Compositions and methods for treating obesity

Abstract

Provided herein are compounds, compositions, uses, and methods for reducing obesity in a subject, or for preventing or treating obesity. In certain embodiments, methods are provided for reducing obesity in a subject and / or for preventing or treating obesity in a subject in need thereof, which can include the step of treatment with a GDP-binding form of Rab1a (Rab1aGDP), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof.

Description

Technical Field

[0001] The present invention generally relates to the treatment of obesity. More specifically, the present invention relates to compositions and methods for enhancing microautophagy to treat obesity and related diseases or conditions. Background Art

[0002] In eukaryotes, there are three known cellular processes by which cytoplasmic contents and / or subcellular organelles can be delivered to or acquired by lysosomes for degradation: macroautophagy (often referred to as autophagy), microautophagy, and chaperone-mediated autophagy. Microautophagy, unlike macroautophagy or chaperone-mediated autophagy, is an autophagic process mediated by the piecemeal engulfment of cytoplasmic targets or cargo (such as proteins, lipids, glycogen, or pathogens) by direct lysosomes (in mammals) or vacuoles (in plants and fungi).

[0003] Microautophagy may promote cytoplasmic protein degradation through multivesicular bodies (MVBs) in late endosomes. In addition, microautophagy can also support the direct delivery of glycogen to lysosomes and its degradation. In this regard, it is considered that (for example) dysfunctional or defective microautophagy may be associated with the development of various metabolic and / or neurological diseases.

[0004] Clearly, the accumulation of specific proteins, lipids, and / or glycogens may be associated with a variety of important diseases, disorders, and conditions. Methods for targeting these proteins, lipids, and / or glycogens are needed.

[0005] Obesity is the leading preventable cause of death worldwide, with an increasing prevalence in adults and children. In fact, the prevalence of obesity has increased significantly over the past few decades and has reached epidemic proportions; more than one-third of adults worldwide are overweight (BMI 25-29.9 kg / m2) or obese (BMI ≥ 30 kg / m2) ( WHO ). Obesity is a complex disease that involves excess body fat that increases the risk of other diseases and health problems, such as heart disease, diabetes, hypertension, and certain cancers (Zhang et al., 2018). Obesity is widely considered to be one of the most serious public health problems of the 21st century because current therapies remain ineffective and mainly focus on suppressing caloric intake. In addition, one of the most effective weight loss drugs, sibutramine, has been withdrawn from the U.S. market due to cardiovascular safety issues. Therefore, in the absence of effective drug treatments, the clinical management of obesity remains a major difficulty. Therefore, anti-obesity drugs that target the molecular and cellular mechanisms associated with obesity are highly desired.

[0006] Alternative, additional and / or improved anti-obesity agents, compositions and / or methods for treating obesity and related diseases or conditions are desired. Summary of the Invention

[0007] As described in detail herein, treatment with microautophagy enhancers comprising a GDP-bound form of Rab1a, such as Rab1a, has been identified as being useful for reducing obesity in obese subjects. S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N GDP-bound form, or another dominant negative (DN) GDP-bound form of Rab1a, or encoding such a Rab1a GDP One or more expressible nucleic acids.

[0008] In one embodiment, provided herein is a method of reducing obesity or preventing or treating obesity in a subject in need thereof, the method comprising:

[0009] The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof to treat the subject;

[0010] This increases the level of Rab1a in the subjects GDP at the cellular level, thereby leading to reduced obesity in the subjects.

[0011] In one embodiment, the obesity is accompanied by at least one of the following conditions: an inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

[0012] In another embodiment, provided herein is a method of reducing body weight in an overweight subject, the method comprising:

[0013] The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof for treating the overweight subject;

[0014] Thereby increasing the Rab1a in the overweight subjects GDP cellular levels, thereby resulting in weight loss in the subject.

[0015] In another embodiment of any one or more of the above methods, the Rab1a GDP May be or may contain Rab1a S25N 、Rab1a N124I、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

[0016] In another embodiment of any one or more of the above methods, the Rab1a GDP May contain the following amino acid sequence:

[0017] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0018] (SEQ ID NO: 6; human Rab1a S25N );

[0019] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0020] (SEQ ID NO: 9; mouse Rab1 N124I );

[0021] human Rab1a D41N or

[0022] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0023] (SEQ ID NO: 18; human Rab1a D47N );

[0024] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0025] In another embodiment of any one or more of the above methods, the Rab1a GDP It can be composed of the following amino acid sequence:

[0026] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0027] (SEQ ID NO: 6; human Rab1a S25N );

[0028] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0029] (SEQ ID NO: 9; mouse Rab1 N124I );

[0030] human Rab1a D41N or

[0031] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0032] (SEQ ID NO: 18; human Rab1a D47N );

[0033] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0034] In another embodiment of any one or more of the above methods, the Rab1a GDP It may comprise or consist of the following amino acid sequence:

[0035] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0036] (SEQ ID NO: 6; human Rab1a S25N );

[0037] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0038] In another embodiment of any one or more of the above methods, the Rab1a GDP It may be in the form of a fusion protein, wherein the Rab1a GDP Fused or otherwise linked directly or indirectly (optionally via a linker) to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby promoting cellular uptake, increasing stability or in vivo half-life, or improving Rab1a GDP another therapeutic, diagnostic or in vivo property of.

[0039] In another embodiment of any one or more of the above methods, the fusion protein may comprise the following amino acid sequence:

[0040] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0041] (SEQ ID NO: 6; human Rab1a S25N );

[0042] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0043] In another embodiment of any one or more of the above methods, the Rab1a GDP It may be in the form of a fusion protein and may comprise the following amino acid sequence:

[0044] MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHL PPGFNEYDFVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTE TTSAILITPEGDDKPGAVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKG YQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILIKAKKGGKSK LMSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0045] (SEQ ID NO: 21);

[0046] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0047] In yet another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may encode Rab1a as defined herein. GDP Any one or more of .

[0048] In yet another embodiment of any one or more of the above methods, the one or more expressible nucleic acids can be DNA-based or RNA-based.

[0049] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids can transiently express the Rab1a in one or more cells of the subject. GDP , or wherein the one or more expressible nucleic acids can be integrated into one or more cell genomes and express the Rab1a in one or more cells of the subject GDP .

[0050] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise a nucleic acid encoding Rab1a GDP and capable of expressing Rab1a in one or more cells of the subject GDP One or more expression vectors, plasmids or mRNA.

[0051] In yet another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0052] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTG GATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0053] (Human Rab1a S25N ORF codon sequence, SEQ ID NO: 5);

[0054] ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGCAGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA

[0055] (Mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or

[0056] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACT TCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTC AAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATC GTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCA ACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0057] (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17);

[0058] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0059] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0060] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0061]

[0062] (SEQ ID NO: 19, MG-008 ORF DNA sequence with a 5' luciferase tag); or

[0063]

[0064] (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag);

[0065] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0066] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0067] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing obesity in a subject in need thereof or for preventing or treating obesity in said subject.

[0068] In another embodiment, provided herein is a use of a GDP-bound form of Rab1a (Rab1aGDP), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof for reducing, preventing, or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

[0069] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof for reducing body weight in an overweight subject.

[0070] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing obesity in a subject in need thereof or for preventing or treating obesity.

[0071] In another embodiment, provided herein is a use of a GDP-bound form of Rab1a (Rab1aGDP), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof, in the manufacture of a medicament for reducing, preventing, or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

[0072] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the manufacture of a medicament for reducing body weight in an overweight subject.

[0073] In another embodiment of any one or more of the above uses, the Rab1a GDP May be or may contain Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

[0074] In another embodiment of any one or more of the above uses, the Rab1a GDP May contain the following amino acid sequence:

[0075] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0076] (SEQ ID NO: 6; human Rab1a S25N );

[0077] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0078] (SEQ ID NO: 9; mouse Rab1 N124I );

[0079] human Rab1a D41N or

[0080] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGV NFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0081] (SEQ ID NO: 18; human Rab1a D47N );

[0082] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0083] In another embodiment of any one or more of the above uses, the Rab1a GDP It can be composed of the following amino acid sequence:

[0084] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0085] (SEQ ID NO: 6; Human Rab1a S25N );

[0086] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0087] (SEQ ID NO: 9; Mouse Rab1 N124I );

[0088] Human Rab1a D41N amino acid sequence; or

[0089] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0090] (SEQ ID NO: 18; Human Rab1a D47N );

[0091] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0092] In another embodiment of any one or more of the above uses, the Rab1a GDP It may comprise or consist of the following amino acid sequence:

[0093] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0094] (SEQ ID NO: 6; human Rab1a S25N );

[0095] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0096] In another embodiment of any one or more of the above uses, the Rab1a GDP It may be in the form of a fusion protein, wherein the Rab1a GDP Fused or otherwise linked directly or indirectly (optionally via a linker) to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby promoting cellular uptake, increasing stability or in vivo half-life, or improving Rab1a GDP another therapeutic, diagnostic or in vivo property of.

[0097] In another embodiment of any one or more of the above uses, the fusion protein may comprise the following amino acid sequence:

[0098] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0099] (SEQ ID NO: 6; human Rab1a S25N );

[0100] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0101] In another embodiment of any one or more of the above uses, the Rab1a GDP It may be in the form of a fusion protein and may comprise the following amino acid sequence:

[0102] MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGFNEYDFVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPGAVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILIKAKKGGKSKLMSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0103] (SEQ ID NO: 21);

[0104] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and preferentially binding GDP.

[0105] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may encode one or more Rab1a as defined herein. GDP .

[0106] In yet another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may be DNA-based or RNA-based.

[0107] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids can transiently express the Rab1a in one or more cells of the subject. GDP , or wherein the one or more expressible nucleic acids can be integrated into the genome of one or more cells of the subject and express the Rab1a in one or more cells of the subject GDP .

[0108] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise a nucleic acid encoding Rab1a GDP and capable of expressing Rab1a in one or more cells of the subject GDP One or more expression vectors, plasmids or mRNA.

[0109] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0110] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0111] (Human Rab1a S25N ORF codon sequence, SEQ ID NO: 5);

[0112] ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGCAGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGA CAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA

[0113] (Mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or

[0114] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAA CTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAA CAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTG CTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0115] (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17);

[0116] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0117] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0118] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0119]

[0120] (SEQ ID NO: 19, MG-008 ORF DNA sequence with a 5' luciferase tag); or

[0121]

[0122] (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag);

[0123] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0124] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0125] In another embodiment, provided herein is a polypeptide comprising the following amino acid sequence:

[0126] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0127] (SEQ ID NO: 6; human Rab1a S25N );

[0128] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0129] (SEQ ID NO: 9; mouse Rab1 N124I );

[0130] human Rab1a D41N or

[0131] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0132] (SEQ ID NO: 18; human Rab1a D47N );

[0133] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP;

[0134] The polypeptide is used for reducing obesity in a subject in need thereof, or for preventing or treating obesity; or for reducing body weight in an overweight subject.

[0135] In one embodiment, the above polypeptides are used to reduce obesity in a subject in need thereof, or to prevent or treat obesity, wherein the obesity is accompanied by at least one of the following conditions: an inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

[0136] In another embodiment, provided herein is a pharmaceutical composition comprising:

[0137] GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or combinations thereof; and

[0138] Another anti-obesity agent.

[0139] In yet another embodiment, provided herein is a kit comprising any one or more of the following:

[0140] GDP-bound form of Rab1a GDP );

[0141] One or more genes encoding Rab1a GDP expressible nucleic acid;

[0142] anti-obesity agents;

[0143] Instructions for performing any one or more of the methods described herein; or

[0144] Any combination thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] These and other features will be further understood with reference to the following figures, in which Rab1a encoded by mRNA GDP Treatment of obese mice:

[0146] Figure 1 shows weight loss in MG008-treated obese mice determined 12 days after injection as described in Example 1;

[0147] Figure 2 Certain amino acid and nucleic acid sequences as described herein are shown.

[0148] Figure 3 Shown is the timeline of mice treated with F11 and the corresponding points at which data were collected.

[0149] Figure 4 Shown are the baseline fat and lean body mass of diet-induced obese (DIO) mice before F11 treatment as assessed by NMR analysis. Figure 4 A shows the correlation between total fat and body weight. Figure 4 B shows the correlation between total lean body mass and body weight. Figure 4 C shows the correlation between total fat and total lean body mass. Figure 4 D shows the correlation between total fat percentage and body weight. Figure 4 E shows the correlation between percent total lean body mass and body weight. Figure 4 F shows the correlation between total fat percentage and total lean body mass percentage.

[0150] Figure 5 Shown are the fat and lean body mass of diet-induced obese (DIO) mice after 3 days of F11 treatment as determined by NMR analysis. Figure 5 A shows the correlation between total fat and body weight. Figure 5 B shows the correlation between total lean body mass and body weight. Figure 5 C shows the correlation between total fat and total lean body mass. Figure 5 D shows the correlation between total fat percentage and body weight. Figure 5E shows the correlation between percent total lean body mass and body weight. Figure 5 F shows the correlation between total fat percentage and total lean body mass percentage.

[0151] Figure 6 Shown are the fat and lean body mass of diet-induced obese (DIO) mice after 17 days of F11 treatment as determined by NMR analysis. Figure 6 A shows the correlation between total fat and body weight. Figure 6 B shows the correlation between total lean body mass and body weight. Figure 6 C shows the correlation between total fat and total lean body mass. Figure 6 D shows the correlation between total fat percentage and body weight. Figure 6 E shows the correlation between percent total lean body mass and body weight. Figure 6 F shows the correlation between total fat percentage and total lean body mass percentage.

[0152] Figure 7 Shown are changes in body weight, fat mass, and lean mass values ​​of diet-induced obese (DIO) mice after 3 days of F11 treatment as evaluated by NMR analyzer. Figure 7 A shows the body weight changes of DIO mice after 3 days of F11 treatment. Figure 7 B shows the changes in total fat in DIO mice after 3 days of F11 treatment. Figure 7 C shows the change in total lean body mass of DIO mice after 3 days of F11 treatment. The change was calculated by the following formula: change (g) = value 3 days after intravenous injection (g) - baseline (before intravenous injection) value (g).

[0153] Figure 8 Shown are changes in body weight, fat mass, and lean body mass values ​​of diet-induced obese (DIO) mice after 17 days of F11 treatment as evaluated by NMR analyzer. Figure 8 A shows the body weight changes of DIO mice after 17 days of F11 treatment. Figure 8 B shows the changes in total fat in DIO mice after 17 days of F11 treatment. Figure 8 C shows the change in total lean body mass of DIO mice after 17 days of F11 treatment. The change value was calculated by the following formula: change value (g) = value 17 days after intravenous injection (g) - baseline (before intravenous injection) value (g).

[0154] Figure 9 Shown are multiple logistic regression analyses of F11 efficacy in diet-induced obese (DIO) mice after 3 days of F11 treatment. Figure 9 A shows multiple logistic regression analysis of F11 efficacy versus body weight change in DIO mice after 3 days of F11 treatment. Figure 9B shows multiple logistic regression analysis of F11 efficacy relative to changes in fat mass in DIO mice after 3 days of F11 treatment. Figure 9 C shows multiple logistic regression analysis of F11 efficacy relative to changes in lean body mass in DIO mice after 3 days of F11 treatment.

[0155] Figure 10 Shown are multiple logistic regression analyses of F11 efficacy in diet-induced obese (DIO) mice after 17 days of F11 treatment. Figure 10 A shows multiple logistic regression analysis of F11 efficacy versus body weight change in DIO mice after 17 days of F11 treatment. Figure 10 B shows multiple logistic regression analysis of F11 efficacy relative to changes in fat mass in DIO mice after 17 days of F11 treatment. Figure 10 C shows multiple logistic regression analysis of F11 efficacy relative to changes in lean body mass in DIO mice after 17 days of F11 treatment.

[0156] Figure 11 Shown are changes in body weight (A) and percentage body weight (B) of diet-induced obese (DOI) mice before and after F11 treatment. DETAILED DESCRIPTION

[0157] Described herein are compounds, compositions, uses and methods for reducing obesity in a subject and / or for preventing or treating obesity in a subject in need thereof. It will be understood that the embodiments and examples are provided for purposes of illustration to those skilled in the art, and that these embodiments and examples are not intended to be limiting in any way.

[0158] Obesity is a complex disease whose causes are often multifactorial. Indeed, several factors, such as diet, physical activity, automation, urbanization, genetic predisposition, medications, psychiatric disorders, economic policies, endocrine disorders, and exposure to endocrine-disrupting chemicals, may contribute to obesity in individuals. One of the hallmarks of obesity is the accumulation of dysfunctional adipose tissue when energy intake exceeds energy expenditure. This triggers metabolic stress by increasing inflammation and levels of fatty acids, triglycerides, and LDL cholesterol, leading to a range of interrelated complications, including insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

[0159] Autophagy is a major intracellular degradation system whose degradation capacity comes from lysosomes. It is a homeostatic and evolutionarily conserved mechanism of autodigestion by which cells degrade and recycle long-lived proteins and excess or damaged organelles to adapt to adverse microenvironmental conditions, including limited nutrient supply (Allyson et al., Cleaning House: Selective Autophagy of Organelles. (2017) Developmental Cell 41, 10–22). Some sensors that interact with the autophagy machinery have evolved to detect fluctuations in key metabolic parameters. In fact, since lysosomal processing of intracellular macromolecules always leads to their breakdown into essential metabolic intermediates, including amino acids, glucose, nucleotides and free fatty acids (FA), autophagy is a key coordinator of energy stress responses at both tissue-specific and systemic levels (Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330: 1344-1348; Galluzzi L, Pietrocola F, Levine B, Kroemer G (2014) Metabolic control of autophagy. Cell 159: 1263-1276). Therefore, autophagy completes tissue-intrinsic metabolic tasks in major organs involved in maintaining the body's energy balance, including adipose tissue, liver and exocrine pancreas. Therefore, insufficient autophagy is associated with metabolic syndrome, which is characterized by at least three of the following five medical conditions: abdominal obesity, hypertension, hyperglycemia, high serum triglycerides and low serum high-density lipoprotein (HDL).

[0160] Autophagy is a highly regulated process by which misfolded proteins and organelles are transported to lysosomes for degradation (Kim & Lee, 2014). There are three different types of autophagy: macroautophagy (often referred to as autophagy), chaperone-mediated autophagy, and microautophagy. In chaperone-mediated autophagy and microautophagy, lysosomal degradation of substrates occurs directly within lysosomes (Parzych & Klionsky, 2014).

[0161] Global and tissue-specific deletions and / or mutations of certain autophagy genes or autophagy-regulating molecules lead to altered lipid metabolism, hepatic lipidosis, and obesity or diabetic phenotypes in animal models (Kim & Lee, 2014; Lee et al., 2016). More specifically, genetic ablation or loss of function of some autophagy-related genes, including Atg7 (Lim et al., 2014), Atg4b (Fernandez et al., 2017), Becn2 (He et al., 2013), and Tfeb (Settembre et al., 2013), at the systemic level or in a tissue-restricted manner, predisposes these animals to metabolic disorders under normal and high-fat diets. Furthermore, obesity is associated with elevated plasma levels of autophagy inhibitors, including DBI / ACBP, in humans and mice (Bravo-San Pedro et al., 2019; Joseph et al., 2020). These findings support a role for autophagy in the development of obesity (obesogenesis) and obesity-related complications (Zhang et al., 2018).

[0162] Autophagy is regulated by multiple signaling molecules, particularly the mechanistic target of rapamycin (mTOR) kinase and the autophagy-related protein (ATG) family. Food intake transiently increases plasma levels of branched-chain amino acids (BCAAs), including leucine, subsequently activating mTOR signaling, thereby inhibiting autophagy (Nicklin et al., 2009; Broer & Broer, 2017). mTOR activation due to increased growth factor and insulin signaling and / or increased BCAA consumption is common in human obesity and experimental models and is considered a major driver of nutritionally induced autophagy inhibition (Shimobayashi & Hall, 2016; Meijer et al., 2015). Conversely, autophagy is able to maintain normal amino acid levels during short-term fasting. Similarly, elevated blood glucose levels activate insulin-like growth factor 1 (IGF1) signaling, leading to AKT1-dependent activation of mTOR by inhibiting TSC2-RHEB signaling. Interestingly, both glucose and amino acids share a similar mechanism of activating mTORC1 in a RAG-dependent manner. In addition, autophagy also controls glucose and energy metabolism by regulating gluconeogenesis (Kim & Lee, 2014).

[0163] Elevated lipid levels are common in obesity and can inhibit autophagy by interrupting the fusion of autophagolysosomes, lysosomal acidification, and hydrolase activity (Wang, 2016). In fact, elevated lipid levels inhibit autophagosome-lysosome fusion (Koga et al., 2010). Autophagy can regulate lipid homeostasis by selective degradation of lipid droplets via lipophagy and the utilization of lipids as energy (Nguyen & Olzmann, 2017). In contrast, there is evidence for the role of adipose autophagy in regulating adipose tissue development, adipogenesis, and lipid metabolism (Tao et al., 2016). In addition, it has been shown that adipose lysosomal dysfunction contributes to autophagosome accumulation and early adipose pathology in obesity (Mizunoe et al., 2017). In addition, insufficient autophagy may promote the transition from obesity to diabetes, thereby highlighting the therapeutic potential of autophagy regulators in preventing and treating diabetes and obesity (Lim et al., 2014).

[0164] The specialized functions of autophagy in metabolic regulation include adipocyte differentiation, accumulation of fat deposits in the liver, maintenance of pancreatic β-cell adaptability, regulation of food intake and inflammatory responses mediated by the central nervous system (CNS), and other processes (Klionsky et al., Autophagy in major human diseases. (2021) EMBO 40: e108863-e108863). In addition, it has been shown that the regulation of autophagy in the central nervous system contributes to weight regulation. More specifically, it has been shown that autophagy inhibition in neuronal subtypes that produce proopiomelanocortin (POMC) promotes the development of obesity by stimulating excessive food intake (Quan et al., 2012).

[0165] Reactive oxygen species (ROS) play a key role in obesity (Lavallard et al., 2012). Excessive ROS production promotes the release of cytochrome c from mitochondria into the cytoplasm, contributing to the development and progression of insulin resistance and diabetes in obesity (Houstis et al., 2006; Petersen et al., 2004). Unfortunately, ROS are an inevitable byproduct of bioenergetics and are primarily produced in mitochondria during the ATP synthesis process (known as oxidative phosphorylation).

[0166] In this regard, the present inventors recognized that, in addition to inhibiting caloric intake, autophagy-lysosome-mediated catabolic processes, particularly microautophagy, can be used to develop effective obesity treatment strategies.

[0167] Stimulating microautophagy (which may involve fragmentary engulfment of target membranes in certain embodiments) by promoting lysosomes to move to the target membrane may be particularly desirable for treating a variety of diseases and / or disorders and / or conditions. Specific intracellular lysosomal localization may be related to different types of lysosomal activity. In addition, lysosomal localization may be related to the activity of mTOR and may regulate autophagic flux. During macroautophagy, mTORC1 may be inactive, and lysosomes may accumulate in the perinuclear region of the cell, which may perform macroautophagy by stimulating the fusion of the wrapped target membrane with the lysosome. On the contrary, during microautophagy, the fragmentary engulfment of the target membrane by lysosomes may occur by lysosome movement and direct interaction with the target membrane, without the need to form autophagosomes. Lysosomes can move in a bidirectional manner along microtubules, and this lysosomal movement is controlled by different motor protein groups raised by different mechanisms.

[0168] In certain embodiments, microautophagy can involve direct engulfment of cytoplasmic cargo at the boundary membrane by autophagic tubes, which can mediate both invagination and vesicle separation into the lysosomal lumen (see Li, W.-W., Li, J. & Bao, J.-K. Microautophagy: lesser-known self-eating. Cell. Mol. Life Sci. 69, 1125–1136 (2011). For example, for DNA, direct lysosomal degradation of target substrates may occur (referred to as fragmentary autophagy—see Fujiwara, Y. et al., Direct uptake and degradation of DNA by lysosomes.—PubMed—NCBI. Autophagy 9, 1167–1171 (2014)). In addition, lysosomes may be able to move to different organelles and / or membrane substrates (e.g., plasma membrane, mitochondria) and may interact directly with them through the recruitment of motor proteins and SNARE proteins (see Andrews, NW Lysosomes and the plasma membrane. J. Cell Biol. 158, 389–394 (2002); Hofmann, I. & Munro, S. An N-terminally acetylated Arf-like GTPase is localized to lysosomes and affects their motility. J. Cell. Sci. 119, 1494–1503 (2006); Fraldi, A. et al. Lysosomal fusion and SNARE function are impaired by cholesterol accumulation in lysosomal storage disorders. The EMBO Journal 29, 3607–3620 (2010); and Pankiv, S. et al. FYCO1 is a Rab7 effector that binds to LC3and PI3P to mediate microtubule plus end–directed vesicle transport. J. Cell Biol. 188, 253–269 (2010)).Lysosome movement to the periphery of the cell and its positioning in the cell may be related to signal transduction (see R. & Bonifacino, JSLlysosome Positioning Influences mTORC2and AKTSignaling.Molecular Cell 75, 26–38.e3 (2019)). In this regard, it is considered that mTORC1, mTORC2 and AKT activation may be important for the peripheral distribution of lysosomes (see Poüs, C. & Codogno, P.Lysosome positioning coordinates mTORC1activity and autophagy.Nature Cell Biology 13, 342–344 (2011); and Cabukusta, B. & Neefjes, J.Mechanisms of lysosomal positioning and movement.Traffic 19, 761–769 (2018)).

[0169] In certain embodiments, microautophagy and / or piecemeal degradation of target substrates and / or membranes can involve movement of lysosomes in the cytosol to the periphery and target membranes (e.g., direct interaction with the target membrane) (see Pu, J., Guardia, CM, Keren-Kaplan, T. & Bonifacino, JS Mechanisms and functions of lysosome positioning. J. Cell. Sci. 129, 4329–4339 (2016); and Katherine R Parzych, DJK An Overview of Autophagy: Morphology, Mechanism, and Regulation. Antioxid. Redox Signal. 20, 460–473 (2014)). In certain embodiments, the movement of lysosomes (from the perinuclear region of the cell) to the cell periphery and the interaction with target membranes / substrates (e.g., glycogen, lipids, proteins) in the cell periphery may be associated with the activation of mTORC1 / mTORC2 (see Rabanal-Ruiz, Y. & Korolchuk, VImTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome. Int J Mol Sci 19, 818 (2018); Jia, R. & Bonifacino, JS Lysosome Positioning Influences mTORC2 and AKTSignaling. Molecular Cell 75, 26–38. e3 (2019)).

[0170] Without wishing to be bound by theory, it is thought that Rab1a DN (a dominant negative form of Rab1a) can stimulate the extracellular distribution of lysosomes (from the perinuclear region) by activating mTORC1 / mTORC2 proteins within the cell without requiring external (or extracellular) signals to activate them (to support extracellular distribution).

[0171] Rab1a GDP or Rab1a GTP Use in reducing obesity:

[0172] As described in detail herein, a GDP-bound form of Rab1a has been identified, such as Rab1a S25N 、Rab1a N124I (mouse Rab1 sequence), Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a or encoding the Rab1aGDP Treatment with one or more expressible nucleic acids that are microautophagy enhancers can be used to reduce obesity in animal models.

[0173] As will be appreciated, in certain embodiments, the methods described herein may be in vitro methods, in vivo methods, or both.

[0174] In one embodiment, provided herein is a method of reducing obesity in a subject in need thereof, the method comprising:

[0175] The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof to treat the subject;

[0176] This increases the level of Rab1a in the subjects GDP at the cellular level, thereby resulting in reduced obesity in the subject.

[0177] In one embodiment of the above method, the obesity is accompanied by at least one of the following conditions: increased inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

[0178] In another embodiment, provided herein is a method of reducing body weight in an overweight subject, the method comprising:

[0179] The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof for treating the overweight subject;

[0180] Thereby increasing the Rab1a in the overweight subjects GDP at the cellular level, leading to weight loss.

[0181] In another embodiment of any one or more of the above methods, the Rab1a GDP May be or may contain Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

[0182] In another embodiment of any one or more of the above methods, the Rab1a GDP May contain the following amino acid sequence:

[0183] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0184] (SEQ ID NO: 6; human Rab1a S25N );

[0185] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0186] (SEQ ID NO: 9; mouse Rab1 N124I );

[0187] human Rab1a D41N or

[0188] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0189] (SEQ ID NO: 18; human Rab1a D47N );

[0190] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0191] In another embodiment of any one or more of the above methods, the Rab1a GDP It can be composed of the following amino acid sequence:

[0192] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0193] (SEQ ID NO: 6; human Rab1a S25N );

[0194] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0195] (SEQ ID NO: 9; mouse Rab1 N124I );

[0196] human Rab1a D41N or

[0197] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0198] (SEQ ID NO: 18; human Rab1a D47N );

[0199] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0200] In another embodiment of any one or more of the above methods, the Rab1a GDP It may comprise or consist of the following amino acid sequence:

[0201] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0202] (SEQ ID NO: 6; human Rab1a S25N );

[0203] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0204] In another embodiment of any one or more of the above methods, the Rab1a GDPIt may be in the form of a fusion protein, wherein the Rab1a GDP Fused or otherwise linked directly or indirectly (optionally via a linker) to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby promoting cellular uptake, increasing stability or in vivo half-life, or improving Rab1a GDP In embodiments not intended to be limiting in any way, the fusion protein can comprise any protein or tag, for example, GFP, YFP, mCherry, a luciferase-specific antibody, an aptamer for identification or delivery to a specific organ, and the like.

[0205] In another embodiment of any one or more of the above methods, the fusion protein may comprise the following amino acid sequence:

[0206] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVK IQSTPVKQSGGGCC

[0207] (SEQ ID NO: 6; human Rab1a S25N );

[0208] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0209] In another embodiment of any one or more of the above methods, the Rab1a GDP It may be in the form of a fusion protein and may comprise the following amino acid sequence:

[0210] MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGFNEYDFVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPGAVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILIKAKKGGKSKLMSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0211] (SEQ ID NO: 21);

[0212] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and preferentially binding GDP.

[0213] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may encode Rab1a as defined herein. GDP Any one or more of .

[0214] In yet another embodiment of any one or more of the above methods, the one or more expressible nucleic acids can be DNA-based or RNA-based.

[0215] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids can transiently express the Rab1a in one or more cells of the subject. GDP , or wherein the one or more expressible nucleic acids can be integrated into one or more cell genomes and express the Rab1a in one or more cells of the subject GDP .

[0216] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise a nucleic acid encoding Rab1a GDP and capable of expressing Rab1a in one or more cells of the subject GDP One or more expression vectors, plasmids or mRNA.

[0217] In yet another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0218] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0219] (Human Rab1a S25N ORF codon sequence, SEQ ID NO: 5);

[0220] ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGC AGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA

[0221] (Mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or

[0222] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAA CTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAA CAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTG CTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0223] (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17);

[0224] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0225] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0226] In another embodiment of any one or more of the above methods, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0227]

[0228] (SEQ ID NO: 19, MG-008 ORF DNA sequence with a 5' luciferase tag); or

[0229]

[0230] (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag);

[0231] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0232] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0233] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing obesity in a subject in need thereof or for preventing or treating obesity in said subject.

[0234] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing, preventing or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

[0235] In another embodiment, provided herein is the use of a GDP-bound form of Rab1a (Rab1aGDP), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof for reducing body weight in an overweight subject.

[0236] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing obesity in a subject in need thereof or for preventing or treating obesity.

[0237] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1aGDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing, preventing or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

[0238] In another embodiment, provided herein is a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing body weight in an overweight subject or for preventing or treating excess weight.

[0239] In another embodiment of any one or more of the above uses, the Rab1a GDP May be or may contain Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

[0240] In another embodiment of any one or more of the above uses, the Rab1a GDP May contain the following amino acid sequence:

[0241] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0242] (SEQ ID NO: 6; human Rab1a S25N );

[0243] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0244] (SEQ ID NO: 9; mouse Rab1 N124I );

[0245] human Rab1a D41N or

[0246] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0247] (SEQ ID NO: 18; human Rab1a D47N );

[0248] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0249] In another embodiment of any one or more of the above uses, the Rab1a GDP It can be composed of the following amino acid sequence:

[0250] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVK IQSTPVKQSGGGCC

[0251] (SEQ ID NO: 6; Human Rab1a S25N )

[0252] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0253] (SEQ ID NO: 9; Mouse Rab1 N124I )

[0254] Human Rab1a D41N amino acid sequence; or

[0255] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0256] (SEQ ID NO: 18; Human Rab1a D47N )

[0257] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

[0258] In another embodiment of any one or more of the above uses, the Rab1a GDP It may comprise or consist of the following amino acid sequence:

[0259] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0260] (SEQ ID NO: 6; human Rab1a S25N );

[0261] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0262] In another embodiment of any one or more of the above uses, the Rab1a GDP It may be in the form of a fusion protein, wherein the Rab1a GDP Fused or otherwise linked directly or indirectly (optionally via a linker) to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby promoting cellular uptake, increasing stability or in vivo half-life, or improving Rab1a GDP another therapeutic, diagnostic or in vivo property of.

[0263] In another embodiment of any one or more of the above uses, the fusion protein may comprise the following amino acid sequence:

[0264] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0265] (SEQ ID NO: 6; human Rab1a S25N );

[0266] Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

[0267] In another embodiment of any one or more of the above uses, the Rab1a GDP It may be in the form of a fusion protein and may comprise the following amino acid sequence:

[0268] MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGFNEYDFVPESFDRDKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPGAVGKVVPFFEAKVVDLDTGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREI LIKAKKGGKSKLMSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0269] (SEQ ID NO: 21);

[0270] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and preferentially binding to GDP.

[0271] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may encode one or more Rab1a as defined herein. GDP .

[0272] In yet another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may be DNA-based or RNA-based.

[0273] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids can transiently express the Rab1a in one or more cells. GDP , or wherein the one or more expressible nucleic acids can be integrated into one or more cell genomes and express the Rab1a in one or more cells GDP .

[0274] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise a nucleic acid encoding Rab1a GDP and capable of expressing Rab1a within the one or more cells GDP One or more expression vectors, plasmids or mRNA.

[0275] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0276] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGA AATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0277] (Human Rab1a S25N ORF codon sequence, SEQ ID NO: 5);

[0278] ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGCAGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA

[0279] (Mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or

[0280] ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCAC CTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAAT TTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA

[0281] (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17);

[0282] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0283] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0284] In another embodiment of any one or more of the above uses, the one or more expressible nucleic acids may comprise the following nucleic acid sequence:

[0285]

[0286] (SEQ ID NO: 19, MG-008 ORF DNA sequence with a 5' luciferase tag); or

[0287]

[0288] (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag);

[0289] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of

[0290] Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

[0291] In another embodiment, provided herein is a polypeptide comprising the following amino acid sequence:

[0292] MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0293] (SEQ ID NO: 6; human Rab1a S25N );

[0294] MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0295] (SEQ ID NO: 9; mouse Rab1 N124I );

[0296] human Rab1a D41N or

[0297] MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC

[0298] (SEQ ID NO: 18; human Rab1a D47N );

[0299] or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP;

[0300] The polypeptide is used for reducing obesity in a subject in need thereof, or for preventing or treating obesity; or for reducing body weight in an overweight subject.

[0301] In another embodiment of the above-mentioned polypeptide used, the obesity is accompanied by at least one of the following conditions: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

[0302] In another embodiment, provided herein is a pharmaceutical composition comprising:

[0303] GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or combinations thereof; and

[0304] Another anti-obesity agent.

[0305] In yet another embodiment, provided herein is a kit comprising any one or more of the following:

[0306] GDP-bound form of Rab1a GDP );

[0307] One or more genes encoding Rab1a GDP expressible nucleic acid;

[0308] anti-obesity agents;

[0309] Instructions for performing any one or more of the methods described herein; or

[0310] Any combination thereof.

[0311] As will be appreciated, in certain embodiments of any of the methods, uses or polypeptides for use as described herein, the obesity may be accompanied by: increased inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

[0312] As will be understood, lysosomal-mediated microautophagy can refer to a cellular process in which cellular lipid or protein or glycogen substrates, or portions thereof, are engulfed and degraded by lysosomes. In this particular aspect, lysosomal-mediated microautophagy is an integral part of cellular bioenergetics (i.e., ATP generation) as well as biosynthetic processes (i.e., synthesis of new biomass by recycling existing "old" materials).

[0313] It will also be understood that reference to increasing lysosomal-mediated microautophagy can refer to an increase in the rate, extent, capacity or efficacy of the lysosomal-mediated microautophagic process in a cell compared to the cell's baseline level, or compared to corresponding treated or untreated control cells, or compared to levels in a reference diseased cell or a reference cell with accumulation of protein, lipid or glycogen substrates.

[0314] It will also be understood that improving the microautophagy of lysosomal mediation can include recovering or improving lysosomal motility or lysosomal bidirectional motility in the cell, and / or can include enhancing, improving, activating or recovering or rescuing the lysosomal motility activity in the cell in addition. This recovery or rescue can result in the raising of autophagy (such as, for example, microautophagy and / or macroautophagy) and / or lysosomal degradation capacity. As described in detail herein, there are several diseases, conditions and cell states in which cell lysosomal motility may be impaired, reduced, blocked or suppressed. Because the microautophagy of lysosomal mediation can relate to lysosomal motility and " fusion and leaving (kiss-and-run) " event, therefore microautophagy enhancing agent can recover or improve the lysosomal motility in the cell. Lysosomal motility can play an important role in some cellular functions, including the microautophagy of lysosomal mediation, the macroautophagy of lysosomal mediation, lysosome regeneration and lysosomal maturation process. Mention that restore lysosomal motility and / or lysosomal bidirectional motility can refer to regulating the level of cell lysosomal motility / bidirectional motility back to the level of corresponding normal or healthy control cells with lysosomal motility / bidirectional motility baseline level.In certain embodiments, this regulation can also regulate the level of degradation capacity (i.e., phagocytosis) back to the level of normal or healthy cells.

[0315] It will be understood that the lysosomal binding-dissociation event between a lysosome and a lipid or protein or glycogen substrate can refer to a lysosome that is combined with a lipid or protein or glycogen substrate (i.e., (for example) lipid droplets or protein aggregates), obtains at least a portion of a lipid or protein or glycogen substrate, and then dissociates from the lipid or protein or glycogen substrate. The lysosomal binding-dissociation (i.e., "binding (on)" and "dissociating (off)") event between a lysosome and a lipid or protein or glycogen substrate can be considered to be a "fusion and leaving" type event. As part of the binding (or "fusion") event, at least a small piece of substrate (i.e., lipid) can be "grabbed" or engulfed (i.e., (for example) cytoplasmic lipid droplets or CLD) by a lysosome from the substrate. In the case of lipid droplet substrates, this can be achieved by forming a fusion pore between a lysosome and the CLD. As part of the dissociation (or "leaving") event, the dissociation (i.e., CLD) of a lysosome and substrate can occur. An increase in lysosomal association-dissociation events can refer to an increase in the rate, extent, or efficacy of lysosomal association-dissociation events in a cell compared to the baseline level of a corresponding treated or untreated control cell, e.g., the same cell under the same conditions but without treatment with a microautophagy modulator or with a compound or composition known not to affect this process.

[0316] It will be appreciated that in certain embodiments, microautophagy enhancers can be used to correct microautophagy defects in cells, or cellular conditions in which microautophagy is reduced.

[0317] By considering the teachings herein, those skilled in the art will understand that a microautophagy enhancer can be any suitable agent that increases or promotes the rate, activity, extent or efficacy of lysosomal-mediated microautophagy in a cell, or increases lysosomal motility or bidirectional motility. In one embodiment, a suitable microautophagy enhancer can be or comprise a GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or combinations thereof.

[0318] The Ras-related protein Rab-1A (Rab1a) is encoded by the RAB1A gene in humans. It controls the trafficking of vesicles from the endoplasmic reticulum (ER) to the Golgi compartment and the cell surface and plays a crucial role in the secretion of IL-8 and growth hormone. Furthermore, in its GTP-bound form, it plays a role in macroautophagy and autophagosome assembly in cellular defense responses against pathogens. It also regulates the motility of endocytic compartments.

[0319] As described in detail herein, it has been identified that lysosomal-mediated microautophagy of target proteins, lipids, or glycogen substrates can be enhanced in cells by treatment with a microautophagy enhancer comprising a GDP-bound form of Rab1a, such as Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

[0320] It will be understood that the specific amino acid or nucleic acid sequence of a particular gene may vary between species. For example, the human Rab1a amino acid sequence may have homologs in other species that have sequence variations from the human sequence. In some embodiments, although homologous sequences may vary between species, the general effect (e.g., phenotypic effect) of the homologous sequence may be substantially similar to the effect of the wild-type sequence in a given cell or subject.

[0321] In a specific embodiment, the microautophagy enhancer can be or comprise the GDP-bound form of Rab1a (Rab1a GDP ), such as Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N or its functional equivalent, or another dominant negative (DN) GDP-bound form of Rab1a. The sequences of human / or mouse Rab1aWT and certain GDP-bound forms thereof are as follows: Figure 2Suitable GDP-bound forms of Rab1a may include any suitable Rab1a variant that is "dominant negative" or that binds GDP preferentially over GTP. Such Rab1a may be identified using techniques known in the art. GDP variants (see, e.g., Chan, C.-C. et al., Systematic Discovery of Rab GTPases with Synaptic Functions in Drosophila. Current Biology 21, 1704-1715 (2011); Tabancay, A.P. et al., Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278, 39921-39930 (2003); and Dumas, J.J., Zhu, Z., Connolly, J.L. & Lambright, D.G. Structural basis of activation and GTP hydrolysis in Rab proteins. Structure 7, 413-s2 (1999), each of which is incorporated herein by reference in its entirety).

[0322] Figure 2 Certain sequences of nucleic acids and amino acids / proteins as described herein are shown. Figure 2 SEQ ID NOs: 1-3 provide human Rab1a, respectively. WT DNA gene sequence, ORF codon sequence and amino acid sequence; SEQ ID NO: 4-6 provide human Rab1a S25N DNA gene sequence, ORF codon sequence and amino acid sequence; SEQ ID NO: 7-9 provide mouse Rab1 N124I DNA gene sequence, ORF codon sequence and amino acid sequence; SEQ ID NO: 10-12 provide human Rab1a Q70L DNA gene sequence, ORF codon sequence and amino acid sequence; SEQ ID NO: 13-15 provide human Rab1a Q63L DNA gene sequence, ORF codon sequence and amino acid sequence; SEQ ID NO: 16-18 provide human Rab1a D47NDNA gene sequence, ORF codon sequence, and amino acid sequence; and SEQ ID NOs: 19-21 provide the MG-008 ORF DNA sequence with a 5' luciferase tag, the MG-008 ORF mRNA sequence with a 5' luciferase tag, and the MG-008 protein sequence with an N-terminal luciferase tag, respectively (for further discussion of SEQ ID NOs: 19-21, see Example 1). Human Rab1a D41N The sequence can be found in https: / / www.addgene.org / 49581 / (This sequence is incorporated herein by reference in its entirety) and is commercially available. In certain embodiments, provided herein are nucleic acids or amino acids comprising any of these sequences. In certain embodiments, provided herein are nucleic acids or amino acids comprising any of these sequences (i.e., comprising any of SEQ ID NOs: 1-21 or Rab1a D41N or an active fragment thereof) of a nucleic acid sequence or amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity.

[0323] Rab1a S25N 、Rab1a D41N 、Rab1a D47N and Rab1a N124I Suitable functional equivalents may include, for example, Rab1a WT or Rab1a S25N or Rab1a N124I or Rab1a D41N or Rab1a D47N having at least 80% (or >85%, or >90%, or >95%, or >99%) sequence identity and preferentially binds GDP over GTP, while also retaining Rab1a as described in detail herein S25N or Rab1a N124I or Rab1a D41N or Rab1a D47N In other embodiments, it will be understood that the microautophagy enhancer can be or comprise one or more Rab1a encoding variants or mutants. GDP An expressible nucleic acid, such as encoding / expressing the GDP-bound form of Rab1a (Rab1a GDP ) any suitable nucleic acid / expression vector (i.e., vector, cassette, mRNA, modified mRNA, plasmid), such as, for example, Rab1a S25N or Rab1a N124I or Rab1a D41Nor Rab1a D47N or its functional equivalent.

[0324] As will be appreciated, sequences are described herein primarily with reference to human and / or mouse homologues. It will be appreciated that functionally equivalent forms and / or variants may exist in a variety of different species, such as different mammals. GDP (DN) or Rab1a GTP Specific sequence modifications and / or mutants of the (DA) forms are generally provided with position and modification / mutation information (e.g., S25N, D41N, D47N, N124I; Q70L, Q67L, Q63L) which, for convenience, are referenced to human and / or mouse homologs / sequences; however, it will be understood that equivalent DN and / or DA forms can be achieved in homologous sequences from other species and / or other sequences related to the human and / or mouse sequences provided herein, although the position and / or nature of the modification / mutation may vary somewhat depending on the particular sequence of interest. For example, Rab1 N124I is a drug / mutation of the mouse sequence. By way of another example, Rab1 Q67L It is a modification / mutation of the mouse sequence and there is no Q at position 67 of human Rab1a; in contrast, there is a Q at position 63 of the human sequence, so the modification / mutation relative to the human sequence is Rab1a Q63L .

[0325] Those skilled in the art will appreciate that the microautophagy-inhibiting agent may be or comprise the GTP-bound form of Rab1a (Rab1a GTP ), one or more encoding Rab1a GTP expressible nucleic acid, Rab1a wild type (Rab1a WT ) or one or more encoding Rab1a WT In certain embodiments, Rab1a GTP Can be or contain Rab1a Q70L 、Rab1a Q67L (in mouse sequence), Rab1a Q63L (in the human Rab1a sequence) or a functional equivalent thereof, or another dominantly active (DA) GTP-bound form of Rab1a. The GTP-bound form of Rab1a may include any Rab1a variant that is "dominantly active" or binds GTP preferentially to GDP. These Rab1a can be identified using techniques known in the art. GTPVariants (see, e.g., Chan, C.-C. et al. Systematic Discovery of Rab GTPases with Synaptic Functions in Drosophila. Current Biology 21, 1704-1715 (2011); Tabancay, A.P. et al., Identification of dominant negative mutants of Rheb GTPase and their use to implicate the involvement of human Rheb in the activation of p70S6K. J. Biol. Chem. 278, 39921-39930 (2003); and Dumas, J.J., Zhu, Z., Connolly, J.L. & Lambright, D.G. Structural basis of activation and GTP hydrolysis in Rab proteins. Structure 7, 413-s2 (1999), each of which is incorporated herein by reference in its entirety), such as for identifying Rab1a Q70L and / or Rab1a Q67L and / or Rab1a Q63L Those.

[0326] It will be appreciated that in certain embodiments, microautophagy enhancers, such as Rab1a GDP Treatment may include, for example, the addition of Rab1a GDP Protein is introduced into cells to express Rab1a in cells GDP , or both.

[0327] It will be understood that the expression of a specific protein in the cell can refer to the production of the polypeptide from the nucleic acid sequence encoding the polypeptide. Gene expression can include both transcription and translation processes, so gene expression can refer to nucleic acid sequences, such as the generation (i.e. transcription) of mRNA, the generation (i.e. translation) of protein, or both. It will also be understood that the overexpression of a specific gene in a cell can refer to the increase in the expression of a specific gene in the cell compared to wild type, baseline, or untreated levels. Any of some methods known in the art can be used to realize the overexpression of a mutant gene or the introduction into a cell. For example, a vector (virus, plasmid or other vector) or its mRNA or chemically modified form comprising one or more copies of a specific gene can be introduced into a cell by transfection, electroporation, viral infection, or another suitable method known in the art, and each copy of the specific gene is driven by a suitable promoter sequence (e.g., constitutive or inducible promoter). Expression vector technologies suitable for making specific genes overexpressed or introducing them into cells are known in the art (see, e.g., Molecular Cloning:A Laboratory Manual (4th edition), 2012, Cold Spring Harbor Laboratory Press). The skilled artisan will recognize, upon consideration of the teachings herein, that the protein encoding a particular protein, such as Rab1a GDP A variety of expressible nucleic acids can be prepared for introduction into cells (e.g., transiently or long-term by integration into the genome) to provide for expression of a protein of interest.

[0328] It will be appreciated that compounds and / or compositions comprising or consisting of one or more nucleic acids and / or proteins as described herein can be used. The compositions may further comprise one or more pharmaceutically acceptable diluents, carriers, excipients, or buffers. The compositions can be used to administer one or more nucleic acids and / or proteins to cells in vitro or in vivo.

[0329] In the context of inserting a nucleic acid sequence into a cell, introduction of a gene may refer to "transfection," "transformation," or "transduction," and may include incorporating or introducing a nucleic acid sequence into a eukaryotic cell, wherein the nucleic acid sequence may optionally be incorporated into the genome of the cell, or transiently expressed (e.g., transfected mRNA). A protein or enzyme may be introduced into a cell by delivering the protein or enzyme itself into the cell, or by expressing mRNA encoding the protein or enzyme within the cell, thereby resulting in its translation.

[0330] As will be known to those skilled in the art, expressible nucleic acids for expressing specific genes may encode or include features as described in "Genes VII", Lewin, B. Oxford University Press (2000) or "Molecular Cloning: A Laboratory Manual", Sambrook et al., Cold Spring Harbor Laboratory, 3rd edition (2001). The nucleotide sequence encoding the polypeptide or protein can be introduced into a suitable vector, such as a commercially available vector. Standard molecular biology techniques can also be used to construct or modify the vector separately, as listed in, for example, Sambrook et al. (Cold Spring Harbor Laboratory, 3rd edition (2001)). Those skilled in the art will recognize that a vector may include nucleotide sequences encoding the desired elements that can be operably linked to the nucleotide sequence encoding the polypeptide or protein. These nucleotide sequences encoding the desired elements may include transcription promoters, transcription enhancers, transcription terminators, translation initiators, translation terminators, ribosome binding sites, 5'-untranslated regions, 3'-untranslated regions, cap structures, polyadenylic acid tails, and / or replication origins. The choice of an appropriate vector can be based on factors including, but not limited to, the size of the nucleic acid to be introduced into the vector, the type of transcriptional and translational control elements desired, the level of expression desired, the copy number desired, whether chromosomal integration is desired, the type of selection process desired, or the host cell or range of hosts intended to be transformed.

[0331] Those skilled in the art will appreciate that the biomolecules and / or compounds described herein can be provided in a pharmaceutical composition with a pharmaceutically acceptable diluent, carrier, or excipient, and / or provided with one or more separate active agents or drugs as part of a pharmaceutical combination or pharmaceutical composition. In certain embodiments, the biomolecules, compounds, and / or pharmaceutical compositions can be administered simultaneously, sequentially, or in combination with other drugs or pharmaceutical compositions in a therapeutic regimen, either alone or as a combined formulation or combination.

[0332] As described herein, the biomolecules, compounds and / or compositions may include one or more pharmaceutically acceptable excipients, diluents and / or carriers. Pharmaceutically acceptable carriers, diluents or excipients may include any suitable carrier, diluent or excipient known to those skilled in the art. Examples of pharmaceutically acceptable excipients may include, but are not limited to, cellulose derivatives, sucrose and starch. Those skilled in the art will recognize that pharmaceutically acceptable excipients may include suitable fillers, binders, lubricants, buffers, glidants and disintegrants known in the art (see, e.g., Remington: The Science and Practice of Pharmacy (2006)). Examples of pharmaceutically acceptable carriers, diluents and excipients can be found in, for example, Remington's Pharmaceutical Sciences (2000-20th Edition) and the United States Pharmacopeia: The National Formulary (USP 24NF19), published in 1999.

[0333] It will also be understood that one or more conservative amino acid replacements are possible. As will be appreciated, conservative amino acid replacements can include replacements of one amino acid with another amino acid of similar properties, such that the folding, activity, or other functionality of the protein is not significantly affected. Examples of aromatic amino acids that can be replaced can include phenylalanine, tryptophan, and tyrosine. Examples of interchangeable hydrophobic amino acids that can be replaced can include leucine, isoleucine, methionine, and valine. Examples of interchangeable polar amino acids that can be replaced can include glutamine and asparagine. Examples of interchangeable basic amino acids that can be replaced can include arginine, lysine, and histidine. Examples of interchangeable acidic amino acids that can be replaced can include aspartic acid and glutamic acid. Finally, examples of interchangeable small amino acids that can be replaced can include alanine, serine, threonine, cysteine, and glycine.

[0334] As described in detail herein, dominant negative (DN) Rab1a (e.g., GDP-bound Rab1a, Rab1a GDP ) can be used to enhance microautophagy, which can provide for the degradation of cellular targets of interest, such as disease-related proteins, glycogen, or lipids. As will be appreciated, any suitable Rab1a DN or Rab1a GDPA variety of Rab1a DN proteins are known to those skilled in the art in view of the teachings herein. In certain embodiments, for example, any suitable dominant negative form of Rab1a in general (i.e., constant / locked Rab1a in its GDP form) can be used to promote lysosome movement toward the cytosol and cell periphery (from the perinuclear region of the cell) and stimulate direct interaction of lysosomes with target substrates.

[0335] In certain embodiments, it is contemplated that expression of Rab1a DN (GDP form) can stimulate the activation of mTORC1 / mTORC2 and AKT based on their effects on lysosomal localization and promotion of lysosome movement to the periphery and to target substrates (see also Jia, R. & Bonifacino, JSLysosome Positioning Influences mTORC2 and AKT Signaling. Molecular Cell 75, 26–38. e3 (2019)).

[0336] It is contemplated herein that various genetic modifications of Rab1a that lock the protein in its constant GDP-bound state can be used to promote direct lysosomal interactions and fragmented engulfment of various target substrates (e.g., one or more protein, lipid, and / or glycogen targets). The constant GDP-bound form (DN) of Rab1a is generally unavailable under normal physiological conditions, where the native protein Rab1a continuously switches between its GTP and GDP forms. It is contemplated that in certain embodiments, genetic mutations and / or amino acid substitutions / modifications can be used to lock the GTPase in its GDP-bound form (or constant GTP form) and prevent it from entering its GTP state (or GDP state). It is contemplated that in certain embodiments, any suitable modification that substantially maintains the integrity of the GDP form / state of the GTPase (which can affect signal transduction and lysosomal migration to the periphery / cytosol) can promote microautophagy and degradation of target substrates through fragmented engulfment of lysosomes.

[0337] In certain embodiments, Rab1a GDP Administration can generally be performed to a particular cell type or subject in need thereof in any suitable manner, which can be selected to suit the particular cell type, subject, and / or indication. GDPNucleic acid sequence is applied to subject or introduced into cell type by any suitable transfection or nucleic acid delivery method, as those skilled in the art will know by considering the teaching content herein.In some embodiments, delivery can be based on DNA or RNA transfection (for example, using conventional transfection agent, such as lipofectamine (Invitrogen), FuGENE (Rosche), using DNA adenovirus (gene therapy) or using modified RNA (i.e. stable RNA) to be delivered to health (for example, using virus or microvesicle, exosome or nuclear outer granule (ectosome))).In some embodiments, protein can be administered or delivered to the cell that it is needed, optionally with any suitable technology or delivery vehicle auxiliary to help protein delivery to one or more cells.

[0338] In one embodiment of the present invention, F11 can be administered to obese or overweight subjects to reduce the subject's weight. F11 is a lipid nanoparticle encapsulating Rab1, which is commercially available from Precision NanoSystems (#50 655W Kent Ave N, Vancouver, BC V6P 6T7). F11 can be administered intravenously, orally, subcutaneously, intramuscularly, sublingually, or by any other route known to those skilled in the art. F11 can be administered in a dose of 0.001-1 mg / kg (mpk), but other doses may be beneficial depending on the subject. F11 treatment can be performed in single or multiple doses. If F11 is administered repeatedly, individual treatments can be separated by hours, days, weeks, months, or years, which is necessary to establish, maintain, or re-establish weight loss. Administration of F11 can reduce the subject's weight and / or fat content, and / or can positively affect HbA1c, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (CRE), or other blood chemistry measurements. F11 treatment may also improve other physical health indicators, including, but not limited to, high blood pressure, high blood sugar, elevated cholesterol levels, inflammation, high serum triglycerides, high resting heart rate, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, sleep apnea and / or elevated markers of cancer development.

[0339] In one embodiment of the present invention, Rab1 encapsulated in lipid nanoparticles can be in the form of a fusion protein, wherein Rab1 is fused or otherwise directly or indirectly linked (optionally through a linker) to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide portion for targeted delivery, thereby promoting the cellular uptake of Rab1, increasing the stability or in vivo half-life of Rab1, or improving another therapeutic, diagnostic or in vivo property of Rab1.

[0340] Example 1: Rab1a DN (GDP form) reduces the body weight of obese mice

[0341] Six-week-old female C57BL / 6 mice (n=10) were fed a high-fat diet for 10 months to generate a diet-induced obesity (DIO) mouse model. The mice were divided into two groups, one group (n=5) was intravenously administered with Rab1a DN In this example, Rab1a DN Also known as MG-008, it is encoded by mRNA and encapsulated with ANM formulation. A control group (n=5) was injected with PBS. Mice continued to be fed HFD for another 18 days, and dietary intake and body weight were recorded every 2-3 days. Figure 1 The left side (red bars) shows the weight loss of mice on day 12 after injection of MG008 (single dose), and the right side (black bars) shows the weight of control mice on day 12. Weight loss in MG008-treated mice was evident throughout the 18 days after MG008 treatment, with the earliest significant weight loss recorded as early as day 4 after MG008 injection (data not shown).

[0342] Example 2: Encapsulated Rab1 lipid nanoparticles (F11) reduce body weight in obese mice

[0343] Male C57BL / 6 mice of about 6 weeks old were fed a high-fat diet (HFD) until their body weight reached at least 40 g (40-50 g). Mice were weighed at the beginning of the HFD and their body weight was monitored weekly. Appropriate weight gain was usually achieved at about 18-26 weeks of age, at which time body composition was determined using NMR, and fatty degeneration was determined using Vevo LAZR-X. Mice were then treated with F11 by intravenous administration. F11 was administered at 0.00625, 0.0125, 0.025, 0.05, or 0.5 mg / kg (mpk). NMR body composition measurements were then performed 1, 3, 5, and 7 weeks after F11 treatment. LAZR-X fatty degeneration measurements were performed at 4 and 7 weeks after F11 treatment. In addition, blood (200 μL) was taken from the submandibular area at 7 weeks after F11 treatment to determine HbA1c levels. Eight weeks after F11 administration, mice were sacrificed and the following measurements were performed: (1) body weight, liver weight, and epididymal fat weight were measured; (2) blood was collected to measure alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine (CRE), and cytokines; (3) images of the liver and epididymal fat were taken; (4) optical coherence tomography (OCT) was performed on the liver; and (5) mice were perfused and tissues were processed for immunohistochemistry and H&E staining.

[0344] The results of these experiments showed that body weight was positively correlated with total fat mass, but not lean mass, at baseline, 3 days after F11 treatment, and 7 days after F11 treatment ( Figure 4-6 , Panels A and B). In addition, at the same 3 time points, the percentage of total fat mass was negatively correlated with the percentage of total lean body mass ( Figure 4-6 , Panel F). Consistent results from baseline, day 3 after intravenous administration of F11, and day 17 after intravenous administration of F11 indicate that F11 proportionally alters fat and lean mass within the same mouse ( Figure 4-6 , Plate F). The changes in lean body mass after 3 days of F11 treatment basically determined the total body weight changes at all F11 doses ( Figure 7 A and 7C). F11 administered at 0.05-0.5 mpk reduced body weight by reducing fat or lean body mass after 3 days of F11 treatment ( Figure 7 The most significant effect on body weight was observed when F11 was administered at 0.5 mpk, as it resulted in a significant decrease in both fat and lean body mass ( Figure 7 Lower doses of F11 (0.025-0.05 mpk) did not significantly alter fat mass, whereas even lower levels of F11 (≤0.0125) appeared to induce fat accumulation ( Figure 7 B).

[0345] After 17 days of F11 treatment, the total body weight changes for all F11 doses were essentially determined by changing the fat content of the mice by continuously feeding them a 60% HFD ( Figure 8 A and 8B). Consistent with the results of 3-day treatment with F11, only 0.5 mpk of F11 treatment was effective in reducing body weight, fat content, and lean body mass content ( Figure 8 Compared to baseline (before intravenous administration of F11), doses of F11 below 0.5 mpk were ineffective in reducing fat mass ( Figure 8 ).

[0346] Figure 9 and 10 The effect of F11 on body weight change (R 2 =0.7278) and fat changes (R 2 =0.7023) was compared with the standard curve of efficacy. Using multiple logistic regression analysis, the effect of F11 on body weight change (R 2 =0.9821) and fat changes (R 2 =0.9639) of the significant standard curve ( Figure 9 A and 9B). Multiple regression analysis indicated that after 3 days of treatment, 0.32 mpk and 0.4 mpk might be the optimal F11 doses for reducing fat and body weight, respectively.

[0347] One or more illustrative embodiments have been described by way of example. It will be apparent to those skilled in the art that changes and modifications may be made without departing from the scope of the invention as defined in the claims.

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[0398] WO2017 / 008141–Lysosomal Degradation of Lipids and Proteins and Method of Use Thereof

[0399] All references cited herein and throughout the specification are incorporated by reference in their entirety.

Claims

1. A method for reducing obesity or preventing or treating obesity in a subject in need thereof, the method comprising: The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof to treat the subject; Thereby increasing the Rab1a in the subject GDP at the cellular level, thereby resulting in reduced obesity in the subject.

2. The method according to claim 1, wherein The obesity is associated with at least one of the following conditions: an inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

3. A method for reducing body weight in an overweight subject, the method comprising: The GDP-bound form of Rab1a (Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or a combination thereof for treating the overweight subject; Thereby increasing the Rab1a in the overweight subjects GDP cellular levels, thereby resulting in weight loss in the subject.

4. The method according to any one of claims 1 to 3, wherein Rab1a GDP Is or contains Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

5. The method according to any one of claims 1 to 4, wherein Rab1a GDP Contains the amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 9; mouse Rab1 N124I ); human Rab1a D41N or MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 18; human Rab1a D47N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

6. The method according to any one of claims 1 to 5, wherein Rab1a GDP It consists of the following amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 9; mouse Rab1 N124I ); human Rab1a D41N or MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 18; human Rab1a D47N ); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and preferentially binding GDP 7. The method according to any one of claims 1 to 5, wherein Rab1a GDP Comprising or consisting of the following amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

8. The method according to any one of claims 1 to 5, wherein Rab1a GDP In the form of a fusion protein, wherein the Rab1a GDP Fusion or direct or indirect linkage, optionally via a linker, to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby facilitating cellular uptake, increasing stability or in vivo half-life, or improving another therapeutic, diagnostic, or Rab1a GDP in vivo properties.

9. The method according to claim 8, wherein The fusion protein comprises the following amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

10. The method according to claim 8 or 9, wherein: Rab1a GDP It is in the form of a fusion protein and comprises the amino acid sequence: MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGFNEYDFVPESFDR DKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPGAVGKVVPFFEAKVVDLD TGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILIKAKKGGKSKLMSSMNPEYDYLFKLLL IGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 21); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

11. The method according to any one of claims 1 to 3, wherein: The one or more expressible nucleic acids encode one or more Rab1a as defined in any one of claims 4 to 10. GDP .

12. The method according to claim 11, wherein: The one or more expressible nucleic acids are DNA-based or RNA-based.

13. The method according to claim 11 or 12, wherein: The one or more expressible nucleic acids transiently express the Rab1a in one or more cells of the subject. GDP , or among them, The one or more expressible nucleic acids are integrated into the genome of one or more cells and express the Rab1a in the one or more cells of the subject. GDP .

14. The method according to any one of claims 1 to 3 or 10, wherein The one or more expressible nucleic acids comprise a nucleic acid encoding the Rab1a GDP and capable of expressing the Rab1a in the one or more cells of the subject GDP One or more expression vectors, plasmids or mRNA.

15. The method according to claim 14, wherein The one or more expressible nucleic acids may comprise the following nucleic acid sequence: ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (human Rab1a S25N ORF codon sequence, SEQ ID NO: 5); ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGCAGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA (mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAA CTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAA CAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTG CTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

16. The method according to claim 14, wherein The one or more expressible nucleic acids may comprise the following nucleic acid sequence: ATGGAAGACGCCAAAAACATAAAGAAAGGCCCGGCGCCATTCTATCCGCTAGAGGATGGAACCGCTGGAGAGCAACTGCATAAGGCTATGAAGAGATACGCCCTGGTTCCTGGAACAATTGCTTTTACAGATGCACATATCGAGGTGAACATCACGTACGCGGAATACTTCGAAATGTCCGTTCGGTTGGCAGAAGCTATGAAACGATATGGGCTGAATACAAATCACAGAATCGTCGTATGCAGTGAAAACTCTCTTCAATTCTTTATGCCGGTGTTGGGCGCGTTATTTATCGGAGTTGCAGTTGCGCCCGCGAACGACATTTATAATGAACGTGAATTGCTCAACAGTATGAACATTTCGCAGCCTACCGTAGTGTTTGTTTCCAAAAAGGGGTTGCAAAAAATTTTGAACGTGCAAAAAAAATTACCAATAATCCAGAAAATTATTATCATGGATTCTAAAACGGATTACCAGGGATTTCAGTCGATGTACACGTTCGTCACATCTCATCTACCTCCCGGTTTTAATGAATACGATTTTGTACCAGAGTCCTTTGATCGTGACAAAACAATTGCACTGATAATGAACTCCTCTGGATCTACTGGGTTACCTAAGGGTGTGGCCCTTCCGCATAGAACTGCCTGCGTCAGATTCTCGCATGCCAGAGATCCTATTTTTGGCAATCAAATCATTCCGGATACTGCGATTTTAAGTGTTGTTCCATTCCATCACGGTTTTGGAATGTTTACTACACTCGGATATTTGATATGTGGATTTCGAGTCGTCTTAATGTATAGATTTGAAGAAGAGCTGTTTTTACGATCCCTTCAGGATTACAAAATTCAAAGTGCGTTGCTAGTACCAACCCTATTTTCATTCTTCGCCAAAAGCACTCTGATTGACAAATACGATTTATCTAATTTACACGAAATTGCTTCTGGGGGCGCACCTCTTTCGAAAGAAGTCGGGGAAGCGGTTGCAAAACGCTTCCATCTTCCAGGGATACGACAAGGATATGGGCTCACTGAGACTACATCAGCTATTCTGATTACACCCGAGGGGGATGATAAACCGGGCGCGGTCGGTAAAGTTGTTCCATTTTTTGAAGCGAAGGTTGTGGATCTGGATACCGGGAAAACGCTGGGCGTTAATCAGAGAGGCGAATTATGTGTCAGAGGACCTATGATTATGTCCGGTTATGTAAACAATCCGGAAGCGACCAACGCCTTGATTGACAAGGATGGATGGCTACATTCTGGAGACATAGCTTACTGGGACGAAGACGAACACTTCTTCATAGTTGACCGCTTGAAGTCTTTAATTAAATACAAAGGATACCAGGTGGCCCCCGCTGAATTGGAGTCGATATTGTTACAACACCCCAACATCTTCGACGCGGGCGTGGCAGGTCTTCCCGACGATGACGCCGGTGAACTTCCCGCCGCCGTTGTTGTTTTGGAGCACGGAAAGACGATGACGGAAAAAGAGATCGTGGATTACGTCGCCAGTCAAGTAACAACCGCCAAAAAGTTGCGCGGAGGAGTTGTGTTTGTGGACGAAGTACCGAAAGGTCTTACCGGAAAACTCGACGCAAGAAAAATCAGAGAGATCCTCATAAAGGCCAAGAAGGGCGGAAAGTCCAAATTGATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (SEQ ID NO: 19, MG-008 ORF DNA sequence with 5' luciferase tag); or AUGGAAGACGCCAAAAACAUAAAGAAAGGCCCGGCGCCAUUCUAUCCGCUAGAGGAUGGAACCGCUGGAGAGCAACUGCAUAAGGCUAUGAAGAGAUACGCCCUGGUUCCUGGAACAAUUGCUUUUACAGAUGCACAUAUCGAGGUGAACAUCACGUACGCGGAAUACUUCGAAAUGUCCGUUCGGUUGGCAGAAGCUAUGAAACGAUAUGGGCUGAAUACAAAUCACAGAAUCGUCGUAUGCAGUGAAAACUCUCUUCAAUUCUUUAUGCCGGUGUUGGGCGCGUUAUUUAUCGGAGUUGCAGUUGCGCCCGCGAACGACAUUUAUAAUGAACGUGAAUUGCUCAACAGUAUGAACAUUUCGCAGCCUACCGUAGUGUUUGUUUCCAAAAAGGGGUUGCAAAAAAUUUUGAACGUGCAAAAAAAAUUACCAAUAAUCCAGAAAAUUAUUAUCAUGGAUUCUAAAACGGAUUACCAGGGAUUUCAGUCGAUGUACACGUUCGUCACAUCUCAUCUACCUCCCGGUUUUAAUGAAUACGAUUUUGUACCAGAGUCCUUUGAUCGUGACAAAACAAUUGCACUGAUAAUGAACUCCUCUGGAUCUACUGGGUUACCUAAGGGUGUGGCCCUUCCGCAUAGAACUGCCUGCGUCAGAUUCUCGCAUGCCAGAGAUCCUAUUUUUGGCAAUCAAAUCAUUCCGGAUACUGCGAUUUUAAGUGUUGUUCCAUUCCAUCACGGUUUUGGAAUGUUUACUACACUCGGAUAUUUGAUAUGUGGAUUUCGAGUCGUCUUAAUGUAUAGAUUUGAAGAAGAGCUGUUUUUACGAUCCCUUCAGGAUUACAAAAUUCAAAGUGCGUUGCUAGUACCAACCCUAUUUUCAUUCUUCGCCAAAAGCACUCUGAUUGACAAAUACGAUUUAUCUAAUUUACACGAAAUUGCUUCUGGGGGCGCACCUCUUUCGAAAGAAGUCGGGGAAGCGGUUGCAAAACGCUUCCAUCUUCCAGGGAUACGACAAGGAUAUGGGCUCACUGAGACUACAUCAGCUAUUCUGAUUACACCCGAGGGGGAUGAUAAACCGGGCGCGGUCGGUAAAGUUGUUCCAUUUUUUGAAGCGAAGGUUGUGGAUCUGGAUACCGGGAAAACGCUGGGCGUUAAUCAGAGAGGCGAAUUAUGUGUCAGAGGACCUAUGAUUAUGUCCGGUUAUGUAAACAAUCCGGAAGCGACCAACGCCUUGAUUGACAAGGAUGGAUGGCUACAUUCUGGAGACAUAGCUUACUGGGACGAAGACGAACACUUCUUCAUAGUUGACCGCUUGAAGUCUUUAAUUAAAUACAAAGGAUACCAGGUGGCCCCCGCUGAAUUGGAGUCGAUAUUGUUACAACACCCCAACAUCUUCGACGCGGGCGUGGCAGGUCUUCCCGACGAUGACGCCGGUGAACUUCCCGCCGCCGUUGUUGUUUUGGAGCACGGAAAGACGAUGACGGAAAAAGAGAUCGUGGAUUACGUCGCCAGUCAAGUAACAACCGCCAAAAAGUUGCGCGGAGGAGUUGUGUUUGUGGACGAAGUACCGAAAGGUCUUACCGGAAAACUCGACGCAAGAAAAAUCAGAGAGAUCCUCAUAAAGGCCAAGAAGGGCGGAAAGUCCAAAUUGAUGUCCAGCAUGAAUCCCGAAUAUGAUUAUUUAUUCAAGUUACUUCUGAUUGGCGACUCAGGGGUUGGAAAGAAUUGCCUUCUUCUUAGGUUUGCAGAUGAUACAUAUACAGAAAGCUACAUCAGCACAAUUGGUGUGGAUUUCAAAAUAAGAACUAUAGAGUUAGACGGGAAAACAAUCAAGCUUCAAAUAUGGGACACAGCAGGCCAGGAAAGAUUUCGAACAAUCACCUCCAGUUAUUACAGAGGAGCCCAUGGCAUCAUAGUUGUGUAUGAUGUGACAGAUCAGGAGUCCUUCAAUAAUGUUAAACAGUGGCUGCAGGAAAUAGAUCGUUAUGCCAGUGAAAAUGUCAACAAAUUGUUGGUAGGGAACAAAUGUGAUCUGACCACAAAGAAAGUAGUAGACUACACAACAGCGAAGGAAUUUGCUGAUUCCCUUGGAAUUCCGUUUUUGGAAACCAGUGCUAAGAAUGCAACGAAUGUAGAACAGUCUUUCAUGACGAUGGCAGCUGAGAUUAAAAAGCGAAUGGGUCCCGGAGCAACAGCUGGUGGUGCUGAGAAGUCCAAUGUUAAAAUUCAGAGCACUCCAGUCAAGCAGUCAGGUGGAGGUUGCUGCUAA (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

17. GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing obesity or preventing or treating obesity in a subject in need thereof.

18. GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing, preventing or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

19. GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof for reducing body weight in a subject.

20. GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing obesity or for preventing or treating obesity in a subject in need thereof.

21. GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP Use of an expressible nucleic acid or a combination thereof in the production of a medicament for reducing, preventing or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

22. Use of a GDP-bound form of Rab1a (Rab1aGDP), one or more expressible nucleic acids encoding Rab1aGDP, or a combination thereof in the manufacture of a medicament for reducing body weight in an overweight subject.

23. The use according to any one of claims 17 to 22, wherein Rab1a GDP Is or contains Rab1a S25N 、Rab1a N124I 、Rab1a D41N 、Rab1a D47N , or another dominant negative (DN) GDP-bound form of Rab1a.

24. The use according to any one of claims 17 to 23, wherein Rab1a GDP Contains the amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 9; mouse Rab1 N124I ); human Rab1a D41N or MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 18; human Rab1a D47N ); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of these sequences and preferentially binding GDP 25. The use according to any one of claims 17 to 24, wherein Rab1a GDP It consists of the following amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 9; mouse Rab1 N124I ); human Rab1a D41N or MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 18; human Rab1a D47N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP.

26. The use according to any one of claims 17 to 24, wherein Rab1a GDP Comprising or consisting of the following amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

27. The use according to any one of claims 17 to 24, wherein Rab1a GDP In the form of a fusion protein, wherein the Rab1a GDP Fusion or direct or indirect linkage, optionally via a linker, to a signal peptide or targeting peptide, a fluorescent peptide or other marker or tracer, or another peptide or non-peptide moiety for targeted delivery, thereby facilitating cellular uptake, increasing stability or in vivo half-life, or improving another therapeutic, diagnostic, or Rab1a GDP in vivo properties.

28. The use according to claim 27, wherein The fusion protein comprises the amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

29. The use according to claim 27 or 28, wherein Rab1a GDP It is in the form of a fusion protein and comprises the amino acid sequence: MEDAKNIKKGPAPFYPLEDGTAGEQLHKAMKRYALVPGTIAFTDAHIEVNITYAEYFEMSVRLAEAMKRYGLNTNHRIVVCSENSLQFFMPVLGALFIGVAVAPANDIYNERELLNSMNISQPTVVFVSKKGLQKILNVQKKLPIIQKIIIMDSKTDYQGFQSMYTFVTSHLPPGFNEYDFVPESFDR DKTIALIMNSSGSTGLPKGVALPHRTACVRFSHARDPIFGNQIIPDTAILSVVPFHHGFGMFTTLGYLICGFRVVLMYRFEEELFLRSLQDYKIQSALLVPTLFSFFAKSTLIDKYDLSNLHEIASGGAPLSKEVGEAVAKRFHLPGIRQGYGLTETTSAILITPEGDDKPGAVGKVVPFFEAKVVDLD TGKTLGVNQRGELCVRGPMIMSGYVNNPEATNALIDKDGWLHSGDIAYWDEDEHFFIVDRLKSLIKYKGYQVAPAELESILLQHPNIFDAGVAGLPDDDAGELPAAVVVLEHGKTMTEKEIVDYVASQVTTAKKLRGGVVFVDEVPKGLTGKLDARKIREILIKAKKGGKSKLMSSMNPEYDYLFKLLL IGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 21); Or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and which preferentially binds GDP.

30. The use according to any one of claims 17 to 22, wherein The one or more expressible nucleic acids encode one or more Rab1a as defined in any one of claims 23 to 29. GDP .

31. The use according to claim 30, wherein The one or more expressible nucleic acids are DNA-based or RNA-based.

32. The use according to claim 30 or 31, wherein The one or more expressible nucleic acids transiently express the Rab1a in one or more cells of the subject. GDP , or among them, The one or more expressible nucleic acids are integrated into the genome of one or more cells and express the Rab1a in the one or more cells of the subject. GDP .

33. The use according to any one of claims 17 to 22 or 30, wherein The one or more expressible nucleic acids comprise a nucleic acid encoding the Rab1a GDP and capable of expressing the Rab1a in the one or more cells of the subject GDP One or more expression vectors, plasmids or mRNA.

34. The use according to claim 33, wherein The one or more expressible nucleic acids comprise the following nucleic acid sequence: ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (human Rab1a S25N ORF codon sequence, SEQ ID NO: 5); ATGGGGGACTACAAGGACGACGATGACAAGGGGGGTAGCGGTGGATCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGATTCTGGGGTTGGAAAGTCCTGCCTTCTCCTTAGGTTTGCAGATGATACGTATACGGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAGATACGAACTATAGAGTTAGATGGGAAAACAATCAAGCTACAGATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACTTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAACGTTAAACAGTGGCTGCAGGAGATAGATCGCTACGCCAGTGAAAATGTCAACAAGTTGTTGGTAGGGATCAAATGTGACCTGACCACAAAGAAAGTAGTAGACTACACAACAGCAAAGGAATTTGCAGATTCCCTTGGAATTCCATTTTTGGAAACCAGTGCTAAGAACGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCTGGAGCTACAGCTGGTGGTGCCGAGAAGTCCAATGTTAAAATCCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGCTGCTGCTAA (mouse Rab1a N124I ORF codon sequence, SEQ ID NO: 8); or ATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGTCTTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGAACTTCAAAATAAGAA CTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAA CAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTG CTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (human Rab1a D47N ORF codon sequence, SEQ ID NO: 17); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

35. The use according to claim 33, wherein The one or more expressible nucleic acids comprise the following nucleic acid sequence: ATGGAAGACGCCAAAAACATAAAGAAAGGCCCGGCGCCATTCTATCCGCTAGAGGATGGAACCGCTGGAGAGCAACTGCATAAGGCTATGAAGAGATACGCCCTGGTTCCTGGAACAATTGCTTTTACAGATGCACATATCGAGGTGAACATCACGTACGCGGAATACTTCGAAATGTCCGTTCGGTTGGCAGAAGCTATGAAACGATATGGGCTGAATACAAATCACAGAATCGTCGTATGCAGTGAAAACTCTCTTCAATTCTTTATGCCGGTGTTGGGCGCGTTATTTATCGGAGTTGCAGTTGCGCCCGCGAACGACATTTATAATGAACGTGAATTGCTCAACAGTATGAACATTTCGCAGCCTACCGTAGTGTTTGTTTCCAAAAAGGGGTTGCAAAAAATTTTGAACGTGCAAAAAAAATTACCAATAATCCAGAAAATTATTATCATGGATTCTAAAACGGATTACCAGGGATTTCAGTCGATGTACACGTTCGTCACATCTCATCTACCTCCCGGTTTTAATGAATACGATTTTGTACCAGAGTCCTTTGATCGTGACAAAACAATTGCACTGATAATGAACTCCTCTGGATCTACTGGGTTACCTAAGGGTGTGGCCCTTCCGCATAGAACTGCCTGCGTCAGATTCTCGCATGCCAGAGATCCTATTTTTGGCAATCAAATCATTCCGGATACTGCGATTTTAAGTGTTGTTCCATTCCATCACGGTTTTGGAATGTTTACTACACTCGGATATTTGATATGTGGATTTCGAGTCGTCTTAATGTATAGATTTGAAGAAGAGCTGTTTTTACGATCCCTTCAGGATTACAAAATTCAAAGTGCGTTGCTAGTACCAACCCTATTTTCATTCTTCGCCAAAAGCACTCTGATTGACAAATACGATTTATCTAATTTACACGAAATTGCTTCTGGGGGCGCACCTCTTTCGAAAGAAGTCGGGGAAGCGGTTGCAAAACGCTTCCATCTTCCAGGGATACGACAAGGATATGGGCTCACTGAGACTACATCAGCTATTCTGATTACACCCGAGGGGGATGATAAACCGGGCGCGGTCGGTAAAGTTGTTCCATTTTTTGAAGCGAAGGTTGTGGATCTGGATACCGGGAAAACGCTGGGCGTTAATCAGAGAGGCGAATTATGTGTCAGAGGACCTATGATTATGTCCGGTTATGTAAACAATCCGGAAGCGACCAACGCCTTGATTGACAAGGATGGATGGCTACATTCTGGAGACATAGCTTACTGGGACGAAGACGAACACTTCTTCATAGTTGACCGCTTGAAGTCTTTAATTAAATACAAAGGATACCAGGTGGCCCCCGCTGAATTGGAGTCGATATTGTTACAACACCCCAACATCTTCGACGCGGGCGTGGCAGGTCTTCCCGACGATGACGCCGGTGAACTTCCCGCCGCCGTTGTTGTTTTGGAGCACGGAAAGACGATGACGGAAAAAGAGATCGTGGATTACGTCGCCAGTCAAGTAACAACCGCCAAAAAGTTGCGCGGAGGAGTTGTGTTTGTGGACGAAGTACCGAAAGGTCTTACCGGAAAACTCGACGCAAGAAAAATCAGAGAGATCCTCATAAAGGCCAAGAAGGGCGGAAAGTCCAAATTGATGTCCAGCATGAATCCCGAATATGATTATTTATTCAAGTTACTTCTGATTGGCGACTCAGGGGTTGGAAAGAATTGCCTTCTTCTTAGGTTTGCAGATGATACATATACAGAAAGCTACATCAGCACAATTGGTGTGGATTTCAAAATAAGAACTATAGAGTTAGACGGGAAAACAATCAAGCTTCAAATATGGGACACAGCAGGCCAGGAAAGATTTCGAACAATCACCTCCAGTTATTACAGAGGAGCCCATGGCATCATAGTTGTGTATGATGTGACAGATCAGGAGTCCTTCAATAATGTTAAACAGTGGCTGCAGGAAATAGATCGTTATGCCAGTGAAAATGTCAACAAATTGTTGGTAGGGAACAAATGTGATCTGACCACAAAGAAAGTAGTAGACTACACAACAGCGAAGGAATTTGCTGATTCCCTTGGAATTCCGTTTTTGGAAACCAGTGCTAAGAATGCAACGAATGTAGAACAGTCTTTCATGACGATGGCAGCTGAGATTAAAAAGCGAATGGGTCCCGGAGCAACAGCTGGTGGTGCTGAGAAGTCCAATGTTAAAATTCAGAGCACTCCAGTCAAGCAGTCAGGTGGAGGTTGCTGCTAA (SEQ ID NO: 19, MG-008 ORF DNA sequence with 5' luciferase tag); or AUGGAAGACGCCAAAAACAUAAAGAAAGGCCCGGCGCCAUUCUAUCCGCUAGAGGAUGGAACCGCUGGAGAGCAACUGCAUAAGGCUAUGAAGAGAUACGCCCUGGUUCCUGGAACAAUUGCUUUUACAGAUGCACAUAUCGAGGUGAACAUCACGUACGCGGAAUACUUCGAAAUGUCCGUUCGGUUGGCAGAAGCUAUGAAACGAUAUGGGCUGAAUACAAAUCACAGAAUCGUCGUAUGCAGUGAAAACUCUCUUCAAUUCUUUAUGCCGGUGUUGGGCGCGUUAUUUAUCGGAGUUGCAGUUGCGCCCGCGAACGACAUUUAUAAUGAACGUGAAUUGCUCAACAGUAUGAACAUUUCGCAGCCUACCGUAGUGUUUGUUUCCAAAAAGGGGUUGCAAAAAAUUUUGAACGUGCAAAAAAAAUUACCAAUAAUCCAGAAAAUUAUUAUCAUGGAUUCUAAAACGGAUUACCAGGGAUUUCAGUCGAUGUACACGUUCGUCACAUCUCAUCUACCUCCCGGUUUUAAUGAAUACGAUUUUGUACCAGAGUCCUUUGAUCGUGACAAAACAAUUGCACUGAUAAUGAACUCCUCUGGAUCUACUGGGUUACCUAAGGGUGUGGCCCUUCCGCAUAGAACUGCCUGCGUCAGAUUCUCGCAUGCCAGAGAUCCUAUUUUUGGCAAUCAAAUCAUUCCGGAUACUGCGAUUUUAAGUGUUGUUCCAUUCCAUCACGGUUUUGGAAUGUUUACUACACUCGGAUAUUUGAUAUGUGGAUUUCGAGUCGUCUUAAUGUAUAGAUUUGAAGAAGAGCUGUUUUUACGAUCCCUUCAGGAUUACAAAAUUCAAAGUGCGUUGCUAGUACCAACCCUAUUUUCAUUCUUCGCCAAAAGCACUCUGAUUGACAAAUACGAUUUAUCUAAUUUACACGAAAUUGCUUCUGGGGGCGCACCUCUUUCGAAAGAAGUCGGGGAAGCGGUUGCAAAACGCUUCCAUCUUCCAGGGAUACGACAAGGAUAUGGGCUCACUGAGACUACAUCAGCUAUUCUGAUUACACCCGAGGGGGAUGAUAAACCGGGCGCGGUCGGUAAAGUUGUUCCAUUUUUUGAAGCGAAGGUUGUGGAUCUGGAUACCGGGAAAACGCUGGGCGUUAAUCAGAGAGGCGAAUUAUGUGUCAGAGGACCUAUGAUUAUGUCCGGUUAUGUAAACAAUCCGGAAGCGACCAACGCCUUGAUUGACAAGGAUGGAUGGCUACAUUCUGGAGACAUAGCUUACUGGGACGAAGACGAACACUUCUUCAUAGUUGACCGCUUGAAGUCUUUAAUUAAAUACAAAGGAUACCAGGUGGCCCCCGCUGAAUUGGAGUCGAUAUUGUUACAACACCCCAACAUCUUCGACGCGGGCGUGGCAGGUCUUCCCGACGAUGACGCCGGUGAACUUCCCGCCGCCGUUGUUGUUUUGGAGCACGGAAAGACGAUGACGGAAAAAGAGAUCGUGGAUUACGUCGCCAGUCAAGUAACAACCGCCAAAAAGUUGCGCGGAGGAGUUGUGUUUGUGGACGAAGUACCGAAAGGUCUUACCGGAAAACUCGACGCAAGAAAAAUCAGAGAGAUCCUCAUAAAGGCCAAGAAGGGCGGAAAGUCCAAAUUGAUGUCCAGCAUGAAUCCCGAAUAUGAUUAUUUAUUCAAGUUACUUCUGAUUGGCGACUCAGGGGUUGGAAAGAAUUGCCUUCUUCUUAGGUUUGCAGAUGAUACAUAUACAGAAAGCUACAUCAGCACAAUUGGUGUGGAUUUCAAAAUAAGAACUAUAGAGUUAGACGGGAAAACAAUCAAGCUUCAAAUAUGGGACACAGCAGGCCAGGAAAGAUUUCGAACAAUCACCUCCAGUUAUUACAGAGGAGCCCAUGGCAUCAUAGUUGUGUAUGAUGUGACAGAUCAGGAGUCCUUCAAUAAUGUUAAACAGUGGCUGCAGGAAAUAGAUCGUUAUGCCAGUGAAAAUGUCAACAAAUUGUUGGUAGGGAACAAAUGUGAUCUGACCACAAAGAAAGUAGUAGACUACACAACAGCGAAGGAAUUUGCUGAUUCCCUUGGAAUUCCGUUUUUGGAAACCAGUGCUAAGAAUGCAACGAAUGUAGAACAGUCUUUCAUGACGAUGGCAGCUGAGAUUAAAAAGCGAAUGGGUCCCGGAGCAACAGCUGGUGGUGCUGAGAAGUCCAAUGUUAAAAUUCAGAGCACUCCAGUCAAGCAGUCAGGUGGAGGUUGCUGCUAA (SEQ ID NO: 20, MG-008 ORF mRNA sequence with 5' luciferase tag); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity thereto and encoding a Rab1a that preferentially binds GDP GDP the nucleic acid sequence of Or a nucleic acid sequence that is equivalent to any of the above sequences due to codon redundancy.

36. A polypeptide comprising the amino acid sequence: MSSMNPEYDYLFKLLLIGDSGVGKNCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 6; human Rab1a S25N ); MGDYKDDDDKGGSGGSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTD QESFNNVKQWLQEIDRYASENVNKLLVGIKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 9; mouse Rab1 N124I ); human Rab1a D41N or MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVNFKIRTIELDGKTIKLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNV KQWLQEIDRYASENVNKLLVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGATAGGAEKSNVKIQSTPVKQSGGGCC (SEQ ID NO: 18; human Rab1a D47N ); or a polypeptide having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any of these sequences and which preferentially binds GDP; The polypeptide is used for reducing obesity in a subject in need thereof, or for preventing or treating obesity; or for reducing body weight in an overweight subject.

37. The polypeptide according to claim 36, wherein The obesity is associated with at least one of the following conditions: an inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders, and sleep apnea.

38. A pharmaceutical composition comprising GDP-bound form of Rab1a GDP ), one or more encoding Rab1a GDP expressible nucleic acids or combinations thereof; and Another anti-obesity agent.

39. A kit comprising any one or more of the following: GDP-bound form of Rab1a GDP ); One or more genes encoding Rab1a GDP expressible nucleic acid; anti-obesity agents; Instructions for carrying out the method as defined in any one of claims 1 to 16; or Any combination thereof.

40. Use of Rab1 encapsulated lipid nanoparticles for reducing, treating or preventing obesity in a subject in need thereof.

41. Use of Rab1 encapsulated lipid nanoparticles for reducing body weight in overweight subjects.

42. Use of Rab1 encapsulated lipid nanoparticles in the manufacture of a medicament for reducing, treating or preventing obesity in a subject in need thereof.

43. Use of Rab1 encapsulated lipid nanoparticles in the manufacture of a medicament for reducing body weight in an overweight subject.

44. The use according to any one of claims 40 to 43, wherein The Rab1 encapsulated lipid nanoparticles were used for administration at 0.005-0.5 mg / kg.

45. The use according to claim 44, wherein The Rab1 encapsulated lipid nanoparticles were used for administration at 0.3, 0.4 or 0.5 mg / kg.

46. ​​The use according to claim 44 or 45, wherein The Rab1-encapsulated lipid nanoparticles are intended for administration via intravenous injection.

47. Use of Rab1 encapsulated lipid nanoparticles for reducing, preventing or treating at least one of the following conditions in a subject in need thereof: inflammatory response, increased abdominal obesity, hypertension, hyperglycemia, high serum triglycerides, low serum high-density lipoprotein (HDL), insulin resistance, glucose intolerance, diabetes, hypertension, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), heart failure, atrial fibrillation, musculoskeletal disorders and sleep apnea.

48. A method for reducing obesity in an obese subject or reducing body weight in an overweight subject, the method comprising: 0.005-0.5 mg / kg of Rab1-encapsulated lipid nanoparticles are administered to the subject.

49. A pharmaceutical composition comprising: Rab1-encapsulated lipid nanoparticles and another anti-obesity agent.

50. A kit comprising: Rab1-encapsulated lipid nanoparticles; optionally another anti-obesity agent; and Instructions for carrying out the method defined in claim 48.

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