Compositions and methods for modulating metabolic pathways

• US 8,617,886 B2
• Filed: 07/13/2012
• Issued: 12/31/2013
• 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:
  US13/549,381
• Publication Number:
  US 20130017283A1
• Time in Patent Office: 536 Days
• Field of Search: 435/375
• US Class Current: 435/375
• 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 formulated for oral consumption, comprising:

(a) at least about 500 mg of leucine and/or at least about 200 mg of one or more leucine metabolites, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

(b) at least about 10 mg of a sirtuin pathway activator;

wherein the components of (a) and (b) are present in an amount that is effective in increasing sirtuin pathway output by at least about 1 fold as compared to that of component (a) or (b) when being used alone, wherein the increased sirtuin-pathway output is evidenced by an increase in a physiological effect selected from the group consisting of fatty acid oxidation, mitochondrial biogenesis, glucose uptake, palmitate uptake, oxygen consumption, weight loss, visceral adipose tissue loss, insulin sensitivity, an inflammation marker level, vasodilatation, and body temperature, when (i) media from myotubes or adipocytes treated with the composition is administered to the other of the myotubes or adipocytes, (ii) the composition is administered to myotubes or adipocytes, or (iii) the composition is administered to a subject,

wherein the composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, and proline, and

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

2. The composition of claim 1, wherein the sirtuin pathway activator is in an amount of at least 35 mg.

3. The composition of claim 1, wherein the sirtuin pathway activator activates one or more of SIRT1, SIRT3, AMPK, and PGC1α

.

4. The composition of claim 1, wherein the composition comprises less than about 1% of the individual amino acids alanine, glutamic acid, glycine, and proline.

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

6. The composition of claim 5, 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.

7. The composition of claim 5, wherein the polyphenol is a hydroxycinnamic acid or a stilbene.

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

9. The composition of claim 1, wherein the composition is formulated as a food composition, tablet, capsule, gel capsule, beverage, or snack bar.

10. A method of enhancing fat oxidation in a subject in need thereof comprising administering to the subject a composition of claim 1 to effect an increase in fat oxidation in the subject.

11. A method of treating diabetes comprising administering to the subject a composition of claim 1 to effect an increase in the insulin sensitivity in the subject.

12. A method of increasing production of irisin in a cell comprising administering to the cell a composition of claim 1 to effect the increase in irisin production.

13. The method of claim 12, wherein the composition comprises leucine and one or more of (i) resveratrol, and (ii) cinnamic acid.

14. The method of claim 12, wherein the composition comprises HMB and one or more of (i) resveratrol, and (ii) cinnamic acid.

16. The method of claim 12, wherein the sirtuin pathway activator is a phosphodiesterase inhibitor.

18. The method of claim 12, wherein the sirtuin pathway activator is a polyphenol or polyphenol precursor.

19. The method of claim 18, 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.

29. A composition of claim 1, 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.

15. A composition comprising:

(a) at least about 500 mg of leucine and/or at least about 200 mg of one or more leucine metabolites, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

(b) at least about 10 mg of a sirtuin pathway activator;

wherein the composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, and proline.

17. The composition of claim 15, wherein the composition is formulated as a food composition, tablet, capsule, gel capsule, beverage or snack bar.

20. The composition of claim 15, wherein the composition comprises less than about 1% of the individual amino acids alanine, glutamic acid, glycine, and proline, and wherein the composition is additionally substantially free of an individual non-branched amino acid selected from the group consisting of arginine, asparagine, aspartic acid, cysteine, glutamine, histidine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, and tyrosine.

23. The composition of claim 15, wherein the sirtuin pathway activator is a hydroxycinnamic acid or a stilbene.

24. The composition of claim 15, wherein the composition comprises less than about 1% of the individual amino acids alanine, glutamic acid, glycine, and proline, and wherein the composition is additionally substantially free of an individual non-branched amino acid selected from the group consisting of arginine, asparagine, aspartic acid, cysteine, glutamine, histidine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, and tyrosine.

21. A composition comprising:

(a) at least about 500 mg of leucine and/or at least about 200 mg of one or more leucine metabolites, wherein the one or more leucine metabolites are selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and HMB; and

(b) at least about 25 mg of a sub-therapeutic amount of an anti-diabetic agent selected from the group consisting of biguanide and thiazolidinedione;

wherein the component of (a) and (b) are present in an amount that, when administered to a subject synergistically increases insulin sensitivity in said subject as compared to administering to a subject component (a) or component (b) alone, and

wherein the composition is substantially free of the individual amino acids alanine, glutamic acid, glycine, and proline.

22. The composition of claim 21, wherein the anti-diabetic agent is a sirtuin pathway activator.

25. The composition of claim 21, wherein the biguanide is metformin or any analog thereof.

26. The composition of claim 21, wherein the composition is formulated as a food composition, tablet, capsule, gel capsule, beverage, or snack bar.

27. The composition of claim 21, wherein said increase in insulin sensitivity is at least about a 1-fold increase.

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

30. A method of potentiating the therapeutic efficacy of a biguanide comprising administering simultaneously or sequentially to a subject component (a) and component (b) of claim 21, wherein the administration of (a) and (b) is in an amount that synergistically increases insulin sensitivity, and wherein component (b) is a biguanide.