15 antisense nucleic acid) or protein (ADRB1 protein) is expressed in the cell (e.g., from a viral vector or a plasmid).

[0093] In embodiments, administering an anti-KLF15 antisense nucleic acid to the subject includes administering to the subject a nucleic acid encoding the anti-KLF15 antisense nucleic acid. In embodiments, the nucleic acid is part of an expression vector. In embodiments, the expression vector is a viral vector, plasmid DNA, a minicircle vector, or a bacterial vector. For example, inembodiments, administering the shRNA to a subject includes administering a nucleic acid encoding the shRNA to the subject.

[0094] " Co-administer" it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies. In embodiments, two or more of the anti-KLF15 antisense nucleic acid, nucleic acid encoding ADRB1, and ADRB1 agonist provided herein including embodiments thereof are coadministered. The compounds provided herein can be administered alone or can be coadministered to the patient. Coadministration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The compositions of the present disclosure can be delivered transdermally, by a topical route, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0095] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0096] A “therapeutic agent” as used herein refers to an agent (e.g., compound or composition described herein) that when administered to a subject will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, orreducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms or the intended therapeutic effect, e g., treatment or amelioration of an injury, disease, pathology or condition, or their symptoms including any objective or subjective parameter of treatment such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a patient’s physical or mental well-being.

[0097] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.METHODS OF TREATMENT

[0098] Provided herein, inter alia, are methods for treating a metabolic disorder in a subject in need thereof including administering to the subject a composition provided herein including embodiments thereof. The composition provided herein including embodiments thereof is contemplated to be effective for inducing and / or upregulating expression of a brown fat marker gene in a white adipocyte cell. For example, Applicant has discovered that the KLF15 inhibitor provided herein including embodiments thereof is effective for inducing and / or upregulating expression of a brown fat marker gene in a white adipocyte cell. In embodiments, the composition provided herein including embodiments thereof effectively decreases expression of a white adipocyte marker gene and induces and / or upregulates expression of a brown fat marker gene in a white adipocyte cell. The composition provided herein including embodiments thereof is therefore contemplated to be effective for treating a metabolic disorder. Thus, provided herein, inter alia, is a method for treating metabolic disorders including administering to a subject a composition provided herein including embodiments thereof.

[0099] As described throughout the specification, including the examples and figures, in embodiments, the composition provided herein including embodiments thereof induces or upregulates expression of a brown fat marker gene in a white adipocyte cell. In embodiments, thebrown fat marker gene is a gene associated with thermogenesis. In embodiments, the brown fat marker gene encodes a protein associated with activating thermogenesis in a brown adipocyte or a beige adipocyte. In embodiments, the brown fat marker gene is Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, Fabp3 or a combination thereof. In embodiments, the composition provided herein including embodiments thereof downregulates or decreases expression of a white adipocyte marker gene. In embodiments, the white adipocyte marker gene is Retn, Tle3, Afp423, or a combination thereof.

[0100] In an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject an effective amount of a Kriippel-like factor 15 (KLF15) inhibitor. The term “Kriippel-like factor 15 inhibitor” or “KLF15 inhibitor” refers to a compound capable of detectably decreasing the expression of the KLF15 protein or gene. In embodiments, the KLF15 inhibitor decreases production of an mRNA encoding KLF15. In embodiments, the KLF15 inhibitor decreases production of the KLF15 protein. Thus, in embodiments, decreasing KLF15 expression may refer to decreasing production of an mRNA encoding KLF15 or KLF15 protein.

[0101] In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%. 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to KFL15 expression in the absence of the KFL15 inhibitor. Expression may be measured using any method well-known in the biological arts, including but not limited to Western blot, ELISA, qPCR, microarray, RNA-seq (RNA-sequencing), Northern blot, and RT-PCR. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 10% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 15% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 20% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 25% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 30% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 35% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 40% relative to KFL15 expression in the absence of theKFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 45% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 50% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 55% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 60% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 65% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 70% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 75% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 80% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 85% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 90% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 95% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 99% relative to KFL15 expression in the absence of the KFL15 inhibitor.

[0102] In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%. 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 10% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 15% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 20% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 25% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 30% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments,the KFL15 inhibitor decreases KLF15 expression by about 35% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 40% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 45% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 50% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 55% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 60% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 65% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 70% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 75% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 80% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 85% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 90% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 95% relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 99% relative to KFL15 expression in the absence of the KFL15 inhibitor.

[0103] In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 1-fold, 1.5- fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold- 8-fold, 9-fold- 10-fold, 20-fold, 30-fold, 40-fold, or 50-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 1- fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 1.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 2-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 2.5-fold relative toKFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 3-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 3.5- fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 4-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 4.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 5.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 6-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 7-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 8-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 9-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 10-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 20-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 30-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 40- fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by at least 50-fold relative to KFL15 expression in the absence of the KFL15 inhibitor.

[0104] In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 1-fold, 1.5- fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 4.5-fold, 5-fold, 5.5-fold, 6-fold, 7-fold- 8-fold, 9-fold- 10-fold, 20-fold, 30-fold, 40-fold, or 50-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 1-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15inhibitor decreases KLF15 expression by about 1.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 2 -fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 2.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 3-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 3.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 4-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 4.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 5.5-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 6-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 7-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 8-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 9-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 10-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 20-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 30-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 40-fold relative to KFL15 expression in the absence of the KFL15 inhibitor. In embodiments, the KFL15 inhibitor decreases KLF15 expression by about 50-fold relative to KFL15 expression in the absence of the KFL15 inhibitor.

[0105] In embodiments, the KLF15 inhibitor is an exogenous KLF15 inhibitor. In embodiments, the KLF15 inhibitor does not occur naturally in a cell. In embodiments, the KLF15 inhibitor is notan endogenous KLF15 inhibitor. For example, in embodiments, the KLF15 inhibitor is not an endogenous miRNA targeting a KLF15 transcript. In embodiments, the KLF15 inhibitor does not include miR-223, miR-376b, miR-181a-5p, miR-133, miR-182-5p, or miR-125a-3p. In embodiments, the KLF15 inhibitor does not include miR-223. In embodiments, the KLF15 inhibitor does not include miR-376b. In embodiments, the KLF15 inhibitor does not include miR-181a-5p. In embodiments, the KLF15 inhibitor does not include miR-133. In embodiments, the KLF15 inhibitor does not include miR-182-5p. In embodiments, the KLF15 inhibitor does not include miR-125a-3p. In embodiments, the KLF15 inhibitor is not an endogenous protein. For example, in embodiments, the KLF15 inhibitor is not an endogenous MEF2A protein, LXR / RXR protein, P300 protein, or PPAR5 protein. In embodiments, the KLF15 inhibitor is not an endogenous MEF2A protein. In embodiments, the KLF15 inhibitor is not an endogenous LXR / RXR protein. In embodiments, the KLF15 inhibitor is not an endogenous P300 protein. In embodiments, the KLF15 inhibitor is not an endogenous PPAR5 protein. In embodiments, the KLF15 inhibitor does not include an endogenous GR antagonist.

[0106] In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. As used herein, “target sequence” and “target nucleic acid” refer to a nucleic acid that a compound (e.g., anti-KLF15 antisense nucleic acid) is designed to affect. Similarly, a “targeting nucleic acid sequence” or “targeting sequence” refers to a region in an antisense nucleic acid capable of hybridizing to a target nucleic acid. In embodiments, hybridization of the targeting nucleic acid sequence to the target sequence results in a detectable and / or measurable change in the amount or expression of the target nucleic acid or protein encoded by the target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the targeting nucleic acid sequence.

[0107] In embodiments, the targeting nucleic acid sequence is at least 80% complementary to the target sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 85% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 90% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 91% complementary to the target nucleic acid sequence within the KLF15transcript. In embodiments, the targeting nucleic acid sequence is at least 92% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 93% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 94% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 95% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 96% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 97% complementary to the target nucleic acid sequence within the KLF15 transcript. . In embodiments, the targeting nucleic acid sequence is at least 98% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 99% complementary to the target nucleic acid sequence within the KLF15 transcript. In embodiments, the targeting nucleic acid sequence is fully complementary to the target sequence within the KLF15 transcript over the entire length of the targeting nucleic acid sequence.

[0108] In embodiments, the anti-KLF15 antisense nucleic acid is at least 50% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 60% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 70% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti- KLF15 antisense nucleic acid is at least 80% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 85% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 90% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 91% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 92% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 93% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 94% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 95% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 96% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 97% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 98% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid is at least 99% complementary to the target nucleic acid over the entire length of the anti-KLF15 antisense nucleic acid and includes a targeting nucleic acid sequence that is 100% or fully complementary to a target nucleic acid.

[0109] In embodiments, the targeting nucleic acid sequence is from 6 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 8 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 10 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 12 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 14 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 16 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 18 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 20 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 22 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 24 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 26 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 28 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 30 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 32 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 34 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 36 to 40 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 38 to 40 nucleotides in length.

[0110] In embodiments, the targeting nucleic acid sequence is from 6 to 38 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 36 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 34 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 32 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 30 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 28 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 26 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 24 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 22 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 18 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 16 nucleotides in length. Inembodiments, the targeting nucleic acid sequence is from 6 to 14 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 12 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 10 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 8 nucleotides in length. In embodiments, the targeting nucleic acid sequence is about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length.[oni] In embodiments, the targeting nucleic acid sequence is from 6 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 8 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 10 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 12 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 14 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 16 to 20 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 18 to 20 nucleotides in length.

[0112] In embodiments, the targeting nucleic acid sequence is from 6 to 18 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 16 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 14 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 12 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 10 nucleotides in length. In embodiments, the targeting nucleic acid sequence is from 6 to 8 nucleotides in length. In embodiments, the targeting nucleic acid sequence is about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nucleotides in length.

[0113] In embodiments, the targeting nucleic acid sequence includes one or more mismatched nucleobases relative to the target nucleic acid. In embodiments, presence of one or more mismatched nucleobases reduces nonspecific antisense activity against a non-target nucleic acid. Thus, in embodiments, specificity of the anti-KLF15 antisense nucleic acid is improved. In embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5 '-end of the targeting nucleic acid. In embodiments, the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3 '-end of the targeting nucleic acid. In certain such embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5'-end ofthe targeting nucleic acid. In certain such embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3 '-end of the targeting nucleic acid.

[0114] In embodiments, the targeting nucleic acid sequence includes 1-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 2-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 3-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 4-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 5-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 6-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 7-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 8-10 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 9-10 mismatched nucleobases relative to the target nucleic acid.

[0115] In embodiments, the targeting nucleic acid sequence includes 1-9 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-8 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-7 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-6 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-5 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-4 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-3 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1-2 mismatched nucleobases relative to the target nucleic acid. In embodiments, the targeting nucleic acid sequence includes 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mismatched nucleobases relative to the target nucleic acid.

[0116] In embodiments, the anti-KLF15 antisense nucleic acid is at least 8 nucleotides in length.In embodiments, the anti-KLF15 antisense nucleic acid is at least 10 nucleotides in length. Inembodiments, the anti-KLF15 antisense nucleic acid is at least 15 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is at least 20 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 80 nucleotides in length. Where the antisense nucleic acid is a double-stranded nucleic acid, in embodiments, each complementary sequence of the double stranded antisense nucleic acid is about is 8 to about 80 nucleotides in length, and the double stranded siRNA is about 8-80 base pairs in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 12 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 16 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 20 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 24 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 28 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 32 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 36 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 40 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 44 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 48 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 52 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 56 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 60 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 64 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 68 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 72 to about 80 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 76 to about 80 nucleotides in length.

[0117] In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 76 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 72 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 68 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 64 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 60 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 56 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 52 nucleotidesin length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 48 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 44 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 40 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 36 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 32 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 28 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 24 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 20 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 16 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 12 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 nucleotides in length.

[0118] For the method provided herein, in embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 8 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 10 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 12 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 14 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 16 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 18 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 20 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 22 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 24 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 26 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 28 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 30 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 32 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 34 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 36 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 38 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid isabout 40 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 42 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 44 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 46 to about 50 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 48 to about 50 nucleotides in length.

[0119] In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 8 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 10 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 12 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 14 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 16 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 18 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 20 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 22 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 24 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 26 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 28 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 30 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 32 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 34 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 36 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 38 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 40 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 42 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 44 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 46 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6 to about 48 nucleotides in length. In embodiments, the anti-KLF15 antisense nucleic acid is about 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 nucleotides in length.

[0120] In embodiments, one or more nucleotides in the anti-KLF15 antisense nucleic acid includes a modified base, a modified sugar, a modified phosphate, or a combination of two or more thereof.In embodiments, the modified base is a 2’0-Methyl modified base, a 2’0-methoxyethoxy modified base, a 2’fluoro modified base, a 5-methyl-cytidine, or pseudouridine. In embodiments, the modified phosphate is phosphoramidate, phosphorodi ami date, phosphorothioate, phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boron phosphonate, or O-methylphosphoroamidite. In embodiments, the modified base is a 2’0-Methyl modified base. In embodiments, the modified phosphate is phosphorothioate. In embodiments, the modified sugar is deoxyribose.

[0121] In embodiments, the anti-KLF15 antisense nucleic acid includes an unmodified sugar, a modified sugar or a combination thereof. In embodiments, the unmodified sugar moiety is a 2'- 0H(H) furanosyl moiety, as found in RNA (e.g. “unmodified RNA sugar moiety”), or a 2'-H(H) moiety, as found in DNA (an “unmodified DNA sugar moiety”). In embodiments an unmodified sugar has one hydrogen at each of the 1', 3', and 4' positions, an oxygen at the 3' position, and two hydrogens at the 5' position. In embodiments, a modified sugar is a modified furanosyl sugar moiety or a sugar surrogate. In embodiments, a modified furanosyl sugar means a furanosyl sugar comprising a non-hydrogen substituent in place of at least one hydrogen of an unmodified sugar moiety. In embodiments, a modified furanosyl sugar is a 2 '-substituted sugar. In embodiments, such modified furanosyl sugar moieties include bicyclic sugars and non-bicyclic sugars. As used herein, “sugar surrogate” means a modified sugar having other than a furanosyl moiety that can link a nucleobase to another group, such as an intemucleoside linkage, conjugate group, or terminal group in an oligonucleotide. In embodiments, a modified nucleosides includes sugar surrogates can be incorporated into one or more positions within an anti-KLF15 antisense nucleic acid.

[0122] In embodiments, the anti-KLF15 antisense nucleic acid includes one or more unmodified nucleotides. In embodiments, the anti-KLF15 antisense nucleic acid includes one or more modified nucleotides. In embodiments, the modified nucleotides include 5-substituted pyrimidines, 6- azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In embodiments, modified nucleotides include 2-aminopropyladenine, 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N- methyladenine, 2-propyl adenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl ( — C=C — CH3) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5- halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7- deazaadenine, 3 -deazaguanine, 3 -deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N- benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleotides include tricyclic pyrimidines, such as l,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-l,3-diazaphenoxazine-2-one (G-clamp). Modified nucleotides may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2- pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

[0123] In embodiments, nucleotides of the anti-KLF15 antisense nucleic acid may be linked together using any intemucleotide linkage. In embodiments, the anti-KLF15 antisense nucleic acids includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) modified intemucleotide linkages. For example, in embodiments, 50% or more of the intemucleotide linkages of an antisense nucleic acid provided herein can be modified intemucleotide linkages. Optionally, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the intemucleotide linkages of an antisense nucleic acid provided herein are modified intemucleotide linkages. Optionally, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% of the intemucleotide linkages of a antisense nucleic acid provided herein are be modified intemucleotide linkages. In embodiments, the intemucleotide linkages include phosphodiester bonds (“P=O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P=S”), and phosphorodi thioates (“HS — P=S”). Representative non-phosphorus containing intemucleotide linking groups include but are not limited to methylenemethylimino ( — CH2 — N(CH3) — O — CH2 — ), thiodiester, thionocarbamate ( — O —C(=O)(NH) — S — ); siloxane ( — O — SiH2 — O — ); and N,N'-dimethylhydrazine ( — CH2 — N(CH3) — N(CH3) — ). In embodiments, modified internucleotide linkages, compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In embodiments, internucleotide linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Representative chiral intemucleotide linkages include but are not limited to alkylphosphonates and phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous-containing intemucleotide linkages are well known to those skilled in the art.

[0124] In embodiments, neutral intemucleotide linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3'-CH2 — N(CH3) — 0-5'), amide-3 (3'-CH2 — C(=O)— N(H)-5'), amide-4 (3'-CH2— N(H)— C(=O)-5'), formacetal (3'-O— CH2— 0-5'), methoxypropyl, and thioformacetal (3'-S — CH2 — 0-5'). Further neutral intemucleotide linkages include nonionic linkages comprising siloxane (di alkyl siloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40- 65). Further neutral intemucleotide linkages include nonionic linkages comprising mixed N, O, S and CH2 component parts.

[0125] In embodiments, the anti-KLF15 antisense nucleic acid includes one or more phosphorothioate linkages. In embodiments, the anti-KLF15 antisense nucleic acid includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more), phosphorothioate linkages and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) modified nucleotides. In embodiments, the anti-KLF15 antisense nucleic acid includes one or more modified nucleotides. In embodiments, anti-KLF15 antisense nucleic acid includes a modification including a 2’ O-Methyl, 2 ’-deoxy-2’ fluoro, 2’-deoxy, a universal base, 5-C-methyl, an inverted deoxy abasic residue incorporation, and a locked nucleic acid. In embodiments, the modification is positioned at the terminal nucleobase of the anti-KLF15 antisense nucleic acid. In embodiments, the modification is not positioned at the terminal nucleobase of the anti-KLF15 antisense nucleic acid. In embodiments, the modification protects against serum-derived nucleases. In embodiments, the anti- KLF15 antisense nucleic acid includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) modified nucleotides. In embodiments, the anti-KLF15 antisense nucleic acid includes one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more), phosphorothioate linkages and one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more) modified nucleotides.

[0126] As described above, the anti-KLF15 antisense nucleic acid may include a targeting nucleic acid sequence capable of hybridizing to a target sequence in a KLF15 transcript. In embodiments, the KLF 15 transcript includes the sequence of SEQ ID NO: !, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO: 1. In embodiments, the KLF 15 transcript includes the sequence of SEQ ID NO:2. In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:3. In embodiments, the KLF 15 transcript includes the sequence of SEQ ID NO:4. In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:5. In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:6.

[0127] In embodiments, the target sequence is about 6 to about 50 nucleotides in length. In embodiments, the target sequence is about 8 to about 50 nucleotides in length. In embodiments, the target sequence is about 10 to about 50 nucleotides in length. In embodiments, the target sequence is about 12 to about 50 nucleotides in length. In embodiments, the target sequence is about 14 to about 50 nucleotides in length. In embodiments, the target sequence is about 16 to about 50 nucleotides in length. In embodiments, the target sequence is about 18 to about 50 nucleotides in length. In embodiments, the target sequence is about 20 to about 50 nucleotides in length. In embodiments, the target sequence is about 22 to about 50 nucleotides in length. In embodiments, the target sequence is about 24 to about 50 nucleotides in length. In embodiments, the target sequence is about 26 to about 50 nucleotides in length. In embodiments, the target sequence is about 28 to about 50 nucleotides in length. In embodiments, the target sequence is about 30 to about 50 nucleotides in length. In embodiments, the target sequence is about 32 to about 50 nucleotides in length. In embodiments, the target sequence is about 34 to about 50 nucleotides in length. In embodiments, the target sequence is about 36 to about 50 nucleotides in length. In embodiments, the target sequence is about 38 to about 50 nucleotides in length. In embodiments, the target sequence is about 40 to about 50 nucleotides in length. In embodiments, the target sequence is about 42 to about 50 nucleotides in length. Inembodiments, the target sequence is about 44 to about 50 nucleotides in length. In embodiments, the target sequence is about 46 to about 50 nucleotides in length. In embodiments, the target sequence is about 48 to about 50 nucleotides in length.

[0128] In embodiments, the target sequence is about 6 to about 48 nucleotides in length. In embodiments, the target sequence is about 6 to about 46 nucleotides in length. In embodiments, the target sequence is about 6 to about 44 nucleotides in length. In embodiments, the target sequence is about 6 to about 42 nucleotides in length. In embodiments, the target sequence is about 6 to about 40 nucleotides in length. In embodiments, the target sequence is about 6 to about 38 nucleotides in length. In embodiments, the target sequence is about 6 to about 36 nucleotides in length. In embodiments, the target sequence is about 6 to about 34 nucleotides in length. In embodiments, the target sequence is about 6 to about 32 nucleotides in length. In embodiments, the target sequence is about 6 to about 30 nucleotides in length. In embodiments, the target sequence is about 6 to about 28 nucleotides in length. In embodiments, the target sequence is about 6 to about 26 nucleotides in length. In embodiments, the target sequence is about 6 to about 24 nucleotides in length. In embodiments, the target sequence is about 6 to about 22 nucleotides in length. In embodiments, the target sequence is about 6 to about 20 nucleotides in length. In embodiments, the target sequence is about 6 to about 18 nucleotides in length. In embodiments, the target sequence is about 6 to about 16 nucleotides in length. In embodiments, the target sequence is about 6 to about 14 nucleotides in length. In embodiments, the target sequence is about 6 to about 12 nucleotides in length. In embodiments, the target sequence is about 6 to about 10 nucleotides in length. In embodiments, the target sequence is about 6 to about 8 nucleotides in length. In embodiments, the target sequence is about 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50 nucleotides in length. In embodiments, the sequence lengths described herein are within nucleic acid sequence of SEQ ID NO: 1. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID NO:1. In embodiments, the sequence lengths described herein are within nucleic acid sequence of SEQ ID NO:2. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID NO:2. In embodiments, the sequence lengths described herein are within nucleic acid sequence of SEQ ID NO:3. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID NO:3. In embodiments, the sequencelengths described herein are within nucleic acid sequence of SEQ ID NO:4. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID NO:4. In embodiments, the sequence lengths described herein are within nucleic acid sequence of SEQ ID NO: 5. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID NO:5. In embodiments, the sequence lengths described herein are within nucleic acid sequence of SEQ ID NO:6. In embodiments, the sequence lengths described herein include a fragment or a portion of the nucleic acid sequence of SEQ ID N0:6.

[0129] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region correspondingto positions 1400 to 1600 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2480 of SEQ ID NO: 1. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2480 of SEQ ID NO: 1.

[0130] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1400 to 1600 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2500 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2400 to 2600 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2500 to 2700 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2500 to 2702 of SEQ ID NO:2. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2600 to 2702 of SEQ ID NO:2.

[0131] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO:3. In embodiments, the target sequence includesa nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO:3 In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1400 to 1600 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2500 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2400 to 2600 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2500 to 2700 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2600 to 2800 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2700 to 2900 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2800 to 3000 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2900 to 3100 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3000 to 3200 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3100 to 3300 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3200 to 3400 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3300 to 3500 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3400 to 3600 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3500 to 3700 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3600 to 3800 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3700 to 3900 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3800 to 4000 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3900 to 4100 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4000 to 4200 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 4100 to 4300 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4100 to 4379 of SEQ ID NO:3. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4200 to 4379 of SEQ ID NO:3.

[0132] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1400 to 1600 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2500 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2400 to 2600 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2500 to 2700 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2600 to 2800 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2700 to 2900 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2800 to 3000 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2900 to 3100 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3000 to 3200 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3100 to 3300 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3200 to 3400 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3300 to 3500 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3400 to 3600 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3500 to 3700 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3600 to 3800 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 3700 to 3900 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3800 to 4000 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3900 to 4100 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4000 to 4200 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4100 to 4300 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4200 to 4400 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4300 to 4500 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4400 to 4600 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4500 to 4700 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4600 to 4800 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4700 to 4900 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4800 to 5000 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4900 to 5100 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4900 to 5133 of SEQ ID NO:4. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 5000 to 5133 of SEQ ID NO:4.

[0133] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1400 to 1600 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2500 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2400 to 2600 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 2500 to 2700 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2600 to 2800 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2700 to 2900 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2800 to 3000 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2900 to 3100 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3000 to 3200 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3100 to 3300 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3200 to 3400 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3300 to 3500 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3400 to 3600 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3500 to 3700 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3600 to 3800 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3700 to 3900 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3800 to 4000 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3900 to 4100 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4000 to 4200 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4100 to 4300 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4200 to 4400 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4300 to 4500 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4400 to 4600 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 4500 to 4700 of SEQ ID NO:5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4500 to 4767 of SEQ ID NO: 5. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4600 to 4767 of SEQ ID NO:5.

[0134] In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1 to 200 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 100 to 300 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 200 to 400 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 300 to 500 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 400 to 600 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 500 to 700 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 600 to 800 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 700 to 900 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 800 to 1000 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 900 to 1100 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1000 to 1200 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1100 to 1300 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1200 to 1400 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1300 to 1500 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1400 to 1600 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1500 to 1700 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1600 to 1800 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 1700 to 1900 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1800 to 2000 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 1900 to 2100 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2000 to 2200 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2100 to 2300 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2200 to 2400 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2300 to 2500 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2400 to 2600 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2500 to 2700 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2600 to 2800 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2700 to 2900 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2800 to 3000 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 2900 to 3100 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3000 to 3200 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3100 to 3300 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3200 to 3400 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3300 to 3500 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3400 to 3600 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3500 to 3700 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3600 to 3800 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleicacid sequence within the region corresponding to positions 3700 to 3900 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3800 to 4000 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 3900 to 4100 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4000 to 4200 of SEQ ID NO:6. In embodiments, the target sequence includes a nucleic acid sequence within the region corresponding to positions 4100 to 4259 of SEQ ID NO:6.

[0135] In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO : 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO:7. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO:8. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO:9. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 10. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 11. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 12. In embodiments, the target sequence within the KLF15 transcript includes the sequence SEQ ID NO: 13. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 14. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 15. In embodiments, the target sequence within the KLF15 transcript includes the sequence of SEQ ID NO: 18. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO:7. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO:8. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO:9. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO: 10. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO: 11. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO: 12. In embodiments, the target sequence within the KLF15 transcript is the sequence SEQ ID NO: 13. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO: 14. In embodiments, thetarget sequence within the KLF15 transcript is the sequence of SEQ ID NO: 15. In embodiments, the target sequence within the KLF15 transcript is the sequence of SEQ ID NO: 18.

[0136] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the anti-KLF15 antisense nucleic acid is an shRNA. In embodiments, the anti-KLF15 antisense nucleic acid is an siRNA. In embodiments, the anti-KLF15 antisense nucleic acid is an ASO.

[0137] In embodiments, the shRNA includes the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the shRNA includes the sequence of SEQ ID NO: 19. In embodiments, the shRNA includes the sequence of SEQ ID NO:20. In embodiments, the shRNA includes the sequence of SEQ ID NO:21. In embodiments, the shRNA is the sequence of SEQ ID NO: 19. In embodiments, the shRNA is the sequence of SEQ ID NO:20. In embodiments, the shRNA is the sequence of SEQ ID NO:21.

[0138] In embodiments, the siRNA includes the sequence of SEQ ID NO: 17. In embodiments, the siRNA is the sequence of SEQ ID NO: 17.

[0139] In embodiments, the ASO includes the sequence of SEQ ID NO: 17, 19, 20, or 21. In embodiments, the ASO includes the sequence of SEQ ID NO: 17. In embodiments, the ASO includes the sequence of SEQ ID NO: 19. In embodiments, the ASO includes the sequence of SEQ ID NO:20. In embodiments, the ASO includes the sequence of SEQ ID NO:21.

[0140] Applicant further demonstrates herein that, in embodiments, the Adrbl agonist provided herein including embodiments thereof is effective for inducing and / or upregulating expression of a brown fat marker gene in a white adipocyte cell. In embodiments, the method further includes administering to the subject a beta-1 adrenergic receptor (ADRB1) agonist. The term “beta-1 adrenergic receptor agonist” or “ADRB1 agonist” as used herein refers to a compound that binds to an ADRB1 protein and activates or increases activity of the ADRB1 protein. For example, the ADRB1 agonist increases the activity of ADRB1 protein resulting from a direct interaction of the agonist to the ADRB 1 protein. In embodiments, the ADRB1 agonist is a selective agonist. For example, in embodiments, the selective ADRB1 agonist does not detectably bind to ARDB2 proteinor ARDB3 protein. In embodiments, the selective ADRB1 agonist binds to ADRB1 protein with at least about 5x, lOx, 15x, 20x, 25x, 50x, lOOx, 200x, 500x, or lOOOx greater affinity than to ADRB2 protein or ARDB3 protein. In embodiments, the ADRB1 agonist is a non-selective agonist. For example, in embodiments, the ADRB 1 non-selective agonist may bind to ADRB 1 and ADRB2 and / or ADRB3. In embodiments, the ADRB1 agonist is an exogenous ADRB1 agonist. In embodiments, the ADRB1 agonist is not an endogenous ADRB1 agonist. For example, in embodiments, the ADRB1 agonist is not a catecholamine endogenous to a cell. In embodiments, the ADRB1 agonist is not norepinephrine (NE) or epinephrine (EPI). In embodiments, the ADRB1 agonist is a synthetic ADRB1 agonist. In embodiments, the ADRB1 agonist does not naturally occur in a cell. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol. In embodiments, the ADRB1 agonist is Isoproterenol. In embodiments, the ADRB1 agonist is Denopamine. In embodiments, the ADRB1 agonist is Dobutamine. In embodiments, the ADRB1 agonist is CL- 316243. In embodiments, the ADRB1 agonist is Etilefrine. In embodiments, the ADRB1 agonist is Racepinephrine. In embodiments, the ADRB1 agonist is Arbutamine. In embodiments, the ADRB1 agonist is Droxidopa. In embodiments, the ADRB1 agonist is Formoterol. In embodiments, the ADRB1 agonist is Salbutamol. In embodiments, the ADRB1 agonist is Terbutaline. In embodiments, the ADRB1 agonist is Metaproterenol. In embodiments, the ADRB1 agonist is Procaterol.

[0141] The term “Xamoterol,” also known as CORWIN®, CARWIN®, CORWIL®, AND XAMTOL®,or the like, refers in the usual and customary sense, to (RS)-N-(2-{[2-hydroxy-3-(4- hydroxyphenoxy)propyl]amino}ethyl)morpholine-4-carboxamide (CAS Registry number 81801-12- 9), or a pharmaceutically acceptable salt thereof.

[0142] The term “Isoproterenol,” also known as Isuprel, Isopropylnorepinephrine, Isopropylnoradrenaline, Isopropydine, WIN-5162, or the like, refers in the usual and customary sense, to 4-[l-hydroxy-2-(isopropylamino)ethyl]benzene-l,2-diol (CAS Registry number 7683-59- 2) , or a pharmaceutically acceptable salt thereof.

[0143] The term “Denopamine,” also known as Kalgut, R(-)-Denopamine, Denopamina or the like, refers in the usual and customary sense, to 4-[(lS)-2-[2-(3,4-dimethoxyphenyl)ethylamino]-l- hydroxyethyl]phenol (CAS Registry number 71771-90-9) , or a pharmaceutically acceptable salt thereof.

[0144] The term “Dobutamine,” also known as Dobutrex, Inotrex, or the like, refers in the usual and customary sense, to (RS)-4-(2-{[4-(4-hydroxyphenyl)butan-2-yl]amino}ethyl)benzene-l,2-diol (CAS Registry number 34368-04-2), or a pharmaceutically acceptable salt thereof.

[0145] The term “CL-316243,” also known as, UNII-52H8DB0TKX, 52H8DB0TKX or the like, refers in the usual and customary sense, to 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2- hydroxyethyl]amino]propyl]-l,3-benzodioxole-2,2-dicarboxylic acid, disodium salt (CAS Registry number 138908-40-4), or a pharmaceutically acceptable salt thereof.

[0146] The term “Etilefrine,” also known as, Effortil, Circupon, Ethylephrine, Ethylphenylephrine or the like, refers in the usual and customary sense, to (RS)-3-[2-(ethylamino)-l- hydroxyethyl]phenol (CAS Registry number 709-55-7), or a pharmaceutically acceptable salt thereof.

[0147] The term “Racepinephrine,” also known as, AsthmaNefrin, Dey-Dose, Micronefrin, Nephron, or the like, refers in the usual and customary sense, to 4-[l-hydroxy-2- (methylamino)ethyl]benzene-l,2-diol (CAS Registry number 329-65-7), or a pharmaceutically acceptable salt thereof.

[0148] The term “Arbutamine,” also known as, Arbutamina, Arbutaminum, or the like, refers in the usual and customary sense, to 4-[(lR)-l-hydroxy-2-{[4-(4- hydroxyphenyl)butyl]amino}ethyl]benzene-l,2-diol (CAS Registry number 128470-16-6), or a pharmaceutically acceptable salt thereof.

[0149] The term “Droxidopa,” also known as, OXEZE®, FORADIL®, SYMBICORT®, or the like, refers in the usual and customary sense, to ((RR,SS)-N-[2-hydroxy-5-[l-hydroxy-2-[l-(4- methoxyphenyl) propan-2-ylamino]ethyl] phenyl]formamide (CAS Registry number 23651-95-8), or a pharmaceutically acceptable salt thereof.

[0150] The term “Formoterol,” also known as, NORTHERA®, DOPS®, or the like, refers in the usual and customary sense, to (2S,3R)-2-Amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid (CAS Registry number 73573-87-2), or a pharmaceutically acceptable salt thereof.

[0151] The term “Salbutamol,” also known as, VENTOLIN®, PROVENTIL®, PRO AIR®, or the like, refers in the usual and customary sense, to (RS)-4-[2-(tert-Butylamino)-l -hydroxy ethyl]-2- (hydroxymethyl)phenol (CAS Registry number 18559-94-9), or a pharmaceutically acceptable salt thereof.

[0152] The term “Terbutaline,” also known as, BRICANYL®, MAREX®, or the like, refers in the usual and customary sense, to (RS)-5-[2-(tert-Butylamino)-l-hydroxyethyl]benzene-l,3-diol (CAS Registry number 23031-25-6), or a pharmaceutically acceptable salt thereof.

[0153] The term “Metaproterenol,” also known as, Orcipren aline, ALUPENT®, METAPREL®, ORCIBEST®, or the like, refers in the usual and customary sense, to (RS)-5-[l-hydroxy-2- (isopropylamino)ethyl]benzene-l,3-diol (CAS Registry number 586-06-1), or a pharmaceutically acceptable salt thereof.

[0154] The term “Procaterol,” also known as, MEPTIN®, or the like, refers in the usual and customary sense, to (±)-(lR,2S)-rel-8-Hydroxy-5-[l-hydroxy-2-(isopropylamino)butyl]-quinolin- 2(lH)-one (CAS Registry number 72332-33-3), or a pharmaceutically acceptable salt thereof.

[0155] As described throughout the specification, Applicant has demonstrated that increasing the increasing expression levels of ADRB1 in the adipocyte cell is effective for treatment of metabolic disorders. For example, in embodiments, increasing the level or concentration of ADRB1 in an adipocyte, increases or upregulates expression of brown fat marker genes in the adipocyte cell and / or activates theromogenesis in the cell. Thus, in embodiments, the method further includes administering to the subject a nucleic acid encoding ADRB1. In embodiments, the nucleic acid encoding ADRB1 is DNA. In embodiments, the nucleic acid encoding ADRB1 is RNA (e.g. mRNA). In embodiments, the nucleic acid encoding the ADRB1 is part of an expression vector. In embodiments, the expression vector is a viral vector.

[0156] The method provided herein including embodiments thereof is therefore contemplated to be effective for treating a variety of metabolic disorders. For the methods provided herein, inembodiments, the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof. In embodiments, the metabolic disorder is obesity. In embodiments, the metabolic disorder is diabetes. In embodiments, the metabolic disorder is metabolic syndrome. In embodiments, the metabolic disorder is risk of cardiovascular disease. In embodiments, the metabolic disorder is Cushing’s syndrome. In embodiments, the metabolic disorder is Prader-Willi syndrome. In embodiments, the metabolic disorder is Congenital Leptin deficiency. In embodiments, the metabolic disorder is Bardet-Biedl syndrome. In embodiments, the metabolic disorder is Alstrom syndrome. In embodiments, the metabolic disorder is Fragile X syndrome. In embodiments, the metabolic disorder is Inborn Errors of Metabolism. In embodiments, the metabolic disorder is Gaucher disease. In embodiments, the metabolic disorder is a Glycogen Storage Diseases. In embodiments, the metabolic disorder is a Mitochondrial disorders.

[0157] As described above, in embodiments, the method provided herein including embodiments thereof is effective for inducing or upregulating expression of a brown fat marker gene in a white adipocyte cell. Thus, for the method provided herein, in embodiments, a beige adipocyte capable of thermogenesis may be generated in white adipocyte tissue. In embodiments, a white adipocyte may undergo beiging, thereby allowing the cell to undergo thermogenesis. Thus, in an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

[0158] In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0159] In embodiments, the method further includes administering to the subject a Kriippel-like factor 15 (KLF15) inhibitor. In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. In embodiments, thetargeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript.

[0160] In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the target sequence of the KLF15 transcript includes the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0161] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA includes the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the siRNA includes the sequence of SEQ ID NO: 17.

[0162] For the method provided herein, in embodiments, the method further includes administering to the subject an effective amount of a nucleic acid encoding beta-1 adrenergic receptor (ADRB1) protein. In embodiments, the nucleic acid encoding the ADRB1 is part of an expression vector.

[0163] In embodiments, the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0164] As described throughout the specification, in embodiments, increasing the activity level of ADRB 1 in a cell, including increasing the expression level of ADRB 1 in the cell, upregulates expression of brown fat marker genes and / or genes associated with thermogenesis. Thus, in an aspect is provided a method of treating a metabolic disorder in a subject, the method including administering to the subject effective amount of a nucleic acid encoding beta-1 adrenergic receptor (ADRB1) protein. In embodiments, the said nucleic acid encoding said ADRB1 protein is part of an expression vector.

[0165] In embodiments, the method further includes administering to the subject an effective amount of a ADRB1 agonist. In embodiments, theADRBl agonist is Xamoterol, Isoproterenol,Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL- 316243, or a combination thereof.

[0166] In embodiments, the comprising administering to the subject an effective amount of a Kriippel-like factor 15 (KLF15) inhibitor. In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. In embodiments, the said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript. In embodiments, the KLF15 transcript comprises the sequence of SEQ ID NO:1, SEQ ID N0:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO: 15, or SEQ ID NO:18.

[0167] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the said anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the the siRNA comprises the sequence of SEQ ID NO: 17.

[0168] In embodiments, the said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0169] The compositions provided herein including embodiments thereof are contemplated to be effective for activating an ADRB1 in a cell. The term “activate” as used herein refers to positively affecting (e g. increasing) the activity or function of a protein relative to the activity or function of the protein in the absence of the composition. In embodiments, activate refers to increasing the concentration or levels of a protein relative to the concentration or level of the protein in the absence of the composition. Thus, in an aspect is provided a method of activating a beta-1 adrenergicreceptor (ADRB1) in a cell, the method including contacting the cell with a Kriippel-like factor 15 (KLF15) inhibitor. As described above, in embodiments, activating an ADRB1 in a cell includes increasing the activating or function of ADRB1 in a cell, or increasing the concentration or level of ADRB1 in a cell. Thus, in an aspect is provided a method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method including contacting the cell with a nucleic acid encoding ADRB1. In another aspect is provided a method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method including contacting the cell with an ADRB1 agonist.

[0170] As described above, in embodiments, the composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist), provided herein increases the activity of ADRB1 in the cell. In embodiments, increasing the activity of ADRB1 in a cell can be assessed by the increase of expression of one or more brown fat marker genes (e.g. Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, Fabp3) or a decrease in the expression of one or more white adipocyte marker genes (e.g. Retn, Tle3, Ajp423'). In embodiments, the activity of ADRB1 in a cell is increased at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist). In certain instances, the activity is 1.5-fold, 2-fold, 3-fold, 4- fold, 5-fold, 10-fold or greater than the activity in the absence of composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist).

[0171] For the method provided herein, in embodiments, the KLF15 inhibitor increases the activity of ADRB1 in the cell. In embodiments, increasing the activity of ADRB1 in a cell can be assessed by the increase of expression of one or more brown fat marker genes (e.g. Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, l abp3) or a decrease in the expression of one or more white adipocyte marker genes (e.g. Retn, Tle3, Afp423'). In embodiments, the activity of ADRB1 in a cell is increased at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the KLF15 inhibitor. In certain instances, the activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or greater than the expression or activity in the absence of the KLF15 inhibitor.

[0172] In embodiments, the composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist) provided herein increases the concentration or level of ADRB1 in the cell. Theconcentration or level of ADRB1 can be assessed by measurement of the level of a transcript (e.g. mRNA) encoding ADRB1 or the ADRB1 protein. In embodiments, the composition (e g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist) is capable of detectably increasing the expression or level of ADRB1 at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the composition (e g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist). In certain instances, expression or level of ADRB1 is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or greater than the expression or activity in the absence of the composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist).

[0173] In embodiments, the KLF15 inhibitor increases the concentration or level of ADRB1 in the cell. In embodiments, the KLF15 inhibitor is capable of detectably increasing the expression or level of ADRB1 at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the KLF15 inhibitor. In certain instances, expression or level of ADRB1 is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or greater than the expression or activity in the absence of the KLF15 inhibitor.

[0174] In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 80% complementary to the target sequence within the KLF15 transcript.

[0175] In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0176] In embodiments, the target sequence of the KLF15 transcript includes the sequence of SEQ ID N0:7, SEQ ID NO:8, SEQ ID NON, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO:14, SEQ ID NO 15, or SEQ ID NO: 18.

[0177] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA includes thesequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the siRNA includes the sequence of SEQ ID NO: 17.

[0178] For the method provided herein, in embodiments, the method further includes contacting the cell with a beta-1 adrenergic receptor (ADRB1) agonist. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0179] In embodiments, the method further includes contacting the cell with an effective amount of a nucleic acid encoding ADRB1. In embodiments, the nucleic acid encoding the ADRB1 is part of an expression vector.

[0180] In embodiments, the cell is an adipocyte. In embodiments, the adipocyte is a white adipocyte. In embodiments, the white adipocyte is a subcutaneous white adipocyte. “Subcutaneous” used in the context of adipocytes, refers to an adipocyte cell located in the subcutaneous adipose tissue (e.g. the layer of adipose tissue under the skin). Thus, subcutaneous adipose tissue refers to the layer of adipose tissue under the skin (vs. the adipose tissue surrounding the internal organs). “Visceral” used in the context of adipocytes, refers to an adipocyte cell located in the adipose tissue surrounding the internal organs.

[0181] “White adipocyte” refers to an adipocyte cell associated with storage of lipids. In embodiments, a white adipocyte typically secretes one or more of leptin, adiponectin and pro- inflammatory cytokines (e.g. TNF-a, IL-6, MCP-1). In embodiments, a white adipocyte is typically characterized by the presence of a large lipid droplet. In embodiments, a white adipocyte expresses one or more white adipocyte marker genes (e.g. Retn, Tle3, Afp423). In embodiments, a white adipocyte has at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% higher expression of a white adipocyte marker gene relative to a brown or beige adipocyte.

[0182] “Brown adipocyte” refers to an adipocyte cell associated with thermogenesis. Typically, in contrast to white adipocytes, a brown adipocyte includes numerous small (multilocular) lipiddroplets. Typically, a brown adipocyte includes more mitochondria than a white adipocyte. In embodiments, a brown adipocyte expresses one or more brown adipocyte marker gene (e g Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, FabpS). In embodiments, a brown adipocyte has at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% higher expression of a brown adipocyte marker gene relative to a white adipocyte.

[0183] “Beige adipocyte” or “brite adipocyte” refers to an adipocyte cell typically found in or adjacent to a white adipocyte depot, that includes cellular and molecular features of brown adipocytes. For example, in embodiments, a beige adipocyte is capable of thermogenesis. In embodiments, a beige adipocyte includes multiple small lipid droplets. In embodiments, a beige adipocyte includes a higher number of mitochondria relative to a white adipocyte. A beige adipocyte may express one or more brown adipocyte markers (e.g Ucpl, Ppargcla, Cidea, Prdml6, Dio2, Cox8b, Fabp3). In embodiments, a beige adipocyte has at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% higher expression of a brown adipocyte marker gene relative to a white adipocyte.

[0184] In embodiments, the cell is in a subject. Thus, in embodiments, the contacting occurs in vivo. In embodiments, the subject is a subject having a metabolic disorder. In embodiments, the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0185] In embodiments, the contacting occurs in vitro. In embodiments, the cell is obtained from the subject or a donor, contacted with a composition (e.g. KLF15 inhibitor, nucleic acid encoding ADRB1, ADRB1 agonist) provided herein. Thus, in embodiments, the contacting occurs ex vivo. In embodiments, the cell is obtained from the subject and contacted with a composition provided herein including embodiments thereof and administered back to the subject. In embodiments, the subject has a metabolic disorder. In embodiments, the cell is obtained from a donor, contacted with a composition provided herein including embodiments thereof, and administered to the subject. In embodiments, the donor is a healthy donor. In embodiments, the donor does not have a metabolic disorder.PHARMACEUTICAL COMPOSITIONS

[0186] The compositions provided herein, including a Kriippel-like factor 15 (KLF15) inhibitor and beta-1 adrenergic receptor (ADRB1) agonist provided herein including embodiments thereof are further contemplated as pharmaceutical compositions.

[0187] In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF15 transcript.

[0188] In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. the target sequence comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

[0189] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA inluces the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the siRNA comprises the sequence of SEQ ID NO: 17.

[0190] In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0191] For the pharmaceutical composition provided herein, in embodiments, the pharmaceutical composition further includes a nucleic acid encoding ADRB1. In embodiments, the nucleic acid encoding the ADRB1 is part of an expression vector.

[0192] In other aspects, the nucleic acid encoding ADRB 1 provided herein including embodiments thereof is contemplated as a pharmaceutical composition. In embodiments, the pharmaceutical composition further includes an anti-KLFl 5 antisense nucleic acid provided hereinincluding embodiments thereof. In embodiments, the pharmaceutical composition further includes an ADRB1 agonist provided herein including embodiments thereof.

[0193] The provided compositions are, inter alia, suitable for formulation and administration in vitro or in vivo. Suitable carriers and excipients and their formulations are described in Remington: The Science and Practice of Pharmacy, 21st Edition, David B. Troy, ed., Lippicott Williams & Wilkins (2005). By pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained. If administered to a subject, the carrier is optionally selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject.

[0194] Pharmaceutical compositions provided herein include compositions wherein the active ingredient (e.g. compositions described herein, including embodiments or examples) is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. When administered in methods to treat a disease, the recombinant proteins described herein will contain an amount of active ingredient effective to achieve the desired result, e.g., modulating the activity of a target molecule, and / or reducing, eliminating, or slowing the progression of disease symptoms. Determination of a therapeutically effective amount of a compound of the invention is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure herein.

[0195] Provided compositions can include a single agent or more than one agent. The compositions for administration will commonly include an agent as described herein dissolved in a pharmaceutically acceptable carrier, preferably an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. These solutions are sterile and generally free of undesirable matter. These compositions may be sterilized by conventional, well known sterilization techniques. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride,calcium chloride, sodium lactate and the like. The concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs.

[0196] Solutions of the active compounds as free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.

[0197] Pharmaceutical compositions can be delivered via intranasal or inhalable solutions or sprays, aerosols or inhalants. Nasal solutions can be aqueous solutions designed to be administered to the nasal passages in drops or sprays. Nasal solutions can be prepared so that they are similar in many respects to nasal secretions. Thus, the aqueous nasal solutions usually are isotonic and slightly buffered to maintain a pH of 5.5 to 6.5. In addition, antimicrobial preservatives, similar to those used in ophthalmic preparations and appropriate drug stabilizers, if required, may be included in the formulation. Various commercial nasal preparations are known and can include, for example, antibiotics and antihistamines.

[0198] Oral formulations can include excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. These compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders. In some embodiments, oral pharmaceutical compositions will comprise an inert diluent or assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 75%of the weight of the unit, or preferably between 25-60%. The amount of active compounds in such compositions is such that a suitable dosage can be obtained.

[0199] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered and the liquid diluent first rendered isotonic with sufficient saline or glucose. Aqueous solutions, in particular, sterile aqueous media, are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion.

[0200] Sterile injectable solutions can be prepared by incorporating the active compounds or constructs in the required amount in the appropriate solvent followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium. Vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredients, can be used to prepare sterile powders for reconstitution of sterile injectable solutions. The preparation of more, or highly, concentrated solutions for direct injection is also contemplated. DMSO can be used as solvent for extremely rapid penetration, delivering high concentrations of the active agents to a small area.

[0201] The formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials. Thus, the composition can be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. Thus, the compositions can be administered in a variety of unit dosage forms depending upon the method of administration. For example, unit dosage forms suitable for oral administration include, but are not limited to, powder, tablets, pills, capsules and lozenges.

[0202] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (suchas Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with the compounds of the invention. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0203] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0204] The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.KITS

[0205] Provided herein are, inter alia, kits including a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist for therapeutic purposes, for example, treatment of metabolic disorders. Thus, in an aspect is provided a kit including a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0206] In embodiments, the KLF15 inhibitor is provided in a first dosage form and the ADRB1 agonist is provided in a second dosage form. In embodiments, a “first dosage form” as provided herein refers to a discrete composition of a KLF15 inhibitor and is separate from other dosage forms. In embodiments, the first dosage form does not include any other active agents. In embodiments, the first dosage form does not include any other therapeutic agent. Likewise, in embodiments, a “second dosage form” as provided herein refers to a discrete composition of the ADRB1 agonist and is separate from other dosage forms (e.g., the first dosage form of the KLF15inhibitor). In embodiments, the second dosage form does not include any other active agents. In embodiments, the second dosage form does not include any other therapeutic agent.

[0207] In embodiments, the first dosage form includes the KLF15 inhibitor present in a specific amount (specific effective amount, specific therapeutic amount). In embodiments, the second dosage form includes the ADRB1 agonist present in a specific amount (specific effective amount, specific therapeutic amount). In embodiments, the amount of the KLF15 inhibitor and the amount of the ADRB1 agonist are a combined therapeutically effective amount. In embodiments, the amount of the KLF15 inhibitor and the amount of the ADRB1 agonist are a combined synergistic amount.

[0208] In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript. In embodiments, the targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF15 transcript.

[0209] In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. the target sequence comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

[0210] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA inluces the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21. In embodiments, the siRNA comprises the sequence of SEQ ID NO: 17.

[0211] In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0212] In embodiments, the kit further includes a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein and a Kriippel-like factor 15 (KLF15) inhibitor. In embodiments, the nucleic acid encoding the ADRB1 is part of an expression vector. In embodiments, the nucleic acid encoding the ADRB1 is provided in a third dosage form. In embodiments, a “third dosage form” as provided herein refers to a discrete composition of the nucleic acid encoding the ADRB1 and is separate from other dosage forms (e.g., the first dosage form of the KLF15 inhibitor, the second dosage form of the ADRB1 agonist). In embodiments, the third dosage form does not include any other active agents. In embodiments, the third dosage form does not include any other therapeutic agent.

[0213] In an aspect is provided a kit including a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein and a Kriippel-like factor 15 (KLF15) inhibitor. In embodiments, the nucleic acid encoding said ADRB1 protein is part of an expression vector.

[0214] In embodiments, the nucleic acid encoding the ADRB 1 is provided in a first dosage form and the KLF15 inhibitor is provided in a second dosage form. In embodiments, a “first dosage form” as provided herein refers to a discrete composition of nucleic acid encoding the ADRB1 and is separate from other dosage forms. In embodiments, the first dosage form does not include any other active agents. In embodiments, the first dosage form does not include any other therapeutic agent. Likewise, in embodiments, a “second dosage form” as provided herein refers to a discrete composition of the KLF15 inhibitor and is separate from other dosage forms (e.g., the first dosage form of the nucleic acid encoding the ADRB1). In embodiments, the second dosage form does not include any other active agents. In embodiments, the second dosage form does not include any other therapeutic agent.

[0215] In embodiments, the KLF15 inhibitor is an anti-KLF15 antisense nucleic acid. In embodiments, the anti-KLF15 antisense nucleic acid includes a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript In embodiments, the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript In embodiments, the KLF15 transcript includes the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6. In embodiments, the target sequence of the KLF15 transcript includes the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0216] In embodiments, the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA). In embodiments, the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA. In embodiments, the shRNA includes the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID N0:21. In embodiments, the siRNA includes the sequence of SEQ ID NO: 17.

[0217] In embodiments, the kit further includes an ADRB1 agonist. In embodiments, the ADRB1 agonist is provided in a third dosage form. In embodiments, a “third dosage form” as provided herein refers to a discrete composition of the ADRB1 agonist and is separate from other dosage forms. In embodiments, the third dosage form does not include any other active agents. In embodiments, the third dosage form does not include any other therapeutic agent. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof. In embodiments, the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0218] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.P EMBODIMENTS

[0219] P Embodiment 1. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of Kriippel-like factor 15 (KLF15) inhibitor.

[0220] P Embodiment 2. The method of P embodiment 1, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0221] P Embodiment 3. The method of P embodiment 2, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0222] P Embodiment 4. The method of P embodiment 3, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

[0223] P Embodiment 5. The method of P embodiment 3 or 4, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NON, SEQ ID NO:5, or SEQ ID NO:6.

[0224] P Embodiment 6. The method of any one of P embodiments 3 to 5, wherein said target sequence within said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0225] P Embodiment 7. The method of any one of P embodiments 3 to 7, wherein said anti- KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0226] P Embodiment 8. The method of P embodiment 7, wherein the shRNA comprises the sequence of SEQ ID NO : 19, SEQ ID NO : 20, or SEQ ID NO : 21.

[0227] P Embodiment 9. The method of P embodiment 7, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0228] P Embodiment 10. The method of any one of P embodiments 1 to 9, further comprising administering to the subject a beta-1 adrenergic receptor (ADRBl) agonist.

[0229] P Embodiment 11. The method of P embodiment 10, wherein the ADRBl agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

[0230] P Embodiment 12. The method of P embodiment 11, wherein the ADRBl agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0231] P Embodiment 13. The method of any one of P embodiments 1 to 12, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0232] P Embodiment 14. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

[0233] P Embodiment 15. The method of P embodiment 14, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

[0234] P Embodiment 16. The method of P embodiment 15, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0235] P Embodiment 17. The method of any one of P embodiments 14 to 16, further comprising administering to the subject a Kriippel-like factor 15 (KLF15) inhibitor.

[0236] P Embodiment 18. The method of P embodiment 17, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

[0237] P Embodiment 19. The method of P embodiment 18, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0238] P Embodiment 20. The method of P embodiment 19, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

[0239] P Embodiment 21 . The method of P embodiment 19 or 20, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0240] P Embodiment 22. The method of any one of P embodiments 19 to 21, wherein said target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ IDNO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0241] P Embodiment 23. The method of any one of P embodiments 18 to 22, wherein said anti- KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0242] P Embodiment 24. The method of P embodiment 23, wherein said shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0243] P Embodiment 25. The method of P embodiment 23, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0244] P Embodiment 26. The method of any one of P embodiments 14 to 25, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0245] P Embodiment 27. A method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method comprising contacting said cell with a Kriippel-like factor 15 (KLF15) inhibitor.

[0246] P Embodiment 28. The method of P embodiment 27, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

[0247] P Embodiment 29. The method of P embodiment 28, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF 15 transcript.

[0248] P Embodiment 30. The method of P embodiment 29, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF 15 transcript.

[0249] P Embodiment 31. The method of P embodiment 29 or 30, wherein said KLF 15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0250] P Embodiment 32. The method of any one of P embodiments 29 to 31, wherein said target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ IDNO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0251] P Embodiment 33. The method of any one of P embodiments 28 to 32, wherein the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0252] P Embodiment 34. The method of P embodiment 33, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0253] P Embodiment 35. The method of P embodiment 33, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0254] P Embodiment 36. The method of any one of P embodiments 27 to 35, further comprising contacting said cell with a beta-1 adrenergic receptor (ADRB1) agonist.

[0255] P Embodiment 37. The method of P embodiment 36, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0256] P Embodiment 38. The method of P embodiment 37, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0257] P Embodiment 39. The method of any one of P embodiments 27 to 38, wherein the cell is an adipocyte.

[0258] P Embodiment 40. The method of P embodiment 39, wherein the adipocyte is a white adipocyte.

[0259] P Embodiment 41. The method of P embodiment 40, wherein the white adipocyte is a subcutaneous white adipocyte.

[0260] P Embodiment 42. The method of any one of P embodiments 27 to 41, wherein the cell is in a subject.

[0261] P Embodiment 43. The method of P embodiment 42, wherein said subject is a subject having a metabolic disorder.

[0262] P Embodiment 44. The method of P embodiment 43, wherein the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader- Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0263] P Embodiment 45. The method of any one of P embodiments 27 to 41, wherein said contacting occurs in vitro.

[0264] P Embodiment 46. A pharmaceutical composition comprising a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0265] P Embodiment 47. The pharmaceutical composition of P embodiment 46, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

[0266] P Embodiment 48. The pharmaceutical composition of P embodiment 47, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0267] P Embodiment 49. The pharmaceutical composition of P embodiment 48, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF 15 transcript.

[0268] P Embodiment 50. The pharmaceutical composition of P embodiment 48 or 49, wherein the KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0269] P Embodiment 51. The pharmaceutical composition of any one of P embodiments 48 to 50, wherein the target sequence comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0270] P Embodiment 52. The pharmaceutical composition of any one of P embodiments 47 to 51, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0271] P Embodiment 53. The pharmaceutical composition of P embodiment 52, wherein the shRNA comprises the sequence of SEQ ID NO:19, SEQ ID NO:20, or SEQ ID NO:21.

[0272] P Embodiment 54. The pharmaceutical composition of P embodiment 52, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0273] P Embodiment 55. The pharmaceutical composition of any one of P embodiments 46 to 54, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0274] P Embodiment 56. The pharmaceutical composition of any P embodiment 55, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0275] P Embodiment 57. A kit comprising a Kruppel-like factor 15 (KLF15) inhibitor and a beta- 1 adrenergic receptor (ADRB1) agonist.

[0276] P Embodiment 58. The kit of P embodiment 57, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0277] P Embodiment 59. The kit of P embodiment 58, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF 15 transcript.

[0278] P Embodiment 60. The kit of P embodiment 59, wherein the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF 15 transcript.

[0279] P Embodiment 61. The kit of P embodiment 59 or 60, wherein the KLF 15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0280] P Embodiment 62. The kit of any one of P embodiments 59 to 61, wherein the target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0281] P Embodiment 63. The kit of any one of P embodiments 58 to 62, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0282] P Embodiment 64. The kit of P embodiment 63, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0283] P Embodiment 65. The kit of P embodiment 63, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0284] P Embodiment 66. The kit of any one of P embodiments 57 to 65, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0285] P Embodiment 67. The kit of P embodiment 66, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.EMBODIMENTS

[0286] Embodiment 1. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of Kriippel-like factor 15 (KLF15) inhibitor.

[0287] Embodiment 2. The method of embodiment 1, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0288] Embodiment 3. The method of embodiment 2, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0289] Embodiment 4. The method of embodiment 3, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

[0290] Embodiment 5. The method of embodiment 3 or 4, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0291] Embodiment 6. The method of any one of embodiments 3 to 5, wherein said target sequence within said KLF15 transcript comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8,SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0292] Embodiment 7. The method of any one of embodiments 3 to 6, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0293] Embodiment 8. The method of embodiment 7, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO: 20, or SEQ ID NO:21.

[0294] Embodiment 9. The method of embodiment 7, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0295] Embodiment 10. The method of any one of embodiments 1 to 9, further comprising administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

[0296] Embodiment 11. The method of embodiment 10, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

[0297] Embodiment 12. The method of embodiment 11, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0298] Embodiment 13. The method of any one of embodiments 1 to 12, further comprising administering to the subject an effective amount of a nucleic acid encoding ADRB1.

[0299] Embodiment 14. The method of embodiment 13, wherein said nucleic acid encoding said ADRB1 is part of an expression vector.

[0300] Embodiment 15. The method of any one of embodiments 1 to 14, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0301] Embodiment 16. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

[0302] Embodiment 17. The method of embodiment 16, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

[0303] Embodiment 18. The method of embodiment 17, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0304] Embodiment 19. The method of any one of embodiments 16 to 18, further comprising administering to the subject a Kriippel-like factor 15 (KLF15) inhibitor.

[0305] Embodiment 20. The method of embodiment 19, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0306] Embodiment 21. The method of embodiment 20, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF 15 transcript.

[0307] Embodiment 22. The method of embodiment 21, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF 15 transcript.

[0308] Embodiment 23. The method of embodiment 21 or 22, wherein said KLF 15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0309] Embodiment 24. The method of any one of embodiments 21 to 23, wherein said target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0310] Embodiment 25. The method of any one of embodiments 20 to 24, wherein the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0311] Embodiment 26. The method of embodiment 25, wherein said anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0312] Embodiment 27. The method of embodiment 26, wherein said shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO 20, or SEQ ID NO:21.

[0313] Embodiment 28. The method of embodiment 26, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0314] Embodiment 29. The method of any one of embodiments 16 to 28, further comprising administering to the subject a nucleic acid encoding ADRB1.

[0315] Embodiment 30. The method of embodiment 29, wherein said nucleic acid encoding said ADRB 1 protein is part of an expression vector.

[0316] Embodiment 31. The method of any one of embodiments 16 to 30, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0317] Embodiment 32. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein.

[0318] Embodiment 33. The method of embodiment 32, wherein said nucleic acid encoding said ADRB 1 protein is part of an expression vector.

[0319] Embodiment 34. The method of embodiment 32 or 33, wherein said method further comprises administering to the subject an effective amount of an ADRB1 agonist.

[0320] Embodiment 35. The method of embodiment 34, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine,Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

[0321] Embodiment 36. The method of embodiment 35, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0322] Embodiment 37. The method of any ones of embodiments 32 to 36, further comprising administering to the subject an effective amount of a Kriippel-like factor 15 (KLF15) inhibitor.

[0323] Embodiment 38. The method of embodiment 37, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0324] Embodiment 39. The method of embodiment 38, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0325] Embodiment 40. The method of embodiment 39, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

[0326] Embodiment 41. The method of embodiment 39 or 40, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0327] Embodiment 42. The method of any one of embodiments 39 to 41, wherein said target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0328] Embodiment 43. The method of any one of embodiments 38 to 42, wherein said anti- KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0329] Embodiment 44. The method of embodiment 43, wherein said anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0330] Embodiment 45. The method of embodiment 44, wherein said shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0331] Embodiment 46. The method of embodiment 44, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0332] Embodiment 47. The method of any one of embodiments 32 to 46, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0333] Embodiment 48. A method of activating a beta-1 adrenergic receptor (ADRB1) in a cell, the method comprising contacting said cell with a Kriippel-like factor 15 (KLF15) inhibitor.

[0334] Embodiment 49. The method of embodiment 48, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0335] Embodiment 50. The method of embodiment 49, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF 15 transcript.

[0336] Embodiment 51. The method of embodiment 50, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF 15 transcript.

[0337] Embodiment 52. The method of embodiment 50 or 51, wherein said KLF 15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0338] Embodiment 53. The method of any one of embodiments 50 to 52, wherein said target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0339] Embodiment 54. The method of any one of embodiments 49 to 53, wherein said anti- KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0340] Embodiment 55. The method of embodiment 54, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0341] Embodiment 56. The method of embodiment 55, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0342] Embodiment 57. The method of embodiment 55, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0343] Embodiment 58. The method of any one of embodiments 48 to 57, further comprising contacting said cell with a beta-1 adrenergic receptor (ADRB1) agonist.

[0344] Embodiment 59. The method of embodiment 58, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0345] Embodiment 60. The method of embodiment 59, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0346] Embodiment 61. The method of any one of embodiments 48 to 60, further comprising administering to the subject an effective amount of a nucleic acid encoding ADRBl.

[0347] Embodiment 62. The method of embodiment 61, wherein said nucleic acid encoding said ADRB 1 protein is part of an expression vector.

[0348] Embodiment 63. The method of any one of embodiments 48 to 62, wherein the cell is an adipocyte.

[0349] Embodiment 64. The method of embodiment 63, wherein the adipocyte is a white adipocyte.

[0350] Embodiment 65. The method of embodiment 64, wherein the white adipocyte is a subcutaneous white adipocyte.

[0351] Embodiment 66. The method of any one of embodiments 48 to 65, wherein the cell is in a subject.

[0352] Embodiment 67. The method of embodiment 66, wherein said subject is a subject having a metabolic disorder.

[0353] Embodiment 68. The method of embodiment 67, wherein the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

[0354] Embodiment 69. The method of any one of embodiments 48 to 65, wherein said contacting occurs in vitro.

[0355] Embodiment 70. A pharmaceutical composition comprising a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0356] Embodiment 71. The pharmaceutical composition of embodiment 70, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

[0357] Embodiment 72. The pharmaceutical composition of embodiment 71, wherein said anti- KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0358] Embodiment 73. The pharmaceutical composition of embodiment 72, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF 15 transcript.

[0359] Embodiment 74. The pharmaceutical composition of embodiment 72 or 73, wherein the KLF 15 transcript comprises the sequence of SEQ ID NO: l, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

[0360] Embodiment 75. The pharmaceutical composition of any one of embodiments 72 to 74, wherein the target sequence comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0361] Embodiment 76. The method of any one of embodiments 71 to 75, wherein said anti- KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0362] Embodiment 77. The pharmaceutical composition of embodiment 76, wherein the anti- KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0363] Embodiment 78. The pharmaceutical composition of embodiment 77, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0364] Embodiment 79. The pharmaceutical composition of embodiment 77, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0365] Embodiment 80. The pharmaceutical composition of any one of embodiments 70 to 79, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0366] Embodiment 81. The pharmaceutical composition of embodiment 80, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0367] Embodiment 82. The pharmaceutical composition of any one of embodiments 70 to 81, further comprising a nucleic acid encoding a ADRB1 protein.

[0368] Embodiment 83. The pharmaceutical composition of embodiment 82, wherein said nucleic acid encoding said AD RBI protein is part of an expression vector.

[0369] Embodiment 84. A kit comprising a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

[0370] Embodiment 85. The kit of embodiment 84, wherein said KLF15 inhibitor is an anti- KLF15 antisense nucleic acid.

[0371] Embodiment 86. The kit of embodiment 85, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0372] Embodiment 87. The kit of embodiment 86, wherein the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript.

[0373] Embodiment 88. The kit of embodiment 86 or 87, wherein the KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID N0:6.

[0374] Embodiment 89. The kit of any one of embodiments 86 to 88, wherein the target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0375] Embodiment 90. The kit of any one of embodiments 85 to 89, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0376] Embodiment 91 . The kit of embodiment 90, wherein the anti-KLFl 5 antisense nucleic acid is an shRNA or an siRNA.

[0377] Embodiment 92. The kit of embodiment 91, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

[0378] Embodiment 93. The kit of embodiment 91, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0379] Embodiment 94. The kit of any one of embodiments 84 to 93, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

[0380] Embodiment 95. The kit of embodiment 94, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

[0381] Embodiment 96. The kit of embodiment 84 to 95, further comprising a nucleic acid encoding a ADRB 1 protein.

[0382] Embodiment 97. The kit of embodiment 96, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

[0383] Embodiment 98. A kit comprising a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein and a Kriippel-like factor 15 (KLF15) inhibitor.

[0384] Embodiment 99. The kit of embodiment 97, wherein said nucleic acid encoding said ADRB 1 protein is part of an expression vector.

[0385] Embodiment 100. The kit of embodiment 98 or 99, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

[0386] Embodiment 101. The kit of embodiment 100, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

[0387] Embodiment 102. The kit of embodiment 101, wherein the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript.

[0388] Embodiment 103. The kit of embodiment 101 or 102, wherein the KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NON, SEQ ID NO:5, or SEQ ID NO:6.

[0389] Embodiment 104. The kit of any one of embodiments 101 to 103, wherein the target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

[0390] Embodiment 105. The method of any one of embodiments 100 to 104, wherein said anti- KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

[0391] Embodiment 106. The kit of embodiment 105, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

[0392] Embodiment 107. The kit of embodiment 106, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO: 20, or SEQ ID NO:21

[0393] Embodiment 108. The kit of embodiment 106, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

[0394] Embodiment 109. The kit of any one of embodiments 98 to 108, further comprising an ADRB1 agonist.

[0395] Embodiment 110. The kit of embodiment 109, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof

[0396] Embodiment 111. The kit of embodiment 110, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.EXAMPLESExample 1: Introduction to Exemplary Experiments

[0397] Adipocytes are the most prominent cell type in mature adipose tissue and, in addition to being involved in energy homeostasis, these cells receive and produce a variety of potent paracrine and endocrine signals in response to physiologic and extrinsic cues (1-4). Different adipose tissue depots have distinct development, maintenance and influence on systemic metabolism. This is most obviously appreciated by comparing BAT and WAT depots (5-7). A substantial amount of WAT maturation occurs postnatally through the differentiation of tissue resident adipocyte progenitor cells (8). Conversely, mature BAT depots are present at birth in humans as well as in many other animals, including mice (9). Evolutionarily, the presence of BAT depots at birth is often attributed to the need for thermogenesis to maintain body temperature during the perinatal period, among other factors (10). Indeed, exposure to cold temperature is a potent physiologic activator of BAT, stimulating increased cellular oxygen consumption rates with uncoupled respirations, within brown adipocytes, that results in the production of heat (thermogenesis) (11, 12). This process is promoted, at least in part, by the P-adrenergic signaling induced by exposure to cold ambient temperatures (13).

[0398] The energy burning capability of BAT has garnered substantial interest not only because of the fascinating biology but also because the pathways regulating the generation and activation of BAT are potentially targetable to develop therapeutic opportunities for obesity, a major health problem for millions of people (11, 14, 15). Yet, some enthusiasm for this approach has been tempered by the fact that humans appear to have few BAT depots at birth and a further decline in the proportional amount of BAT compared to WAT depots occurs with aging (16).

[0399] However, more recently, it was discovered that some WAT depots, such as subcutaneous WAT, contain heterogenous types of adipocytes, including adipocytes that possess cellular and molecular features of brown adipocytes (17, 18). These adipocytes have been referred to as ‘brite’ (for ‘brown within white) or ‘beige’ adipocytes (19-21). The precise origin of these cells remains incompletely understood, leaving it an open question if they are derived from a distinct progenitor population or share a common progenitor with white adipocytes or are converted from white adipocytes (19, 20, 22-26). Alternatively, and perhaps most likely, all these possible pathways occur and contribute to the composition of the WAT in vivo, with the origin of individual adipocytes determined by variables in context, developmental stage and stimulation that provokes the ‘beiging’ of the WAT.

[0400] Given the substantial number of white adipocytes in most humans, it is enticing to contemplate targeting pathways that are critical to the maintenance of white adipocytes to promote therapeutic benefits. However, it remains poorly understood which factors are necessary to maintain white adipocyte properties. A major outstanding question remains: What are the context and depotspecific nature of these factors?

[0401] Kruppel-like factors (KLFs) are zinc finger motif containing transcription factors that regulate development and systemic metabolism (27-29). There are 17 KLF family members and dysregulation of KLFs result in diseases, including obesity and the development of diabetes (28). We found that the Klf family member Klfl5 effects adipose tissue, including regulating adipogenesis, lipid storage and BAT. In this study, we describe our findings revealing a previously unrecognized and distinct role for KLF 15 as a necessary factor for the maintenance of white adipocyte properties selectively in the subcutaneous WAT depot.Example 2: KLF15 Maintenance of White Adipocytes

[0402] Klfl5 expression is higher in WAT compared to BAT and is suppressed by 0-adrenergic signaling.

[0403] To elucidate the context specific, as well as the most physiologically potent activities of KLF15 in adipose tissue, we surveyed the expression levels of Klf 15 across three major types of adipose: visceral, subcutaneous and intrascapular brown in wild-type (WT) mice. Strikingly, we found that the expression levels of Klfl5 is -75% lower in brown adipose tissue (BAT) comparedwith white (WAT) (FIG. 1 A). These results suggest physiological implications for these differences, including raising the possibility of a requirement to downregulate Klfl5 levels for proper brown fat function. Brown fat responds to P-adrenergic signaling with the induction of thermogenesis (13), and this is a primary physiological function of this tissue. Therefore, we tested the impact of - adrenergic stimulation on KlfI5 expression in adipose tissues. We found that exposing WAT to the P-adrenergic stimulant isoproterenol in tissue culture resulted in downregulation of Klfl5 expression (FIG. IB). To test if these results were relevant in vivo, we injected WT mice with the P-adrenergic agonist CL-316243 and discovered that this treatment results in a -50% downregulation in Klfl5 expression levels in WAT (FIG. 1 C). There are three different adrenergic receptor family members (ADRB 1-3). Interestingly, the three adrenergic receptors have distinct properties as well as both ligand-dependent and constitutive activation (reviewed in (34). We compared the expression levels of these receptors across the adipose types and found that Adrbl is the most differentially expressed in BAT compared to WAT (FIG s ID and 5A). An analogous pattern was observed when the expression levels of the adrenergic receptors were compared in human white and brown adipocytes (35). Adrbl is a particularly interesting, and perhaps distinct, adrenergic receptor; for example, overexpression of Adrbl in white adipocytes is sufficient to generate constitutive activity and mimics the effect of systemic infusion of agonists, even in the absence of additional agonists (36). These findings also indicate that increasing the expression level of the Adrbl alters white adipocytes in contexts where other adrenergic receptors are present.

[0404] Deletion <A' Klfl5 disrupts maintenance of white adipocyte properties and induces Adrbl expression.

[0405] To begin to probe the physiological relevance of the above findings, we generated aKlf!5 floxed mouse line using CRISPR / Cas9 to insert loxP sites surrounding exons 1-3 of the Klfl5 gene (A7 / 75-floxed). We then harvested white adipocytes from these mice and infected them with an adenovirus that expresses Cre recombinase (cleaving the loxP sites, knocking-out Klf'15) or control adenovirus (FIG. IE). Cre infected adipocytes had lower expression levels of Klfl5 compared to controls (FIG. IF), demonstrating that Cre exposure properly results in efficient deletion of Klfl5 in the cells. We discovered that deletion of Klfl5 substantially induces the expression of genes that are critical to brown fat identity and function, including the expression of the canonical brown fat gene Ucpl (FIG. IF). These results are particularly striking because they support that there is plasticity inmature adipocytes, where core properties of white adipocytes can be modulated independently from adipogenesis.

[0406] When we measured the expression levels of 0 -adrenergic receptors in response to deletion of Klfl5, we discovered A\a\ Adrhl was upregulated, while the other adrenergic receptors were unaffected or down regulated (FIG. 1G). piAR protein levels also increase with Klfl5 deletion (FIG. 1H). These findings are intriguing, in part, because overexpression oiAdrbl in subcutaneous white adipose tissue (iWAT) is sufficient to induce Ucpl expression and beiging of this white fat depot (36, 37). Furthermore, piAR is more sensitive to stimuli than other adrenergic receptors (38). Therefore, our results suggest a plausible pathway by which KLF15 could modulate the maintenance of white adipocytes and beiging in iWAT.

[0407] We next probed if the induction of brown fat genes that occurs after deletion of Klfl5 is mechanistically connected to the increased expression o Adrbl. Adrenergic receptor activation leads to increased phosphorylation of p38 MAP kinase which, in turn, induces Ucpl expression (39). To test if this pathway is stimulated by the deletion of KIfl5, we monitored the levels of p38 phosphorylation. Indeed, deletion of Klfl5 leads to a marked increase in the levels of phosphorylated p38 in mature adipocytes (FIG. II). Furthermore, we found that inhibition of p38 MAP kinase suppresses the induction of Ucpl with Klfl5 deletion (FIG. 1J).

[0408] As mentioned, 01 AR activation can occur by both ligand-dependent and constitutive mechanisms. As no additional ligand was added to observe the induction of brown fat genes with Klfl5 deletion, our results raise the possibility that ligand-independent signaling was occurring because of the constitutive activation of the 01 AR receptor. However, adrenergic receptor agonists are present in cell culture medium (40), which could stimulate the pathway. Therefore, to integrate this question further, we assessed the effect of an adrenergic receptor antagonist. We discovered that the antagonist propranolol diminishes, but does not abolish, the induction of Ucpl expression in Klfl5 deleted adipocytes (FIG. 5B). Reciprocally, we tested the effect of stimulation with an adrenergic receptor agonist. These experiments revealed that the addition of an agonist enhances the induction of Ucpl in Klfl5 deleted adipocytes (FIG. 1H). Together, these results support a model where the induction of Adrbl that occurs with KIJ15 deletion results in both ligand-dependent and constitutive 01AR activation in the mature adipocytes.

[0409] To investigate this activity of KLF15 selectively in mature adipocytes in vivo, we crossed the Klfl5-floxed mice with transgenic mice expressing Cre recombinase under the control of the adiponectin promoter and regulatory elements (Adipoq-Cre). Adipoq-Cre mice have been verified to selectively express Cre in mature adipocytes (41), enabling conditional deletion oh Klfl5 in mice that have both floxed Klfl5 and the Adipoq-Cre transgene (Adipo-Klfl 5 cKO mice) in their genomes. Indeed, we verified that K If 15 is efficiently and selectively knocked-out in mature adipocytes and not in other tissues (FIG. 2A) nor in the adipose stromal vascular fraction (SVF) (FIG. 2B) of Adipo-Klfl 5 cKO mice. When we harvested the WAT Adipo-Klfl5 cKO mice, we noted that the iWAT had a browner appearance compared to iWAT from either Adipoq-Cre or 7 / 75-floxed mice (FIG. 2C). In addition, the mass of the iWAT was less in Adipo-Klfl 5 cKO mice compared to littermate controls (FIG. 2D). We discovered that the iWAT from Adipo-Klfl 5 cKO had substantially higher expression levels of multiple genes involved in brown fat identity and function (FIG. 2E) and that upregulation of Ucpl was restricted to mature adipocytes isolated from the iWAT (FIG. 5C); we did not detect any induction of Ucpl in either visceral WAT (gWAT) or BAT (FIG.s 5D and 5E).

[0410] We also tested if there were analogous changes in the expression levels of the adrenergic receptors, as we discovered in our ex vivo experiments (FIG. 1G). Consistent with our findings in tissue culture, the in vivo studies revealed that only Adrbl was selectively upregulated m Adipo- Klfl 5 cKO in iWAT (FIG.s 2F-2H). As multiple factors, including external ones, can impact adrenergic signaling, to rigorously verify these results, we directly compared the ratio of expression levels of Adrbl to Adrb3 in Adipo-Klfl5 cKO mice compared to sex matched littermates as individual paired replicates. The results of these orthogonal testing of the findings, which controls for any ‘crosstalk’ between Adrbl and Adrb3 (42), confirmed that Adrbl expression in iWAT is selectively upregulated in Adipo-Klfl 5 cKO mice (FIG. 21 and FIG. 5F and 5G). Finally, we tested if the expression change translates into altered protein levels of 01AR. Using Immunoblotting we established 01AR protein levels are increased in the iWAT oh Adipo-Klfl 5 cKO mice (FIG. 21 and 2K).

[0411] Recently, non-canonical and adrenergic-independent thermogenic pathways have been described in adipocytes (43, 44). To evaluate if Klfl 5 affects these mechanisms, we measured theexpression levels of genes involved in these pathways. We did not detect evidence that these pathways were altered by deletion of Klfl5 (FIG. 5H). These results further support that modulation of Adrbl by Klfl5 is a primary mechanism for the beiging of mature adipocytes that we observed.

[0412] Together, our results indicate that deletion of Klfl5 in the Adipo-Klfl5 cKO mice disrupts maintenance of white adipocyte properties and induces beiging selectively in the mature adipocytes within the iWAT depot. To investigate this further, as well as test the findings using an independent approach, we generated a second mouse line by crossing A7 / 75-floxed mice with transgenic mice expressing Cre under the regulation of Prxl promoter and regulatory element (Prxl-Cre). We (45) and others (46) previously demonstrated that this Prxl-Cre transgenic mouse line efficiently and preferentially targets the iWAT fat depot adipocyte progenitor cells over gWAT. Indeed, we found that mice generated by this cross that have both floxed Klfl5 and the Prxl-Cre transgene (Prxl- Klfl5 cKO) have substantially lower levels of Klfl5 expression selectively in the iWAT compared to other tissues as well as littermate controls (FIG.s 3A and 3B). In addition, the iWAT depot- specifically weigh less, are browner and have smaller adipocytes than controls (FIG. 3C-3E and FIG. 6A, B). While total body weights were not significantly different (FIG. 6C and 6D), this may have been impacted by the observed adipose depot-restricted effects combined with variable compensatory changes in food consumption (FIG. 6E).

[0413] Expression profiling revealed that the levels of pan-adipocyte expressing genes were similar in Prxl-Klfl5 cKO mice compared to littermate controls (FIG. 3F). Notably, the Prxl-Klfl5 cKO iWAT has decreased expression of some white adipocyte marker genes (FIG. 3G) as well as significantly higher expression levels of multiple brown fat marker genes (FIG. 3H). Furthermore, the expression level of Ardbl, but not Ardb2 or Ardb3. is upregulated in Prxl-Klfl5 cKO iWAT as quantified in absolute levels (FIG. 31) as well as relative to Adrb3 expression in littermate controls (FIG. 3J). Immunoblotting confirmed that these expression differences translate into higher protein levels of UCP1 and plAR in Prxl-Klfl5 cKO iWAT (FIG. 3K and FIG. 6F).

[0414] Having established, using two mouse model systems, that deletion of Ktfl5 in iWAT induces 01 AR and disrupts mature white adipocyte maintenance, we next investigated the functional implications of these finding. We measured the energetics of primary iWAT harvested from Prxl- Klfl5 cKO compared to littermate controls in response to the selective p l AR agonist Xamoterol aswell as the adrenergic agonist Isoproterenol. We discovered that iWAT with Klfl5 deleted has an enhanced response to agonist stimulation, resulting in substantially higher induced oxygen consumption rates (OCRs) (FIG. 3L and FIG. 6G).

[0415] The above results indicate that deletion of Klfl5 stimulates upregulation of the 01AR and results in adipocytes with enhanced responsiveness to adrenergic stimulation. We next investigated the systemic implications of these findings in vivo. By monitoring singly housed mice in metabolic cages, we found that that Prxl-Klfl5 cKO mice have higher energy expenditure per total body mass compared to littermate controls, which becomes significantly further induced by acute cold exposure, a physiologically relevant stimuli (FIG.s 3M and 2N). Of note, hQPrxl-Klfl5 cKO mice are also more competent at maintaining their body temperature during cold exposure, and this occurs without any change locomotor activity (FIG.s 7A and 7B). These findings demonstrate that, even though this activity of KLF15 is cell-autonomous and restricted to the iWAT depot in mice, deletion of Klfl5 in iWAT has physiological implications.

[0416] Our ex vivo studies revealed that adipocytes with Klfl5 deleted have increased Adrbl expression and enhanced adrenergic sensitivity. We also found Adrbl expression levels are increased in the iWAT of mice with Klfl5 deletion. To assess the in vivo implications of these findings, we administered adrenergic agonists to the mice and monitored the effect on energy expenditure. We discovered that the Prxl-Klfl5 cKO mice, housed in a thermoneutral environment, have enhanced energy expenditure immediately following injections with agonists, consistent with increased sensitivity to adrenergic stimulation during the short half-lives of these drugs (FIG. 7, C- F). As with cold exposure, the increased energy expenditure was not caused by increased activity (FIG. 7G).

[0417] KLF15 modulates adipocyte sensitivity to 0-adrenergic stimulation.

[0418] Having discovered that the deletion of Klfl5 in iWAT has systemic implications in vivo, we were motivated to further define the mechanisms driving this effect. Our results indicate that the Pl AR receptor is upregulated in iWAT in both of our mouse models with Klfl5 deletions. Furthermore, our findings demonstrate that this effect is cell-autonomous and occurs rapidly, as we detected marked changes m Adrbl following acute deletion of Klfl5 in cells (FIG. 1G), suggesting that this change is proximal to, and potential directly caused by, KLF15 action. This model wasparticularly intriguing because adrenergic signaling stimulates a brown fat expression profile in iWAT, as well as promotes cellular energy utilization in adipocytes through the induction of uncoupled respirations. Of note, prior work by others implicated 03 AR as the primary adrenergic receptor expressed in white adipocytes in rodents (47). Our results raise the exciting possibility that targeting KLF 15 could induce an alternative adrenergic input pathway for white adipocytes that promotes energy utilization. To test this model, we acutely deleted Klf 15 in white adipocytes using adenoviral infection of adipocytes. We then measured the expression levels of Adrbl and Ucpl both at the basal state as well as after stimulation with Xamoterol. We discovered that not only are basal levels of Adrbl and Ucpl expression higher in adipocytes after acute deletion of Klf 15 but also Klfl5 deleted adipocytes have a more robust response to the 01AR agonist that is cell-autonomous (FIG. 4A and 4B). Adrenergic signaling stimulates the induction of cAMP production within responsive cells (48). Therefore, we quantified cAMP levels in A7 / 75-deleted adipocytes. Indeed, we found that deletion of Klf 15 results in increased cAMP levels in the adipocytes (FIG. 4C). These findings indicate that deletion of Klf 15 in white adipocytes enhances cellular sensitivity to adrenergic stimulation through the 01 AR receptor.

[0419] Adrbl is a KLF15 target gene.

[0420] KLF15 functions as a transcription factor to both positively and negatively regulate the expression of genes by binding to a canonical DNA binding site sequence (FIG. 8A) in target genes (49). The rapid and substantial induction of Adrbl expression after Kl 15 knockdown suggested that expression of Adrbl could be directly modulated by KLF15. Interestingly, there is contextspecificity to KLF 15 action as Klf 15 expression was found to stimulate expression of the alpha- adrenergic receptor Adrala in models of nephric tubules (50). To probe deeper into the specific relationship between Klf 15 and Adrbl in white adipocytes, we acutely overexpressed Klf 15 in adipocytes using adenoviral infection; we discovered that overexpression of Klf 15 downregulates Adrbl expression (FIG. 8B), further suggesting that Adrbl is directly regulated by KLF15. Therefore, we scanned the promoter proximal region of the Adrbl gene and identified a KLF 15 binding site sequence 23 bps downstream of the transcriptional start site of Adrbl. Importantly, we found that this putative binding site is highly conserved, including in humans (FIG. 4D). We subcloned the endogenous Adrb 1 promoter and proximal region, containing this putative KLF 15I l lbinding site, into a promoter-less luciferase reporter construct. We then transfected adipocytes with this luciferase reporter and co-transfected with either a Klfl5 expression vector or an empty control vector. Luciferase assays revealed that co-transfection with the Klfl5 expression vector inhibits Adrbl promoter activity compared to control infected cells (FIG. 4E). Furthermore, mutating the putative KLF15 biding site, using site directed mutagenesis of the Adrbl luciferase reporter construct (FIG. 8C), prevented KLF15 inhibition of Adrbl promoter activity (FIG. 8D), indicating that this binding site was necessary and sufficient for this KLF15 activity. Finally, we performed chromatin immunoprecipitation (ChIP) studies using primary iWAT isolated from WT mice as well as mice with a flag(3x) knocked-intoKlfl5 gene (51) (Klfl5f AGcompared with iWAT from Klfl5 cKO mice as a control. We performed ChIP on the putative KLF15 binding site in the Adrbl gene and found enriched occupancy at that site in both the iWAT of Klfl53xFLAGmice and in WT mice (performed with anti-KLF15 and anti-FLAG respectively) as well as compared to a distinct site located adjacent to the KLF15 binding site (FIG.s 4F-4H). Together, these data indicate that this site is a bona fide KLF15 binding site and response element in the Adrbl gene.

[0421] KLF15 activity is conserved in primary human adipose cells.

[0422] We next tested for evidence that this pathway is conserved and relevant to humans. First, we injected wild-type mice with a panel of piAR agonists, including ones that are FDA approved drugs for use in humans, and collected iWAT tissue. Strikingly, we discovered that these drugs provoked a substantial induction of Ucpl expression in the iWAT (FIG. 41). Next, we purchased human primary stromal vascular fractions harvested from subcutaneous abdominal white adipose tissue biopsies. We differentiated these cells in culture and then knocked down hKLF15 expression in the mature human adipocytes using adenoviral infection of Klfl5 shRNA compared to control shRNA infection (FIG. 4J). This approach resulted in >80% knockdown of AKLF15 in the human adipocytes (FIG. 4K). Strikingly, acute knockdown of hKLF15 resulted in a marked induction of both hARDBl and hUCPl in the primary human adipocytes (FIG. 4K). Importantly, we found that induction of hUCPl was hADRBl dependent (FIG. 8E), implicating this pathway as the primary mechanism for the observed induction of hUCPl. In further support of this result, while knockdown of hADRBl blocked the induction of hUCPl, it did not alter the level of phosphorylated hormonesensitive lipase (pHSL) (FIG.s 8F and G), indicating that the increased level of lipolysis withhKLF15 knockdown observed by us (FIG. 8H) and others (32) is not the major driver of the induction hUCPl expression.

[0423] We next tested functional effects of hKLF15 in human adipocytes by measuring cellular energetics. Using a Seahorse analyzer, we discovered that knockdown of hKLF15 induces increased OCRs in human white adipocytes (FIG. 4L and 4M) without changing mitochondrial content (FIG. 81); analogous to what we observed in our studies using mouse models described above. Finally, we discovered that knockdown of hKLF15 in human white adipocytes results in an enhanced induction of the OCR in response to adrenergic agonists Xamoterol and Dobutamine (FIG. 4N and FIG. 8J and 8K). These results support that targeting hKLF15 increases sensitivity to adrenergic stimulation in human adipocytes.

[0424] Discussion

[0425] In this study, we discovered that Klfl5 has a previously unrecognized depot-specific role in mature adipocytes in subcutaneous fat depots. We revealed that KLF15 is necessary to maintain white adipocyte characteristics in iWAT. Furthermore, our results elucidate that the surprising mechanism of this action includes altering the adipocyte sensitivity to 0-adrenergic stimulation. Our findings support that this pathway is conserved in humans.

[0426] We and others found that 7 / 75 is expressed at relatively low levels in BAT and, reciprocally, Adrbl is robustly expressed in BAT at levels substantially above iWAT (FIG. s 1, A and D and FIG. 5 A and (52)). We believe this defines the context-specific nature of the Klfl5-Adrbl pathway we identified in white adipocytes, where KLF15 regulation of Adrbl is a germane event that modulates white adipocyte maintenance. This, along with the use of distinct mouse models and assays that are not directly comparable, also likely explains differences observed in our study compared to studies focused on Klfl5 in BAT (33); It likely that increasing the already high levels of Adrbl expression present in BAT is relatively less impactful compared to the context of mature white adipocytes. It will be of future interest to identify if there are additional factors driving the high expression of Adrbl in BAT but we believe the low levels of Klfl5 are likely relevant.

[0427] While understanding the mechanisms that regulate transcription of adrenergic receptors is of broad interest because of the potential implications for physiology as well as drug development,current knowledge in this area is limited. The findings of this study elucidate thatis a direct target gene of KLF15 in white adipocytes. Furthermore, we reveal evidence that increased expression ol Adrbl in white adipocytes results in enhanced piAR signaling through a combination of tonic receptor activity and increased sensitivity to agonists. Together, our results define this previously unrecognized mechanism as critical to white adipocyte maintenance.

[0428] Within WAT depots, we also elucidated that the Klfl5-Adrbl-Ucpl pathway is context specific to iWAT. Subcutaneous and visceral adipose depots have numerous distinctions, including divergent implications for metabolic risk as well as competency to beige (17, 53). Therefore, the context-specificity we identified may be the result of fundamental distinctions in the cell populations. However, when we examined CHIP-Seq data sets from Roh et al (54), we were intrigued to discover that the Adrbl locus undergoes epigenetic modifications in adipocytes in different contexts (FIG. 8L). Our studies identified Adrbl as a direct target gene of KLF15. It is tempting to speculate that these molecular mechanisms work together where different adipose depots and system signals are integrated by epigenetic differences as well as gating by KLF15 to generate context-specific responses in Adrbl expression.

[0429] Intriguingly, while ADRB3 appears to play a prominent role in rodent brown fat activation, ADRB1 is the predominant adrenergic receptor in human BAT (55). Furthermore, expression of ADRB3 is not detectable in human WAT (35, 47). These observations likely, at least partially, explain why attempts to develop ADRB3 agonist as therapeutics for obesity in humans have not been successful (35). We identified KLF15 as a negative regulator of ADRB1 that is conserved in primary human adipose cells. These discoveries not only expand our understanding of adipose biology, including the plasticity of mature white adipocytes, but they also elucidate and define previously unrecognized pathways with plausible prospects for being more relevant, and therefore potentially more effective, therapeutic targets for humans than other approaches.Example 3: Methods

[0430] Sex as a biological variable

[0431] Our study examined male and female animals, and similar findings are reported for both sexes.

[0432] Animal models

[0433] Mice were maintained on standard rodent chow diet withl2-hour light and dark cycles. All mice were in C57BL / 6J background. Both male and female mice of various ages (young mice:5-7 weeks old; adult mice: 8-16 weeks old) were used in these studies. A7 / 75-floxed mice were generated using CRISPR / Cas9 to insert loxP sites into the Klfl5 gene to surround exons 1-3. The Prxl-Cre mice (Stock No. 005584), and Adipoq-Cre (Stock No. 028020) mice were purchased from Jackson Laboratory. Prxl-Klfl5 cKO mice were generated from flox / flox, Cre / + or flox / +, Cre / + male mice cross with flox / flox, + / + female mice. 753XHagmice were generously provided by Dr. Saptarsi M. Haidar (University of California, San Francisco).

[0434] For all in vivo studies, cohorts of at least three mice per genotype or treatment group were used, and experiments were repeated at least three independent times. Whole-body energy metabolism was measured using a Comprehensive Lab Animal Monitoring System (CLAMS) in the UCSF Nutrition & Obesity Research Center (NORC) core facility by a technician who was blinded to the genotypes. Age-matched mice at 7-8-weeks old were individually housed in rodent incubators at 30°C for 4 weeks prior to being placed in metabolic chambers for 5 days.

[0435] For the cold exposure studies, mice were housed in thermoneutral rodent incubators for 6 weeks prior to the experiments. These mice were then placed in metabolic chambers and exposed to a gradient of cold from 30°C to 10°C and then 4°C. Rectal temperatures were recorded 7h after mice were place in 10°C at 7am.

[0436] For drug administration to mice, CL316243 (1 mg / kg / day, Sigma-Aldrich, C5976), Denopamine (8 ng / g / day, Sigma-Aldrich, D7815), Xamoterol (10 pg / g / day, Tocris, 0905) and Dobutamine (10 pg / g / day, Sigma-Aldrich, D0676), were injected intraperitoneally once a day.

[0437] Cell culture

[0438] Isolation of stromal vascular fractions (SVF) from adipose depots were performed as previously described (30). Mouse adipocyte differentiation was induced by treating confluent preadipocytes with DMEM containing 10% FBS, 0.5 mM isobutyl methylxanthine (IBMX), 125 nM indomethacin, 2 pg / ml dexamethasone, 5 pg / ml insulin, 1 nM T3 and 1 pM rosiglitazone. Two days after induction, cells were switched to maintenance medium containing 10% FBS, 5 pg / ml insulin, 1nM T3 and 1 pM rosiglitazone. Mouse cells were fully differentiated six days after inducing differentiation. To stimulate thermogenesis, differentiated cells were incubated with 10 pM isoproterenol for 4 hours or 1 pM Xamoterol for 3 hours before collecting samples. For inhibiting phosphorylation of p38 MAPK, adipocytes were pretreated with 15 pM SB202190 for 24h before collecting samples.

[0439] Human subcutaneous preadipocytes were purchased (PT-5020, Lonza) and differentiated according to the company’s instructions and as we previously described (56). Briefly, confluent preadipocyte were treated with Preadipocyte Growth Medium-2 (PGM-2TM) containing 10% FBS, 2 mM glutamine, IBMX (1 : 1000, PT-5020, Lonza), indomethacin (1 :500, PT-5020, Lonza), dexamethasone (1 : 1000, PT-5020, Lonza), insulin (1 : 100, PT-5020, Lonza), 1 nM T3 and 1 pM rosiglitazone. Five days after induction, cells were switched to maintenance medium containing 10% FBS, 2 mM glutamine, insulin (1 : 100, PT-5020, Lonza), 1 nM T3 and 1 pM rosiglitazone for 5 days.

[0440] Histology

[0441] Freshly isolated adipose depots were fixed in 4% PF A, and then submitted for embedding, sectioning, and hematoxylin and eosin staining at the UCSF Histology and Biomarker Core.

[0442] Mitochondrial Function and Respiration

[0443] For tissue respiration assays, 5 mg of adipose tissue were dissected from iWAT depots using a 2 mm surgical biopsy punch (96-1160, Sklar), placed into XF24 Islet Capture Microplates (101122-100, Agilent) and pre-incubated with Seahorse XF DMEM medium (103575-100, Agilent) with 25 mM glucose and 25 mM HEPES. The tissue was then rinsed again. After removal of the final rinse, running media (Seahorse XF DMEM medium with 25 mM glucose) was added and any remaining rinse media was removed. Finally, 480 pL of running media was added to all sample and control wells. After 3 cycles of basal measurements in the XF Extracellular Flux Analyzer (Seahorse Biosciences), Xamoterol InM was injected into each well and measurements continued. O2 consumption was normalized to tissue weight and finally presented in the form of percentage of basic OCRs.

[0444] For human differentiated adipocyte, -15,000 cells were seeded in each well of Seahorse XFe24 Cell Culture Microplates (100777-004, Agilent). Differentiated human adipocytes were infected with Adenovirus and then washed twice and pre-incubated in XF medium (containing 25 mM glucose, 2 mM glutamine and 1 mM pyruvate) for 1 h at 37 °C without CO2. Oligomycin (1 mM), FCCP (4 mM), and Rotenone / Antimycin A (0.5 mM) were preloaded into cartridges and injected into XF wells in succession during the time course. For stimulation, 10 pM Xamoterol or 1 pM Dobutamine was injected after basal OCR measuring. OCR was measured and data were analyzed using Agilent Seahorse Analytics.

[0445] RNA purification, Reverse Transcription, RT- PCR and Quantification of Mitochondrial Copy Number

[0446] Total RNAs from tissues were purified using QIAzol Lysis Reagent (QIAGEN) and pellet pestle (KIMBLE). Chloroform extraction of RNA was performed with tissue lysates depleted of lipid. RNAs in the aqueous phase were purified using RNeasy Mini Kit according to manufacturer’s instructions (QIAGEN). Total RNAs from cells were purified using RNeasy Mini Kit (QIAGEN). cDNA was synthesized using iScript cDNA Synthesis kit (BioRad) according to the manufacturer’s protocol. RT-qPCR was performed using Biorad CFX96 system and TaqMan primers. Relative mitochondrial DNA content in human adipocytes was assessed by qPCR and calculated from copy number of the mtDNA encoded MtCOl gene and the nuclear DNA encoded Ndufvl gene.

[0447] DNA constructs and transfection

[0448] Adrbl-W , the 5’ Flanking sequence of the mouse Adrbl gene were amplified by PCR from mouse genomic DNA and subcloned into the pGL4.26 [Luc2 / minP / Hygro] basic reporter gene vector (Promega) through DNA assembly (E2621G, NEB). The plasmid containing the regions between -216 to 40 from the transcriptional start site were obtained by annealing oligonucleotides 5’-TCAGAAACATGCTGAGGTCCC-3’ (SEQ ID NO:28) and 5’-GCCGAGCTGCGGAGG-3’ (SEQ ID NO:29). The AdrblAAuX. plasmid was generated from Adrbl-W plasmid by performing sit directed mutagenesis (E0554S, NEB). Klfl5 (NM_023184) mouse tagged (Myc-DDK) ORF was cloned into pCMV6-Entry (MR206548, ORIGENE). All plasmids were purified using the HiPure Plasmid Midiprep Kit (K210004, ThermoFisher). Differentiated adipocytes were transfected using Lipofectamine 3000 transfection reagent (Invitrogen) according to the manufacturer’s protocol.

[0449] Luciferase Reporter Assay

[0450] Transfections with 500 ng of plasmid DNA containing A Adibl promoter-luciferase reporter constructs Adrbl-W or Adrbl-MuX) along with 100 ng of pRL-TK were performed in differentiated WT and Prxl-Klfl5 cKO adipocytes in 48-well plates. A combination of p3XFLAG- CMV 7.1 or pCMV-Klfl5 with Adrbl-WT and pRL-TK were transfected into WT adipocyte cells. 48h post-transfection, luciferase activities were measured through GloMax Microplate Reader (Promega) by using the Dual -Luciferase Reporter Assay protocol.

[0451] Immunoblotting

[0452] For preparation of whole cell extracts from tissues, fresh or frozen tissue samples were homogenized using pellet pestle (KIMBLE) in 0.2 mL of protein extraction buffer (78510, ThermoFisher) containing Complete Protease Inhibitor Cocktail EDTA-free (1 1836170001, Sigma- Aldrich). The homogenate was centrifuged at 4°C for 30 min at 15,000 g and the supernatant portion containing the protein fraction was isolated using syringes and needles (38438, BD), avoiding the lipid fraction. Protein lysates were loaded into 10% SDS-PAGE gels and transferred to a 0.2 pm nitrocellulose (1620112, Bio-Rad) or PVDF (1620177, Bio-Rad) membrane and immunoblotted using UCP1 antibody (1: 1000, Abl0983; Abeam), ADRB1 antibody (1 : 1000, ab3442; Abeam), ADRB2 antibody (1 :400, abl82136; Abeam), P-actin antibody (1 :5000, A5441; Sigma- Aldrich), GAPDH antibody (1:300, sc-365062; Santa Cruz), p38 MAPK Antibody (1: 1000, #9212, Cell Signaling Technology), Phospho-p38 MAPK (Thrl80 / Tyrl82) Antibody (1 : 1000, #9211, Cell Signaling Technology), P-Tubulin Antibody (1 : 1000, #2146, Cell Signaling Technology)

[0453] Chromatin Immunoprecipitation

[0454] Chromatin immunoprecipitation was performed as previously described (57) with minor modifications. Briefly, adipose tissues were isolated from subcutaneous fat pads of 10-12 adult mice. White adipose tissues were minced with scissors in 5 mL DMEM containing 2% FBS. 600 pL 2% collagenase type 2 were added into minced adipose tissues, then placed at 37°C for 1 hour and 20 minutes. Samples were mixed by gently inverting tubes every 15 minutes. Nuclei extraction from the fixed adipocytes were performed using Covaris ultrasonicator (S220) at 4°C with a peak power of 75 W, a duty factor of 2%, and 200 cycles / burst for 2.5 minutes in a sonication tube (520135,Covaris) within 1 mL Farnham lab buffer. Isolated nuclei were resuspended in ImL shearing buffer supplemented with Complete Protease Inhibitor Cocktail EDTA-free (11836170001, Sigma- Aldrich) and transfer into a new sonication tube (520135, Covaris). Nuclei were sonicated at 4°C with a peak power of 50 W, a duty factor of 10%, and 200 cycles / burst for 8-10 minutes to shear the chromatin. The DNA was fragmented into ~200bp (Agilent TapeStation 4200).Immunoprecipitation was performed with 10 pL of KLF15 antibody (ab2647, Abeam) on WT and Prxl-Klfl5 cKO subcutaneous adipocytes respectively; 6pL FLAG antibody (Fl 804, Sigma- Aldrich) or 6pL normal mouse IgG control (sc-2025, Santa Cruz) on Klfl5 ^AGsubcutaneous adipocytes overnight at 4°C. Antibody -bound chromatins were pulled down with Pierce™ ChlP- grade Protein A / G Magnetic Beads (26162, Thermos Fisher), washed, eluted, and reverse crosslinked. DNA was extracted by phenol / chloroform / isoamyl alcohol and ethanol precipitated. The immunoprecipitated DNA from single experiment was quantified by qPCR using 3 different primers and regular PCR products were visualized after electrophoresis in 2% agarose gels (19E1004, 3: 1 Super Sieve; IB SCI). The primer sequences are listed in supporting data file.

[0455] Adenovirus and Lentivirus infection

[0456] SVF isolated from 5-7-weeks old A7 / 75-fl / fl mice were equally seeded into 48-well plates. Differentiated cells were infected with Ad-Cre (Vector Development Laboratory (VDL)). Ad-GFP or Ad-Empty (VDL) were used as controls (termed Ad-Control). Differentiated human adipocytes were infected with sh-Ctrl or sh-Klfl5 (Welgen). The hairpin sequence of sh-Klfl5 was the same as previously reported (30). Cells were harvested 48 hours after infection for RT-qPCR. For the ADRB 1 rescue experiment, adipocytes with hKLF15 knockdown were infected with control shRNA (sc-108080, Santa Cruz) and 01AR shRNA (sc-29580-V, Santa Cruz) lentiviral particles.

[0457] Lipolysis assay

[0458] Adipocytes were washed and incubated in PGM-2TM medium containing 2 mM glutamine and 2% fatty acid-free BSA (A7030, Sigma-Aldrich) for 1 h. Aliquots of medium were taken to assay for glycerol content using Glycerol-Glo (J3150, Promega) according to the manufacturer's protocol. Glycerol content was normalized to total cellular protein content determined by a Bradford Assay (Thermo Scientific).

[0459] Measurements of cAMP Content

[0460] Adipocytes infected with Ad-Control or Ad-Cre were used...

Claims

WHAT IS CLAIMED IS:

1. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of Kruppel-like factor 15 (KLF15) inhibitor.

2. The method of claim 1, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

3. The method of claim 2, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

4. The method of claim 3, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

5. The method of claim 3, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

6. The method of claim 3, wherein said target sequence within said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO: 15, or SEQ ID NO: 18.

7. The method of claim 3, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

8. The method of claim 7, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

9. The method of claim 7, wherein the siRNA comprises the sequence of SEQ ID N0: 17.

10. The method of claim 1, further comprising administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

11. The method of claim 10, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

12. The method of claim 11, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

13. The method of claim 1, further comprising administering to the subject an effective amount of a nucleic acid encoding ADRB1.

14. The method of claim 13, wherein said nucleic acid encoding said ADRB1 is part of an expression vector.

15. The method of claim 1, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

16. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of a beta-1 adrenergic receptor (ADRB1) agonist.

17. The method of claim 16, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

18. The method of claim 17, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

19. The method of claim 16, further comprising administering to the subject a Kriippel-like factor 15 (KLF15) inhibitor.

20. The method of claim 19, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

21. The method of claim 20, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

22. The method of claim 21, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

23. The method of claim 21, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

24. The method of claim 21, wherein said target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

25. The method of claim 20, wherein the anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

26. The method of claim 25, wherein said anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

27. The method of claim 26, wherein said shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

28. The method of claim 26, wherein the siRNA comprises the sequence of SEQID N0:17.

29. The method of claim 16, further comprising administering to the subject a nucleic acid encoding ADRB1.

30. The method of claim 29, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

31. The method of claim 16, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

32. A method of treating a metabolic disorder in a subject, the method comprising administering to the subject an effective amount of a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein.

33. The method of claim 32, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

34. The method of claim 32, wherein said method further comprises administering to the subject an effective amount of an ADRB1 agonist.

35. The method of claim 34, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol or a combination thereof.

36. The method of claim 35, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

37. The method of claim 32, further comprising administering to the subject an effective amount of a Kriippel-like factor 15 (KLF15) inhibitor.

38. The method of claim 37, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

39. The method of claim 38, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

40. The method of claim 39, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence of said KLF15 transcript.

41. The method of claim 39, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

42. The method of claim 39, wherein said target sequence of said KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

43. The method of claim 38, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

44. The method of claim 43, wherein said anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

45. The method of claim 44, wherein said shRNA comprises the sequence SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:2146. The method of claim 44, wherein the siRNA comprises the sequence of SEQ ID N0: 17.

47. The method of claim 32, wherein said metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

48. A method of activating a beta-1 adrenergic receptor (ADRB 1) in a cell, the method comprising contacting said cell with a Kriippel-like factor 15 (KLF15) inhibitor.

49. The method of claim 48, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

50. The method of claim 49, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

51. The method of claim 50, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF15 transcript.

52. The method of claim 50, wherein said KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

53. The method of claim 50, wherein said target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

54. The method of claim 49, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

55. The method of claim 54, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

56. The method of claim 55, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

57. The method of claim 55, wherein the siRNA comprises the sequence of SEQID N0:17.

58. The method of claim 48, further comprising contacting said cell with a beta-1 adrenergic receptor (ADRB1) agonist.

59. The method of claim 58, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

60. The method of claim 59, wherein the ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.61 . The method of claim 48, further comprising administering to the subject an effective amount of a nucleic acid encoding ADRB1.

62. The method of claim 61, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

63. The method of claim 48, wherein the cell is an adipocyte.

64. The method of claim 63, wherein the adipocyte is a white adipocyte.

65. The method of claim 64, wherein the white adipocyte is a subcutaneous white adipocyte.

66. The method of claim 48, wherein the cell is in a subject.

67. The method of claim 66, wherein said subject is a subject having a metabolic disorder.

68. The method of claim 67, wherein the metabolic disorder is obesity, diabetes, metabolic syndrome, risk of cardiovascular disease, Cushing’s syndrome, Prader-Willi syndrome, Congenital Leptin deficiency, Bardet-Biedl syndrome, Alstrom syndrome, Fragile X syndrome, or a combination thereof.

69. The method of claim 48, wherein said contacting occurs in vitro.

70. A pharmaceutical composition comprising a Kriippel-like factor 15 (KLF 15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

71. The pharmaceutical composition of claim 70, wherein said KLF 15 inhibitor is an anti -KLF 15 antisense nucleic acid.

72. The pharmaceutical composition of claim 71, wherein said anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF 15 transcript.

73. The pharmaceutical composition of claim 72, wherein said targeting nucleic acid sequence is at least 80% complementary to said target sequence within the KLF 15 transcript.

74. The pharmaceutical composition of claim 72, wherein the KLF 15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

75. The pharmaceutical composition of claim 72, wherein the target sequence comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 18.

76. The method of claim 71, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

77. The pharmaceutical composition of claim 76, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

78. The pharmaceutical composition of claim 77, wherein the shRNA comprises the sequence of SEQ ID NO : 19, SEQ ID NO : 20, or SEQ ID NO : 21.

79. The pharmaceutical composition of claim 77, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

80. The pharmaceutical composition of claim 70, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

81. The pharmaceutical composition of claim 80, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

82. The pharmaceutical composition of claim 70, further comprising a nucleic acid encoding a ADRB 1 protein.

83. The pharmaceutical composition of claim 82, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

84. A kit comprising a Kriippel-like factor 15 (KLF15) inhibitor and a beta-1 adrenergic receptor (ADRB1) agonist.

85. The kit of claim 84, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

86. The kit of claim 85, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

87. The kit of claim 86, wherein the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript.

88. The kit of claim 86, wherein the KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

89. The kit of claim 86, wherein the target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

90. The kit of claim 85, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

91. The kit of claim 90, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

92. The kit of claim 91, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21.

93. The kit of claim 91, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

94. The kit of claim 84, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof.

95. The kit of claim 94, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

96. The kit of claim 84, further comprising a nucleic acid encoding a ADRB 1 protein.

97. The kit of claim 96, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

98. A kit comprising a nucleic acid encoding a beta-1 adrenergic receptor (ADRB1) protein and a Kriippel-like factor 15 (KLF15) inhibitor.

99. The kit of claim 97, wherein said nucleic acid encoding said ADRB1 protein is part of an expression vector.

100. The kit of claim 98, wherein said KLF15 inhibitor is an anti-KLF15 antisense nucleic acid.

101. The kit of claim 100, wherein the anti-KLF15 antisense nucleic acid comprises a targeting nucleic acid sequence complementary to a target sequence within a KLF15 transcript.

102. The kit of claim 101, wherein the targeting nucleic acid sequence is at least 80% complementary to the target sequence of the KLF15 transcript.

103. The kit of claim 101, wherein the KLF15 transcript comprises the sequence of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, or SEQ ID NO:6.

104. The kit of claim 101, wherein the target sequence of the KLF15 transcript comprises the sequence of SEQ ID NO:7, SEQ ID NO:8, SEQ ID NON, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:18.

105. The method of claim 100, wherein said anti-KLF15 antisense nucleic acid is an antisense oligonucleotide (ASO), a short hairpin RNA (shRNA) or a small interfering (siRNA).

106. The kit of claim 105, wherein the anti-KLF15 antisense nucleic acid is an shRNA or an siRNA.

107. The kit of claim 106, wherein the shRNA comprises the sequence of SEQ ID NO: 19, SEQ ID NO:20, or SEQ ID NO:21108. The kit of claim 106, wherein the siRNA comprises the sequence of SEQ ID NO: 17.

109. The kit of claim 98, further comprising an ADRB1 agonist.

110. The kit of claim 109, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, Etilefrine, Racepinephrine, Arbutamine, Droxidopa, Formoterol, Salbutamol, Terbutaline, Metaproterenol, Procaterol, or a combination thereof111. The kit of claim 110, wherein said ADRB1 agonist is Xamoterol, Isoproterenol, Denopamine, Dobutamine, CL-316243, or a combination thereof.

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