Compositions and methods for modulating metabolic pathways

• US 8,623,924 B2
• Filed: 07/13/2012
• Issued: 01/07/2014
• Est. Priority Date: 07/15/2011
• Status: Active Grant

• Current Assignee: Nusirt Sciences, Inc.
• Original Assignee: Nusirt Sciences, Inc.
• Inventors: Zemel, Michael, Grindstaff, E. Douglas II, Bruckbauer, Antje
• Primary Examiner(s): Sullivan, Daniel
• Assistant Examiner(s): LOVE, TREVOR M
• Application Number:
  US13/549,399
• Publication Number:
  US 20130017284A1
• Time in Patent Office: 543 Days
• Field of Search: 514/740
• US Class Current: 514/740
• CPC Class Codes: A23L 2/52 Adding ingredients adding preservatives A23L2/44
• CPC Class Codes: A23L 33/175 Amino acids
• CPC Class Codes: A23L 33/30 Dietetic or nutritional methods, e.g. for losing weight A23L33/10 takes precedence
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/191 having two or more hydroxy groups, e.g. gluconic acid
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/194 having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/336 having three-membered rings, e.g. oxirane, fumagillin
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 36/87 : Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
• CPC Class Codes: A61K 38/22 : Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 45/06 : Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/08 : for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications

Abstract

Compositions and methods useful for inducing an increase in fatty acid oxidation or mitochondrial biogenesis, reducing weight gain, inducing weight loss, or increasing Sirt1, Sirt3, or AMPK activity are provided herein. Such compositions can contain synergizing amounts of a sirtuin-pathway activators, including but not limited to resveratrol, in combination with beta-hydroxymethylbutyrate (HMB), keto isocaproic acid (KIC), leucine, or combinations of HMB, KIC and leucine.

Claims

1. A composition comprising:

(a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and hydroxymethylbutyrate (HMB); and

(b) a sirtuin-pathway activator;

wherein molar ratio of component (a) to (b) in said composition is greater than about 20, and wherein the composition when administered to a subject in need thereof synergistically enhances mitochondrial biogenesis as measured by a decrease in weight gain of a subject, a decrease in visceral adipose volume of a subject, an increase in fat oxidation of a subject, an increase in irisin production of a subject, an increase in insulin sensitivity of a subject, an increase of glucose uptake in muscle of a subject, a decrease in inflammation markers, an increase in vasodilatation, and/or an increase in body temperature;

wherein the composition is substantially free of non-branched amino acids; and

wherein the composition comprises at least about 500 mg of leucine and/or at least about 200 mg of the one or more leucine metabolites.

2. The composition of claim 1, wherein the sirtuin pathway activator activates one or more of SIRT1, SIRT3, AMPK, and PGC1 α

.

3. The composition of claim 1, wherein mitochondrial biogenesis is increased by at least about 1, 3, 5, 6, 8, 10, 15, 20, or 50 fold.

4. The composition of claim 1, wherein the sirtuin pathway activator is a polyphenol or polyphenol precursor.

5. The composition of claim 4, wherein the polyphenol or polyphenol precursor is selected from the group consisting of chlorogenic acid, resveratrol, caffeic acid, cinnamic acid, ferulic acid, piceatannol, ellagic acid, epigallocatechin gallate, grape seed extract, and any analog thereof.

6. The composition of claim 4, wherein the polyphenol is a hydroxycinnamic acid or a stilbene.

7. The composition of claim 1, wherein the composition further comprises an anti-diabetic agent.

8. The composition of claim 1, wherein the composition is formulated as a unit dosage in liquid or solid form for oral consumption.

9. The composition of claim 1, wherein the mitochondrial biogenesis is about 20% greater than the additive effect of component (a) and component (b) as if each of component (a) and component (b) exerted its effect independently.

10. A food composition comprising:

(a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and hydroxymethylbutyrate (HMB);

(b) a sirtuin pathway activator, wherein (a) and (b) are present in an amount that synergistically effect an increase in sirtuin pathway output as measured by a decrease in weight gain of a subject, a decrease in visceral adipose volume of a subject, an increase in fat oxidation of a subject, an increase in insulin sensitivity of a subject, an increase of glucose uptake in muscle of a subject, an increase in vasodilatation, and/or an increase in body temperature; and

(c) a food carrier;

wherein molar ratio of component (a) to (b) in said composition is greater than about 20;

wherein the composition is substantially free of non-branched amino acids; and

wherein the composition comprises at least about 500 mg of leucine and/or at least about 200 mg of the one or more leucine metabolites.

11. The composition of claim 10, wherein the sirtuin pathway activator is a polyphenol or polyphenol precursor.

12. The composition of claim 10, wherein the sirtuin pathway activator is a phosphodiesterase inhibitor.

13. The composition of claim 10, wherein the increase in sirtuin pathway output is at least about 1, 3, 5, 6, 8, 10, 15, 20, or 50 fold.

14. The composition of claim 10, wherein the composition further comprises an anti-diabetic agent.

15. A method of enhancing fat oxidation in a subject in need thereof comprising administering to the subject a composition of claim 10 to effect an increase in the fat oxidation in the subject.

16. The composition of claim 10, wherein the sirtuin pathway output is about 20% greater than the additive effect of component (a) and component (b) as if each of component (a) and component (b) exerted its effect independently.

17. A composition comprising a unit dosage suitable for oral ingestion, said unit dosage comprising:

(a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and hydroxymetylbutyrate (HMB); and

(b) a substantially homogeneous population of polyphenol or polyphenol precursor molecules;

wherein the unit dosage is effective in inducing an increase in sirtuin pathway output as measured by a decrease in weight gain of a subject, a decrease in visceral adipose volume of a subject, an increase in fat oxidation of a subject, an increase in insulin sensitivity of a subject, an increase of glucose uptake in muscle of a subject, an increase in vasodilatation, and/or an increase in body temperature;

wherein molar ratio of component (a) to (b) in said composition is greater than about 20;

wherein the composition is substantially free of non-branched amino acids; and

wherein the composition comprises at least about 500 mg of leucine and/or at least about 200 mg of the one or more leucine metabolites.

18. The composition of claim 17, wherein the polyphenol or polyphenol precursor molecules are selected from the group consisting of chlorogenic acid, resveratrol, caffeic acid, cinnamic acid, ferulic acid, piceatannol, ellagic acid, epigallocatechin gallate, grape seed extract, and any analog thereof.

19. The composition of claim 17, wherein the increase in sirtuin pathway output is at least about 1, 3, 5, 6, 8, 10, 15, 20, or 50 fold.

20. The composition of claim 17, wherein the composition further comprises an anti-diabetic agent.

21. A method of enhancing fat oxidation in a subject in need thereof comprising administering to the subject a composition of claim 17 to effect an increase in the fat oxidation in the subject.

22. A method of treating diabetes comprising administering to the subject a composition of claim 17 to effect an increase in the insulin sensitivity in the subject.