Cyclopropane Fatty Acid Modulators of Peroxisome Proliferator-Activated Receptors

Abstract

Formula I: A compound or its derivative, or its salt or prodrug, having the structure of TIFF2025524142000026.tif2292, wherein m = 2 and n is an odd number between 4 and 20, and Formula II: Disclosed is a compound or its derivative, or its salt or prodrug, having the structure of TIFF2025524142000027.tif2696, wherein m and n are independently integers between 2 and 20. Also provided are compositions and methods of using the compounds for the therapeutic modulation of peroxisome proliferator-activated receptor (PPAR).

Description

Background Art

[0001] Cyclopropane fatty acids (CpFAs), first discovered in the 1950s, are long-chain lipids containing a cyclopropane ring introduced onto the double bond of a fatty acid by bacteria and certain plants. Some CpFAs, such as lactobacillic acid and dihydrosterculic acid, have been identified in foods (cheese, milk, and fat only from animals given silage), and CpFAs have been detected in human fat, serum, and liver, and they are thought to be stored or metabolized by incomplete β-oxidation. These observations support the idea that gut-derived CpFAs are natural components of human lipids and are stored and released in white adipose tissue, similar to “classical” fatty acids.

[0002] Little is known about the biological activity of CpFAs, but recent studies have demonstrated that lactobacillic acid binds to the γ isoform of the peroxisome proliferator-activated receptor (PPARγ), a nuclear receptor involved in lipid assimilation, catabolism, or storage, oxidative metabolism, and mitochondrial function.

Summary of the Invention

[0003] The present disclosure features compounds, compositions, and methods of use of CpFAs having an affinity for binding to peroxisome proliferator-activated receptors (PPARs). The PPAR family of nuclear receptors is known to promote metabolic health in the liver and adipose tissue and to select other tissues upon activation: for example, leading to improved insulin sensitivity, reduction of the consequences of type 2 diabetes and prediabetes, improvement of lipid homeostasis, and reduction of lipotoxicity. For example, PPAR-δ has been shown to promote fatty acid uptake, β-oxidation, and insulin secretion / sensitivity, and PPAR-α has been shown to promote proper uptake, use, and catabolism of fatty acids. PPAR-γ has been shown to promote proper lipid storage in tissues and to support insulin sensitivity and glycemic control and is the target of type 2 diabetes therapeutics, i.e., thiazolidinediones. Concerns regarding safety, high drug costs, and the cost of monitoring liver function using synthetic PPAR ligands have hindered their widespread use and acceptance.

[0004] As described in the present disclosure, CpFAs of bacterial origin have been identified. These CpFA heterologous lipids exhibit binding affinity for PPARα, δ, and / or γ and are absorbed and delivered to the liver via the portal vein and to peripheral tissues via intrahepatic drained blood or lymphatic lipid transport and / or can be released from lipid stores. CpFAs are also metabolites that are resident in the intestinal lumen and are thus expected to have more local metabolism and activity around intestinal tissue.

[0005] In one aspect, the present disclosure provides, for use as a medicament, a compound of formula I:

Chemical formula

[0006] In another aspect, the present disclosure provides a method for treating or managing a peroxisome proliferator-activated receptor (PPAR)-responsive condition in a subject in need of treatment or management, the method comprising administering a nutritional supplement or a pharmaceutical composition to the subject, the composition comprising a compound or its derivative, or its salt or prodrug, represented by formula I:

Chemical formula

Chemical formula

[0007] In another aspect, the disclosure is a pharmaceutical composition for treating or managing a PPAR-responsive condition in a subject in need of treatment or management, the composition comprising a compound of Formula I:

Chemical formula

[0008] In another aspect, the present disclosure relates to a method of treating or managing a PPAR-responsive state in a subject in need of treatment or management, the method comprising administering to the subject a pharmaceutical composition according to any of the embodiments of the above aspect.

[0009] In another aspect, the present disclosure relates to a nutritional supplement for promoting PPAR regulation in a subject in need of promotion, the supplement having the formula I:

Chemical formula

[0010] In another aspect, the present disclosure is a method for treating or managing an angiopoietin-like 4 (Angptl4)-responsive state in a subject in need of treatment or management, the method comprising administering a nutritional supplement or a pharmaceutical composition to the subject, the composition being of Formula I: [Chemical formula] a compound or its derivative, or its salt or prodrug, and mixtures thereof, represented by, wherein m = 2 and n is an odd number between 4 and 20; Formula II: [Chemical formula] A compound or derivative thereof, or a salt or prodrug thereof, and mixtures thereof, represented by formula (I) wherein m and n are independently integers between 2 and 20; and a therapeutically effective amount of an isolated cyclopropane fatty acid selected from the group consisting of a combination of a compound represented by formula (I) and a compound represented by formula (II); and a nutraceutical or pharmaceutically acceptable carrier, additive, adjuvant or vehicle. In some embodiments, when the PPAR-responsive phenotype is a PPAR-γ-responsive phenotype, the compound represented by formula (II) is not lactobacillic acid. In some embodiments, the nutraceutical or pharmaceutical composition comprises a compound represented by formula (I) wherein n = 9 or n = 11. In some embodiments, the compound represented by formula (I) can be cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD), cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD), or a combination thereof. In some embodiments, the nutraceutical or pharmaceutical composition comprises a compound represented by formula (II) wherein m is 5 or 7 and n is an odd number between 6 and 18. In some embodiments, the compound represented by formula (II) can be cis-9,10-methylene-hexadecanoic acid, lactobacillic acid, dihydrosterculic acid, or a combination thereof. In some embodiments, the nutraceutical or pharmaceutical composition can be administered orally, topically or parenterally. In some embodiments, the nutraceutical or pharmaceutical composition comprises from about 1 mg to about 5 g of the isolated cyclopropane fatty acid. In some embodiments, the nutraceutical or pharmaceutical composition is administered 1 to 4 times a day. In some embodiments, the method comprises administering the isolated cyclopropane fatty acid in a daily amount of about 1 mg to about 10 mg, about 1 mg to about 30 mg, about 10 mg to about 100 mg, about 100 mg to about 500 mg, about 0.5 g to about 1 g, about 1 g to about 2 g, about 2 g to about 4 g, about 4 g to about 6 g or about 6 g to about 10 g. In some embodiments, the Angptl4-responsive phenotype can be selected from the group consisting of obesity, insulin resistance, diabetes, hypertriglyceridemia and hepatic steatosis. In some embodiments, a prodrug form of the cyclopropane fatty acid is administered.In some embodiments, the nutritional or pharmaceutical composition further comprises a prodrug form of a compound represented by Formula I or Formula II.

[0011] In another aspect, the present disclosure relates to a method of treating or managing an Angptl4-responsive condition in a subject in need of treatment or management, the method comprising administering to the subject a pharmaceutical composition according to any of the embodiments of the above aspect.

[0012] In another aspect, the present disclosure relates to a functional food or feed composition comprising a PPAR-modulating amount of a compound of Formula I:

Chemical formula

Chemical formula

[0013] In another aspect, the present disclosure relates to a method of treating or managing an Angptl4-responsive or PPAR-responsive condition in a subject in need of treatment or management, the method comprising administering to the subject a nutraceutical supplement or functional food or feed composition according to any of the embodiments of the above aspect.

[0014] It is apparent that the compounds represented by Formulas I, II and III, including all subgenera described herein, may have one or more stereocenters. The present disclosure contemplates and encompasses each stereoisomer of any compound included in the present disclosure, and mixtures of such stereoisomers.

[0015] Details of one or more examples are described in the following description. Other features, objects, and advantages will be apparent from the description and claims.

Brief Description of the Drawings

[0016] This specification describes non-limiting and non-exhaustive exemplary embodiments. The drawings generally show, as examples rather than limitations, the various embodiments described herein.

[0017] Refer to the exemplary embodiments shown in the drawings:

[0018]

Figure 1

[0019]

Figure 2

[0020]

Figure 3

[0021]

Figure 4

[0022]

Figure 5

[0023]

Figure 6

[0024]

Figure 7

Mode for Carrying Out the Invention

[0025] The present disclosure features compounds, compositions, and methods for the therapeutic and health - or function - promoting modulation of peroxisome proliferator - activated receptors (PPARs). As used herein, the term "treatment" refers to an intervention such as treating a disease or disorder and providing a physically or mentally beneficial, useful, or desirable result or effect. The PPAR modulators of the present disclosure have the formula I:

Chemical formula

[0026] The PPAR modulator is of formula II:

Chemical formula

[0027] As used herein, a "prodrug" refers to or includes a compound that may or may not have pharmacological activity per se, but is converted, metabolized, or bioactivated in vivo in other ways to form a therapeutically active CpFA as a PPAR modulator. Thus, in some examples, the prodrug is formulated and / or administered for the therapeutic modulation of peroxisome proliferator-activated receptor (PPAR). The prodrugs of the present disclosure have the formula III: CH3-(CH2) m -CH=CH-(CH2) n -COOH (III) represented by, wherein m = 2, n is an odd number between 4 and 20, and is a monounsaturated odd-chain fatty acid or a derivative thereof, or a pharmaceutically acceptable salt, solvate or complex thereof, which is converted in vivo to the cyclopropane fatty acid of formula I by bacterial cyclopropane synthase, or wherein m and n are independently integers between 2 and 20, and is a monounsaturated odd-chain fatty acid or a derivative thereof, or a pharmaceutically acceptable salt, solvate or complex thereof, which is converted in vivo to the cyclopropane fatty acid of formula II by bacterial cyclopropane synthase. Such fatty acids can be naturally occurring or synthetic. In one example of formula III, n is 7, 9 or 11, or a stereoisomer thereof, or a combination thereof. In some examples, the prodrug of formula II is octadecenoic acid. In some examples, the prodrug of formula I is 11-pentadecenoic acid or 13-heptadecenoic acid. In one example of formula III, n is 9 or 11, or a stereoisomer thereof, or a combination thereof. In some examples, the prodrug according to formula III is myristoleic acid, palmitoleic acid, cis-vaccenic acid, vaccenic acid, paullinic acid, oleic acid, elaidic acid, 11-eicosenoic acid, erucic acid, brassidic acid, nervonic acid, sapienic acid or gadoleic acid, petroselinic acid.

[0028] The compounds represented by formulas I and II and their prodrugs can be used in isolated form. As used herein, the term "isolated" refers to a compound produced by a process of purification / isolation from a chemical synthesis reaction, or from a complex composition such as a bacterial fermentation or a plant extract. The process of purification / isolation provides an effective amount of the compound or its prodrug for therapeutic use. The purified / isolated preparation can consist essentially of or consist of the compounds represented by formulas I and / or II, thereby producing a new composition that exhibits, for example, significantly different characteristics from a fermentation product or a plant extract. In some examples, purification / isolation improves the formulation properties of the compound (e.g., enables improved tableting) or the bioavailability of the compound as compared to the unpurified starting composition.

[0029] The compounds represented by Formulas I and II and prodrugs thereof can be used in various combinations. For example, combinations for use in the therapeutic modulation of PPAR include two or more species encompassed by Formula I, such as cis-11,12-MPD and cis-13,14-MHD, two or more species encompassed by Formula II, such as at least two of cis-9,10-methylene-hexadecanoic acid, lactobacillic acid, and dihydrosterculic acid, at least one species encompassed by Formula I and at least one species encompassed by Formula II, two or more species encompassed by Formula III, such as vaccenic acid and oleic acid, and at least one species encompassed by Formula I and / or Formula II and / or Formula III. The combinations can be formulated by mixing the isolated compounds and exhibit characteristics significantly different from those of the isolated compounds. In some instances, the combinations exhibit an improvement in therapeutic outcome or a synergistic effect.

[0030] Suitable pharmaceutically acceptable salts include metal salts, such as aluminum, alkali metal salts, such as lithium, sodium or potassium, alkaline earth metal salts, such as calcium or magnesium, and ammonium or substituted ammonium salts.

[0031] The compounds described herein can be pharmaceuticals. As used herein, "pharmaceutical" refers to or includes compounds of Formula I and / or Formula II in any form suitable for use for medical purposes, such as pharmaceuticals, pharmaceutical formulations or products, nutritional supplements or supplement formulations, veterinary formulations, food products, functional foods or feed compositions or supplements, and / or used for the prevention, treatment or management of certain conditions where modulation of one or more PPARs is beneficial. The compounds have an affinity for at least one of the PPAR isoforms α, γ or δ, such as human PPAR isoforms, and can confer efficacy in the prevention, treatment or management of weight disorders, insulin resistance, hyperinsulinemia, impaired glucose tolerance, metabolic disorders, diabetes in obese individuals, diabetic complications, chronic inflammatory disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, gastrointestinal disorders, gastroesophageal reflux, diverticulitis, gastrointestinal ulcers, arthritis, rheumatoid arthritis, polyarthritis, asthma, eye inflammation, dry eye, skin disorders, psoriasis, cancer, liposarcoma, prostate cancer, cervical, breast, multiple myeloma, pancreatic cancer, neuroblastoma, bladder cancer, lipid disorders, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, low blood plasma high density lipoprotein (HDL), fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cardiovascular disease, and atherosclerosis. In some instances, the affinity for one or more of the PPAR isoforms α, γ or δ confers efficacy in the prevention, management or treatment of metabolic syndrome, dyslipidemic conditions such as elevated hypertriglyceridemia (HTG), triglyceride levels, LDL cholesterol levels and / or VLDL cholesterol levels, obesity or overweight conditions, fatty liver disease, peripheral insulin resistance and / or diabetic conditions, type 2 diabetes, or a decrease in plasma insulin, blood glucose and / or serum triglycerides, and combinations of these conditions. Thus, in certain instances, the pharmaceutical is for the prevention, treatment or management of diabetes, fatty liver disease, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. The present disclosure encompasses the use of the compounds of Formulas I and II for other uses, including the manufacture of pharmaceuticals.

[0032] The present disclosure describes a pharmaceutical composition comprising a compound represented by formula I and / or formula II as an active ingredient and / or a compound represented by formula III as its prodrug. As used herein, "pharmaceutical composition" (or "preparation" or "production") includes a compound represented by the above formula I or formula II as an active ingredient in any form suitable for medical purposes. The composition may include a pharmaceutically acceptable carrier, additive, adjuvant or vehicle. As used herein, "carrier" refers to a diluent, disintegrant, sedimentation inhibitor, surfactant, flow promoter, binder, lubricant, and other additives and vehicles in or with which the compound is administered. The route of administration typically determines the type of carrier. The pharmaceutical composition can be formulated for oral administration to humans or animals, but the examples are not limited thereto. The pharmaceutical composition can be formulated for any other route by which the active ingredient can be efficiently absorbed and utilized, such as intravenous, parenteral, subcutaneous, intramuscular, oral, intranasal, ocular, rectal, vaginal or topical administration. The pharmaceutical composition can be formulated for local or systemic effects, or a combination thereof. The compound and composition can be formulated as tablets, coated tablets, capsules, aerosols, powders, granules, suppositories, solutions, dispersions, suspensions, syrups, emulsions, creams, ointments, gels, lotions, and sprays using formulation aids. Non-limiting examples of formulation aids include diluents, binders, excipients, extenders, humectants, tableting aids, disintegrants, adsorption promoters, absorbents, buffers, wetting agents, suspending agents, solvents, gel formers, matrix formers, solubilizers, emulsifiers, lubricants, encapsulating agents, sustained release coating agents, enteric coating agents, sweeteners, flavoring agents, fragrances, preservatives, pH regulators, antioxidants, stabilizers, stearin, or mixtures thereof. The composition may contain the compound in the range of about 0.1% to about 99.9% by weight, such as about 10% to 50% or about 30% to about 95% by weight.

[0033] The amount of the compounds of formula I, II and / or III present in the pharmaceutical composition or its unit dose may be an amount that can provide a medical benefit upon single or multiple administrations. For example, the amount of the compounds of formula I, II and / or III in a unit dose may be from about 1 mg to about 10 mg, from about 1 mg to about 30 mg, from about 10 mg to about 100 mg, from about 100 mg to about 500 mg, from about 0.5 g to about 1 g, from about 1 g to about 2 g, from about 2 g to about 4 g, from about 4 g to about 6 g or from about 6 g to about 10 g.

[0034] The pharmaceutical compositions of the present disclosure may include, in addition to the compounds represented by formula I, II and / or III, one or more additional active ingredients as co-administered components. The dose of the co-administered component, or the ratio of two or more co-administered components, may be determined based on clinically appropriate protocols. The addition of the co-administered component may enhance the action of the compounds represented by formula I, II and / or III of the present disclosure or the co-administered component, and / or may enable a reduction in the dose of the compounds represented by formula I, II and / or III or the co-administered component, thereby avoiding harmful or undesirable side effects as compared to single drug administration while achieving the desired therapeutic result. In some examples, the co-administered component is an anti-diabetic agent, an anti-diabetic complication agent, a lipid-lowering agent, an anti-hypertensive agent, an anti-obesity agent, a fatty liver disease agent, or a combination thereof. The co-administered component may be a low molecular weight compound, a high molecular weight protein, a polypeptide, an antibody or a vaccine.

[0035] Examples of anti-diabetic agents include insulin preparations, α-glucosidase inhibitors, biguanide drugs (e.g., phenformin, metformin, buformin or salts thereof (e.g., hydrochloride, fumarate, succinate)), secretagogues (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glycopyramide, glimepiride, glypidide, glibuzole, repaglinide, nateglinide, mitiglinide or calcium hydrates of these), GLP-1 receptor agonists, dipeptidyl peptidase IV inhibitors, β3 agonists, amylin agonists, phosphotyrosine phosphatase inhibitors, gluconeogenesis inhibitors (e.g., glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists), sodium-glucose cotransporter inhibitors, 11β-hydroxysteroid dehydrogenase inhibitors, adiponectin or its agonists, IKK inhibitors, leptin resistance improvers, somatostatin receptor agonists, and glucokinase activators, one or more of which may be mentioned.

[0036] Examples of anti-diabetic complication agents include, for example, aldose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112, ranirestat), neurotrophic factors (e.g., NGF, NT-3, BDNF), neurotrophic factor production / secretion promoters, PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g., pimagedine, pyridoxanthine, N-phenacylthiazolium bromide, pyridoline, pyridoxamine), reactive oxygen species scavengers (e.g., thioctic acid), cerebrovascular dilators (e.g., tiapride, mexiletine), somatostatin receptor agonists, apoptosis signal-regulating kinase-1 (ASK-1), one or more of which may be mentioned.

[0037] Examples of lipid-lowering agents include, for example, HMG-CoA reductase inhibitors (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipanthyl, itavastatin, rosuvastatin or salts thereof), fibrate compounds (e.g., bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate, clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, ronifibrate, simfibrate, theofibrate), ezetimibe, squalene synthase inhibitors, ACAT inhibitors (e.g., avasimibe, eflucimibe), anion exchange resins (e.g., cholestyramine), probucol, nicotinic acid drugs (e.g., nicomol, nicertol), omega-3 fatty acids, niacin, ethyl eicosapentanoate, phytosterols (e.g., soy sterol, γ-oryzanol) and one or more of proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors.

[0038] Examples of antihypertensive agents include, for example, angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril), angiotensin II antagonists (e.g., losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan medoxomil), calcium antagonists (e.g., manidipine, nifedipine, nicardipine, amlodipine, efonidipine), potassium channel openers (e.g., levcromakalim) and clonidine and one or more of them.

[0039] Examples of anti-obesity drugs include, for example, anti-obesity drugs that act on the central nervous system (e.g., naltrexone-bupropion, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphepramone, dextroamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists, neuropeptide Y antagonists, cannabinoid receptor antagonists, ghrelin antagonists; 11β-hydroxysteroid dehydrogenase inhibitors, pancreatic lipase inhibitors (e.g., orlistat, cetilistat), β3 agonists, appetite-suppressing peptides (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (e.g., lintitript), liraglutide, and one or more of feeding inhibitors).

[0040] The present disclosure describes a nutraceutical composition, such as a supplement, a functional food or feed composition, a food or feed supplement, a food or feed additive, an enteral nutrition composition, a veterinary formulation, or other nutraceutical formulation, comprising a compound represented by formula I and / or formula II as an active ingredient and / or a compound represented by formula III as its prodrug. As used herein, "nutraceutical" refers to a product that is extracted from and / or added to a food source and provides a medical, health, or functional benefit. A nutraceutical aids in the prevention, management, or treatment of any one or combination of the above conditions. Nutraceutically acceptable carriers, media, diluents, and additives include those suitable for human or animal consumption and / or those used in the food industry. The present disclosure describes a functional food or feed composition, such as a food or feed supplement, a food or feed additive, or a nutraceutical formulation, comprising a compound represented by formula I and / or formula II or its prodrug. "Food (or feed) composition" refers to a liquid, semi-solid, or solid food or nutritional composition suitable for human or animal consumption, including fluid and semi-solid beverage compositions. For example, a feed composition can be provided to livestock or companion animals. Companion animals include, but are not limited to, cats, dogs, horses, and other mammals. The functional food or feed composition of the present disclosure can be provided and / or sold as a food, feed, or beverage product labeled by its intended therapeutic use or function, such as "for promoting liver health", "for regulating metabolism", or other purposes described herein.

[0041] The amount of formula I, II, and / or III present in a nutraceutical composition, such as a functional food or feed composition, is an amount that can provide a medical benefit over one or multiple administrations. For example, the amount of formula I, II, and / or III in a single administration can be about 1 mg to about 10 mg, about 10 mg to about 100 mg, about 100 mg to about 500 mg, about 0.5 g to about 1 g, about 1 g to about 2 g, about 2 g to about 4 g, about 4 g to about 6 g, or about 6 g to about 10 g.

[0042] In some instances, the nutritional supplement compositions of the present disclosure include one or more additional ingredients as further nutritional supplements. Examples include caffeine, amino acids, creatine, glucosamine, chondroitin, collagen, essential fatty acids, antioxidants, vitamins, coenzyme Q10, minerals, essential oils, extracts (e.g., herb or fruit extracts), prebiotics, and probiotics. The further nutritional supplements can be included for antioxidant support of cells from damage caused by free radicals and oxidative stress, to support joint health, improve joint mobility, reduce joint pain, improve cognitive function, memory, concentration, and overall mental ability, promote a healthy gut microbiota, improve digestion, support overall gut health, support healthy cholesterol levels, promote heart health, reduce the risk of heart disease, increase energy levels, improve vitality, fight fatigue, support immune function, strengthen the body's natural defense mechanisms, support weight loss, increase metabolism, reduce body fat, promote healthy skin, reduce signs of aging, and improve skin elasticity.

[0043] Exemplary essential fatty acids include polyunsaturated fatty acids (PUFAs), such as omega-3 fatty acids selected from α-linolenic acid (18:3, ALA), stearidonic acid (18:4), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5; EPA), docosatetraenoic acid (22:4), n-3 docosapentaenoic acid (22:5; n-3 DPA), and docosahexaenoic acid (22:6; DHA), such as omega-6 fatty acids selected from linoleic acid (18:2), γ-linolenic acid (18:3), eicosadienoic acid (20:2), dihomo-γ-linolenic acid (20:3), arachidonic acid (20:4), docosadienoic acid (22:2), adrenic acid (22:4), and n-6 docosapentaenoic acid (22:5), and omega-9 fatty acids such as mead acid (20:3), but are not limited thereto. Essential fatty acids can be provided in the form of oils derived from marine foods, plant-derived oils, and algae-derived oils. The derived oils can also be hydrogenated or partially hydrogenated.

[0044] In some examples, the nutritional supplement composition of the present disclosure includes at least one pharmaceutically acceptable substance, such as the above-mentioned combination components for pharmaceutical compositions.

[0045] The present disclosure describes a method that includes administering to a subject a therapeutically effective amount of a compound represented by formula I and / or formula II as an active ingredient, or a prodrug thereof in an amount sufficient to provide a therapeutic effect after conversion to a compound represented by formula I and / or formula II. As used herein, "therapeutically effective amount" refers to, or includes, the amount of a compound according to formula I and / or formula II that produces the desired treatment, health or functional effect, i.e., an amount effective to achieve its intended purpose. Although the needs of individual subjects can vary, the dosing regimen for treating a condition using the disclosed products of the present disclosure is selected according to various factors including the type of subject, age, weight, gender, diet and medical condition. The subject can be an adult, juvenile, infant or fetus. A therapeutically effective amount of a compound may be included in a pharmaceutical composition, and in foods, food supplements, nutritional supplements or dietary products. In some examples, the therapeutically effective amount is a "prophylactically effective amount" that prevents a pathological condition or its signs or symptoms in a subject at risk of developing that condition. "Treatment" or "management" includes any therapeutic application that can benefit a human or non-human mammal. "Health or function" refers to a desired physiological outcome even in the absence of an overt disease or pre-disease. Both human and veterinary treatments are within the scope of the present disclosure. Treatment can relate to an existing condition or can be prophylactic, e.g., preventive. The term "chronic treatment" refers to, or includes, treatment that continues for weeks or years.

[0046] The route of administration depends on various factors such as the characteristics of the compound, such as onset of action and bioavailability, the formulation of the compound, the intended therapeutic effect, the condition of the subject, etc. In some examples, the methods of the present disclosure include oral, ocular, otic (auditory), sublingual, buccal, inhalation, intranasal, parenteral, intravenous (IV), intramuscular (IM), subcutaneous (SC), intradermal (ID), topical (e.g., administration to internal tissue surfaces (e.g., gastrointestinal surfaces) and / or external tissue surfaces (e.g., skin, eyes, ears)), transdermal, rectal, vaginal, epidural and intrathecal routes of administration, or combinations of routes.

[0047] The present disclosure describes a method comprising administering to a subject a therapeutically effective amount of a compound represented by formula I and / or formula II as an active ingredient, or a prodrug thereof in an amount sufficient to provide a therapeutic effect after conversion to a compound represented by formula I and / or formula II, and the second active ingredient as described above, i.e., the co-administered ingredient. The compounds of formula I, II and / or III and the co-administered ingredient can be administered to the subject simultaneously or alternately. The compounds represented by formula I, II and / or III and the co-administered ingredient can be administered to the subject as two or more formulations or preparations each containing the compound, or as a single preparation containing both active ingredients.

[0048] The methods of the present disclosure may include the control of metabolism and / or the promotion of health. As an example, methods of treating (or preventing or managing) diabetes, metabolic syndrome, secondary diabetes, pancreatic diabetes, extra-pancreatic / endocrine or drug-induced diabetes, or exceptional forms of diabetes (e.g., diseases caused by lipodystrophy, myotonia or insulin receptor disorders) are described. The methods include administering a compound of formula I and / or formula II or a prodrug thereof to a subject in need thereof. The subject in need of treatment may be identified, for example, as having metabolic syndrome and may be a subject characterized by hyperinsulinemia, insulin resistance, obesity, impaired glucose tolerance, hypertension, abnormal blood lipids or dyslipidemia. The methods may include the treatment and / or prevention of peripheral insulin resistance and / or the treatment and / or prevention of type diabetes, or the reduction of insulin in plasma, blood glucose, glycated hemoglobin and / or serum triglycerides.

[0049] Another exemplary method includes a method of treating (or preventing) obesity or managing a weight control condition, including administering a compound of formula I and / or formula II or a prodrug thereof to a subject in need thereof. The subject in need of treatment may be, for example, obese, may require weight control, and / or may have an increased insulin resistance.

[0050] Another exemplary method includes a method of treating (or managing or preventing) an increase in blood lipids in a human, including administering a compound of formula I and / or formula II or a prodrug thereof to a human in need thereof. The human may have a dyslipidemic condition, such as hypertriglyceridemia (HTG), an elevated triglyceride level, an elevated LDL cholesterol level and / or an elevated VLDL cholesterol level.

[0051] Another exemplary method includes treating (or managing or preventing) a liver disease, such as non-alcoholic liver disease, such as non-alcoholic steatohepatitis (NASH), or non-alcoholic fatty liver disease (NAFLD), which comprises administering a compound represented by Formula I and / or Formula II or a prodrug thereof to a subject in need thereof. The subject in need of treatment and / or prevention can be overweight or obese and / or can have diabetes, hyperlipidemia, metabolic syndrome or a poor diet.

[0052] An appropriate daily dosage of a compound represented by Formula I, Formula II or a prodrug thereof according to the present disclosure for the treatment, management and / or prevention of the conditions listed above can be in the range of about 1 mg to about 10 g, about 1 mg to about 30 mg, about 30 mg to about 100 g, about 100 mg to about 1 g or about 1 g to about 10 g of the compound per day. The daily dosage can be about 1 mg to about 3 g, about 1 mg to about 10 g, about 1 to about 30 mg, about 50 mg to about 1 g, about 10 mg to about 2 g, about 50 mg to about 500 mg, about 50 mg to about 200 mg, about 100 mg to about 1 g, about 100 mg to about 500 mg or about 100 mg to about 250 mg. The dosage varies depending on the compound used, the mode of administration, the desired treatment and the disorder presented. The specific dosage level and frequency of administration for any particular patient can vary and depends on various factors including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, weight, general health status, gender, diet, mode and time of administration, rate of excretion, drug combination, severity of the particular condition, and the individual being treated. The compounds, medicaments, nutritional supplements, veterinary formulations, food or feed compositions and / or pharmaceutical compositions of the present disclosure can be administered according to a regimen of 1 to 10 times per day, such as once, twice, three times or four times per day. For oral and parenteral administration to human patients, the daily dosage level of the drug can be a single dose or divided doses.

Examples

[0053] The following examples are provided for illustrative purposes only and do not limit the claims provided herein.

[0054] Example 1 This example describes newly identified ligands for the PPAR nuclear receptor: cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD) and cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD). Two odd-chain-length long-chain fatty acids containing a rare cyclopropane ring, not previously reported (Figures 1A and 1B), were deduced and predicted from the structure of cis-3,4-methylene-heptanoyl carnitine (cis-3,4-MHC, Figure 1C); the latter molecule has been previously reported in the chemical literature. Without being bound by theory, cis-3,4-MHC is thought to be a derivative of cis-11,12-MPD and cis-13,14-MHD and is generated by several cycles of β-oxidation. Previously published studies have shown that in sedentary women with insulin resistance, serum levels of this medium-chain acyl carnitine increase significantly during exercise and decrease at rest with weight loss and exercise intervention.

[0055] Long-chain cyclopropane fatty acids (CpFAs) such as cis-11,12-MPD and cis-13,14-MHD may be present in the mammalian intestine and, in the case of cis-11,12-MPD and cis-13,14-MHD, are thought to originate primarily from the microbial metabolism of odd-chain fatty acid precursors. This conclusion is derived from observations regarding various even-chain CpFAs described elsewhere in the scientific literature. The odd-chain CpFAs of the present disclosure are useful throughout the body for improving metabolic health, but are particularly useful in the liver as it is the initial tissue that interacts with gut-derived signals. Based on initial results, cis-11,12-MPD and cis-13,14-MHD can be metabolized in the liver but also reach and be stored in other organ sites including adipose tissue. Similar to other CpFA PPAR modulators, the actions of cis-11,12-MPD and cis-13,14-MHD to prevent or treat disease or improve health or function can also occur in the gastrointestinal tract.

[0056] Example 2 In a pilot test using the stored samples, the presence of cis-11,12-MPD and cis-13,14-MHD in the feces of piglets was confirmed by first synthesizing true chemical standards using standard organic chemistry methods and then using the standards in the mass spectrometry library. In subsequent co-pilot tests in the tissue-specific blood catheter insertion model, the portal blood kinetics of cis-11,12-MPD and cis-13,14-MHD in the blood of growing pigs were consistent with the intestine as the origin site for entry into the body (Figure 2), which was consistent with the existing literature knowledge supporting the production of CpFA from intestinal sources in mammals.

[0057] Example 3 Using the Schrodinger Molecular Modeling Suite (version 12.8.117 release 2021-2), the binding of cis-11,12-MPD and cis-13,14-MHD to PPAR family member proteins was evaluated (Figure 3). Molecular modeling is a commonly used in silico tool used to evaluate the binding ability of molecules to targets related to medicine and health, including nuclear receptors, cell surface receptors, channels and enzymes. Positive controls included well-established PPAR-binding molecules: rosiglitazone and GW1929 (PPAR-γ activators), the drug GW9662 (PPAR-γ antagonist), and several fatty acids (arachidonic, oleic and lactobionic acids) known or proposed in the literature to bind to PPAR. The results obtained as follows revealed that CpFAs including cis-11,12-MPD and cis-13,14-MHD strongly bind to PPAR-α, PPAR-δ and PPAR-γ (Figure 4A and B). cis-11,12-MPD and cis-13,14-MHD bound to all forms of PPAR, but the binding energy pattern showed that the binding to PPAR-δ (-60 kcal / mol) was the strongest compared to PPAR-α and PPAR-γ (-40 kcal / mol) (a lower negative binding energy indicates a higher binding affinity). In some cases, the binding energy was similar to that of the PPAR-selective pharmacological ligands, namely fenofibrate, GW501516 and rosiglitazone for PPARα, δ and γ respectively. The highest binding affinity was determined to be for PPARδ, then PPARα, and finally the γ subunit. These results also showed that the CpFAs lactobionic acid and dihydrosterculic acid have unexpected binding affinities for PPAR-α and PPAR-δ, which is a new observation. Previous reports had only suggested the PPAR-γ isoform for lactobionic acid.

[0058] This study revealed that cis-11,12-MPD and cis-13,14-MHD, being natural ligands, may have a safety profile improved over PPAR-targeting drugs. Also, cis-11,12-MPD and cis-13,14-MHD are likely to affect liver metabolism and liver health more specifically than other tissues, compared to current pharmaceuticals targeting the PPAR family. Thus, odd-chain CpFAs are strong candidates for the targeting of diseases associated with disrupted liver metabolism. Since cis-11,12-MPD and cis-13,14-MHD can bind to PPAR-α, PPAR-δ, and PPAR-γ, they may be able to modulate several metabolic pathways at once; this could be advantageous over currently available, more isoform-specific pharmaceuticals. Finally, PPAR-modulating CpFAs, including cis-11,12-MPD and cis-13,14-MHD, should have advantages over typical oral PPAR-targeting drugs, as the latter are not formulated to treat or prevent gastrointestinal conditions, whereas CpFAs are typically found or introduced at this site.

[0059] Example 4 To identify agonist compounds, binding events of numerous CpFAs and fatty acids in the PPAR ligand-binding domain were analyzed using time-resolved FRET (TR-FRET). The assays indicate the amount of ligand required to bind to the receptor, cause a conformational change, and recruit coactivator peptides. These assays showed that several CpFAs bind to the ligand-binding domains of PPAR-α and PPAR-δ in line with agonist activity (Figs. 5A–B), while the results for PPAR-γ suggest complex interactions of several CpFAs with PPAR-γ and a change in the ligand-binding domain of this receptor (Fig. 5C).

[0060] Example 5 The angiopoietin-like 4 (Angptl4) gene can be upregulated by PPAR induction. To test the effect of CpFA on the regulation of Angptl4 expression, Angptl4 mRNA expression levels were quantified by real-time qPCR in cultured mouse 3T3-L1 cells. Figure 6 shows that Angptl4 mRNA transcripts provide a functional readout of the agonistic and antagonistic actions of PPAR in living cells. Figures 7A - C show the dose-dependent responses to representative CpFAs in mouse 3T3-L1 cells. These results indicate that Angptl4 expression can be induced by CpFA in mouse 3T3-L1 cells.

[0061] Method: Docking was performed using Maestro of the Schrodinger Suite (v12.8.117). Ligand structures were downloaded from PubChem, and human PPAR structures were downloaded from the Protein Data Bank and AlphaFold database when applicable. Glide-XP docking and Prime MM-GBSA post-processing were performed for each ligand-receptor pair, and the free binding energy (ΔG in kcal / mol) was analyzed using R version 3.6.2.

[0062] The 2D chemical structure files were obtained from the public database (PubChem) for all ligands except cis-11,12-MPD and cis-13,14-MHD translated from the SMILES structure using the NIH SMILES translator. In Figure 4A, the following PDB crystallization structures were used for docking: PPAR-α (1KKQ, 2P54), PPAR-δ (3TKM), PPAR-γ (3BC5, 5LSG, 5DWL, 3VSO). In Figure 4B, the following PDB crystallization structures: PPAR-α (2ZNN, 3KDU, 3VI8, 4BCR, 6KAX, 6KB0, 6KB6, 6KB8, 6KBA), PPAR-δ (1Y0S, 2B50, 2Q5G, 3TKM, 5U3V, 5U3W, 5U46, 5ZXI, 6A6P), PPAR-γ (2Q5S, 2Q61, 3B0Q, 3B0R, 3BC5, 3WMH, 4A4V, 4EM9, 5TTO). For PPARα, γ and δ, the AI-generated AlphaFold structures (available from the alphafold.ebi.ac.uk site) were also used. In both Figures 4A and 4B, the ligand and protein structures were created according to the standard Schrodinger software protocol. Molecules sharing letters were not significantly different from each other at p<0.05 (post hoc Tukey's Honest Significant Difference test after ANOVA).

[0063] Materials and Reagents: The TR-FRET binding assay was performed using the "LanthaScreen TR-FRET Coactivator Assay" kit provided by ThermoFisher Scientific. Reference PV4684 was used for PPAR-α, reference PV4685 for PPARδα, and reference PV4548 for PPARγα. All non-CpFA high-affinity PPAR agonists and antagonists were purchased from Cayman Chemicals. All lipids and CpFA except cis-11,12-MPD, cis-13,14-MHD and CPOA2H were also purchased from Cayman Chemicals. cis-11,12-MPD, cis-13,14-MHD and CPOA2H were custom synthesized by Larodan AB as a paid service.

[0064] Binding of Selected CpFAs to PPAR Subtypes: The procedure was consistent across all three TR-FRET kits. First, all ligands were prepared at 100-fold concentration in 100% DMSO and subsequently diluted in a 12-point dilution series in 100% DMSO. Each 100-fold agonist dilution was further diluted 2-fold in the complete nuclear receptor buffer provided in the kit. Each PPAR ligand-binding domain (LBD) was prepared at 4-fold concentration in cold complete nuclear receptor buffer. Also, a solution containing 500 nM fluorescein conjugated to coactivator peptides specific to PPARα, δ, and γ (PGC1a, C33, and TRAP220 / DRIP-2, respectively) and 20 nM Tb anti-GST antibody was prepared. Subsequently, all ligands and solutions were added in quadruplicate to separate 384-well assay plates, covered, and incubated at room temperature for 1 hour. Finally, the plates were read at wavelengths of 520 nm and 495 nm. Data were analyzed using GraphPad Prism 9.5.1. The 520 / 495 ratio was plotted on a logarithmic scale against the concentration of the ligand. Nonlinear curve fitting was performed using the 4PL method of GraphPad Prism according to the manufacturer's recommendations.

[0065] 3T3-L1 Cell Culture and PPAR Activation: 3T3-L1 preadipocytes were cultured in growth medium (Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum (CS), 1X penicillin / streptomycin, and 1X glutamax) and seeded in multiwell (12-well or 24-well) plates. The PPAR specificity of gene target activation was determined in 3T3-L1 preadipocytes using well-known agonists and antagonists for PPAR-α, PPAR-δ, or PPAR-γ. On the day of treatment, the preadipocytes were serum-starved with 0.25% CS in growth medium for 2 - 4 hours. The cells were pretreated in serum-starved medium with stepwise increasing concentrations (0, 0.1, 1, and 10 μM) of PPAR antagonists (GW6471 for PPAR-α, GSK3787 for PPARδ, and T0070907 for PPARγ). After 1 hour, selective PPAR agonists were added (GW7647 (PPAR-α), GW501516 (PPAR-δ), and rosiglitazone (PPAR-γ)) and incubated for 24 hours. Lysates were collected for RNA extraction. To test whether CpFA exhibits an agonistic effect on PPAR isoforms, 3T3-L1 preadipocytes were serum-starved with 0.25% CS for 2 - 4 hours. CpFA treatment (final concentrations 37.5, 75, and 150 μM) was prepared with 0.25% serum-starved medium and 3% BSA, followed by heating (55°C) and sonication for 30 minutes. The treated samples were cooled to 37°C and then added to 3T3-L1 preadipocytes and incubated for 24 hours. Lysates were collected for RNA isolation.

[0066] Angptl4 expression analysis: RNA was isolated from cell lysates using the Qiagen 96 Total RNA kit. cDNA was synthesized and plated in triplicate in 384-well plates. RT-qPCR was performed using TaqMan Fast-Advanced master mix and TaqMan reagents and primers (18S, rplp0, angplt4) and analyzed using a Thermo Fisher Scientific QuantStudio 6 Flex PC system. Relative gene expression was analyzed using the fold difference algorithm (2^(-ΔΔCt)) using the geometric mean of two housekeeping genes (18S, RPLP0) compared to the relevant vehicle control.

[0067] Other embodiments of the present disclosure are possible. The above description includes specific examples, which are presented for illustrative and explanatory purposes and should not be construed as limiting the scope of the disclosure. For example, specific combinations and sub-combinations of features and aspects of the above embodiments are within the scope of the present disclosure. The various features and aspects of the disclosed embodiments may be combined with each other or replaced to form various embodiments. All structural, chemical, and functional equivalents to the elements of the above examples known to those skilled in the art are included in the claims of this patent. Accordingly, the scope of the present disclosure should not be limited by the above specific examples.

[0068] An element, component, or method step in this disclosure is not intended to be dedicated to the public, whether or not the element, component, or method step is explicitly recited in the claims. References to elements in the singular are not intended to mean "one and only one" unless explicitly stated otherwise, but rather "one or more." As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes elements, steps, or components specified in the claims of the scope. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel features of the claims of the scope. In each instance herein, any one of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with either of the other two terms. The examples illustratively described herein may be appropriately implemented in the absence of any one or more elements not specifically disclosed herein. The scope of this disclosure should be determined by the appended claims and their legal equivalents.

Claims

1. Formula I: 【Chemistry 1】 A pharmaceutical product comprising a compound or its derivative, or a salt or prodrug thereof, as shown by the formula, where m = 2 and n is an odd number between 4 and 20.

2. The pharmaceutical agent according to claim 1 for the treatment or management of a PPAR-responsive state or an angiopoietin-like 4 (Angptl4)-responsive state.

3. The pharmacopoeia according to claim 1 or 2, wherein the pharmacopoeia is for the treatment or management of weight disorders, insulin resistance, hyperinsulinemia, impaired glucose tolerance, metabolic disorders, diabetes mellitus in obese individuals, diabetic complications, chronic inflammatory disorders, inflammatory bowel disease, ulcerative colitis, Crohn's disease, gastrointestinal disorders, gastroesophageal reflux, diverticulitis, gastrointestinal ulcers, arthritis, rheumatoid arthritis, polyarthritis, asthma, ocular inflammation, dry eye, skin disorders, psoriasis, cancer, liposarcoma, prostate cancer, cervical cancer, breast cancer, multiple myeloma, pancreatic cancer, neuroblastoma, bladder cancer, dyslipidemia, hyperlipidemia, dyslipidemia, diabetic dyslipidemia, mixed dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, hypohigh-density lipoprotein (HDL), fatty liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, cardiovascular disease, and atherosclerosis.

4. The pharmaceutical product according to claim 1 or 2, wherein n = 9 or n = 11.

5. The pharmaceutical product according to claim 1 or 2, wherein the compound represented by formula I is cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD), cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD), or a combination thereof.

6. A pharmaceutical composition for treating or managing a peroxisome proliferator-activated receptor (PPAR)-responsive state in an organism requiring treatment or management, wherein the composition comprises formula I: 【Chemistry 2】 An isolated PPAR ligand or its derivative, or a salt or prodrug thereof, as shown in the formula, where m = 2 and n is an odd number between 4 and 20; Pharmaceutical carriers, additives, adjuvants or vehicles A pharmaceutical composition containing the above.

7. The composition according to claim 6, wherein n = 9 or n = 11.

8. The composition according to claim 7, wherein the isolated PPAR ligand represented by formula I is cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD), cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD), or a combination thereof.

9. A composition according to any one of claims 6 to 8, formulated for oral, topical, or non-enteral administration.

10. The composition according to any one of claims 6 to 8, formulated as a solid or liquid dosage form.

11. The composition according to claim 10, wherein the dosage form is a tablet, coated tablet, capsule, powder, granule, liquid, dispersant, suspension, syrup, emulsion, or spray.

12. The composition according to any one of claims 6 to 8, wherein the pharmaceutical carrier, additive, adjuvant, or vehicle is selected from the group consisting of diluents, binders, excipients, bulking agents, humectants, tableting aids, disintegrants, adsorption enhancers, absorbents, buffers, wetting agents, suspending agents, solvents, gel-forming agents, matrix-forming agents, solubilizers, emulsifiers, lubricants, encapsulating agents, delayed-release coating agents, enteric coating agents, sweeteners, flavoring agents, fragrance agents, preservatives, and combinations thereof.

13. Formula II: 【Transformation 3】 The composition according to any one of claims 6 to 8, further comprising a compound or derivative thereof, a salt thereof, or a prodrug, represented by the formula, where m and n are independently integers between 2 and 20.

14. The composition according to any one of claims 6 to 8, further comprising a co-administered component as a further active pharmaceutical ingredient.

15. The composition according to claim 14, wherein the concomitant component is selected from the group consisting of antidiabetic drugs, antidiabetic complication drugs, dyslipidemia drugs, antihypertensive drugs, anti-obesity drugs, fatty liver disease drugs, and combinations thereof.

16. A nutritional supplement for promoting peroxisome proliferator-activated receptor (PPAR) regulation in a target organism requiring such promotion, wherein the supplement comprises formula I: 【Chemistry 4】 An isolated PPAR ligand or its derivative, or a salt or prodrug thereof, as shown in the formula, where m = 2 and n is an odd number between 4 and 20; Nutritionally acceptable carriers, additives, adjuvants or vehicles Nutritional supplements containing [specific ingredient / component].

17. The supplement according to claim 16, wherein n = 9 or n = 11.

18. The supplement according to claim 17, wherein the isolated PPAR ligand represented by formula I is cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD), cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD), or a combination thereof.

19. A supplement according to any one of claims 16 to 18, formulated for oral, topical, or non-enteral administration.

20. The supplement according to any one of claims 16 to 18, formulated as a tablet, coated tablet, capsule, aerosol, powder, granule, suppository, liquid, dispersant, suspension, syrup, emulsion, cream, ointment, gel, lotion, or spray.

21. The supplement according to any one of claims 16 to 18, further comprising a combination ingredient as an additional nutritional supplement, the combination ingredient being selected from the group consisting of: a nutritional supplement for antioxidant support of cells from damage caused by free radicals and oxidative stress; a nutritional supplement for supporting joint health; a nutritional supplement for improving joint mobility and reducing joint pain; a nutritional supplement for improving cognitive function, memory, concentration or overall mental ability; a nutritional supplement for promoting a healthy gut microbiota; a nutritional supplement for improving digestion and supporting overall gut health; a nutritional supplement for supporting healthy cholesterol levels; a nutritional supplement for promoting heart health and reducing the risk of heart disease; a nutritional supplement for increasing energy levels, improving vitality or combating fatigue; a nutritional supplement for supporting immune function or strengthening the body's natural defense mechanisms; a nutritional supplement for supporting weight loss, increasing metabolism or reducing body fat; a nutritional supplement for promoting healthy skin, reducing signs of aging or improving skin elasticity; and combinations thereof.

22. Formula II: 【Transformation 5】 A supplement according to any one of claims 16 to 18, further comprising a compound or derivative thereof, a salt thereof, or a prodrug, represented by the formula, where m and n are independently integers between 2 and 20.

23. PPAR-controlling quantity, Equation I: 【Transformation 6】 A compound or its derivative, or a salt or prodrug thereof, as shown in the formula, where m = 2 and n is an odd number between 4 and 20; Food carriers A functional food or feed composition containing the above.

24. The composition according to claim 23, wherein n = 9 or n = 11.

25. The composition according to claim 24, wherein the compound represented by formula I is cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD), cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD), or a combination thereof.

26. A composition according to any one of claims 23 to 25, comprising a prodrug form of a compound represented by formula I.

27. The composition according to any one of claims 23 to 25, wherein the composition contains a compound represented by formula I in an amount of about 50 mg to about 2 g per serving.

28. Formula II: 【Transformation 7】 The composition according to any one of claims 23 to 25, further comprising a compound or derivative thereof, or a salt or prodrug thereof, represented by the formula, where m and n are independently integers between 2 and 20.

29. The composition according to any one of claims 23 to 25, wherein the composition is a food suitable for human consumption.

30. The composition according to claim 29, wherein the food is a solid, semi-solid, or liquid food.

31. The composition according to any one of claims 23 to 25, wherein the composition is a feed suitable for consumption by animals.

32. The composition according to any one of claims 23 to 25, further comprising caffeine, amino acids, creatine, glucosamine, chondroitin, collagen, essential fatty acids, antioxidants, vitamins, minerals, essential oils, extracts, prebiotics and probiotics, and further nutritional supplements selected from the group consisting of combinations thereof.

33. The composition according to any one of claims 23 to 25, further comprising a co-administered component as an active pharmaceutical ingredient.

34. The composition according to claim 33, wherein the concomitant component is selected from the group consisting of a drug for treating diabetes, a drug for treating diabetic complications, a drug for treating dyslipidemia, an antihypertensive drug, an anti-obesity drug, a drug for treating fatty liver disease, and combinations thereof.

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