Compositions for treating or preventing obesity and insulin resistance disorders

• US 20060111435A1
• Filed: 07/01/2005
• Published: 05/25/2006
• Est. Priority Date: 12/29/2003
• Status: Active Grant

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation), The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Sinclair, David A., Alexander-Bridges, Maria
• Granted Patent: US 8,017,634 B2
• Time in Patent Office: Days
• US Class Current: 514/456
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/12 Ketones
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/455 Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 31/706 containing six-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin

Abstract

Provided herein are methods and compositions for modulating the activity or level of a sirtuin, thereby treating or preventing obesity or an insulin resistance disorder, such as diabetes in a subject. Exemplary methods comprise contacting a cell with a sirtuin activating compound or an inhibitory compound to thereby increase or decrease fat accumulation, respectively.

Claims

1. A method for treating or preventing insulin resistance disorder in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that increases the activity and/or protein level of a sirtuin in a cell.

2. The method of claim 1, wherein the agent is a sirtuin-activating compound, or a salt or prodrug thereof.

3. The method of claim 1, wherein the sirtuin-activating compound comprises a compound selected from the group of compounds consisting of compounds of formulas 1-18, 23-47, 52 and 54-87.

4. The method of claim 3, wherein the sirtuin-activating compound is resveratrol, fisetin, butein, piceatannol or quercetin.

5. The method of claim 1, further comprising administering to the subject a second agent that:

(i) increases the activity or protein level of a sertuin in a cell;

increases the activity or protein level of 5′

-AMP-activated protein kinase (AMPK) in a cell;

or is an anti-diabetic agent.

6. The method claim 5, wherein the second agent is an anti-diabetic agent.

19. The method of claim 1, wherein the subject is human.

7. A method for reducing the weight of a subject, or preventing weight gain in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that increases the activity or protein level of a sirtuin in a cell.

8. The method of claim 7, wherein the agent is a sirtuin-activating compound, or a salt or prodrug thereof.

9. The method of claim 7, wherein the sirtuin-activating compound comprises a compound formula selected from the group of compounds consisting of compounds of formulas 1-18, 23-47, 52 and 54-87.

10. The method of claim 9, wherein the sirtuin-activating compound is resveratrol, fisetin, butein, piceatannol or quercetin.

11. The method of claim 7, further comprising administering to the subject a second agent that:

(i) increases the activity or protein level of a sertuin in a cell;

increases the activity or protein level of 5′

-AMP-activated protein kinase (AMPK) in a cell;

or is an anti-obesity agent.

12. The method claim 11, wherein the second agent is an anti-obesity agent.

20. The method of claim 7, wherein the subject is human.

13. A method for promoting weight gain in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of an agent that reduces the activity or protein level of a sirtuin in a cell.

14. The method of claim 13, wherein the agent is a sirtuin-inhibitory compound.

15. The method of claim 13, wherein the sirtuin-inhibitory compound comprises a formula selected from the group consisting of formulas 19-21, 48-51, 53 and 88-90.

16. The method of claim 13, wherein the sirtuin-inhibitory compound is nicotinamide.

17. The method of claim 13, further comprising administering to the subject a second agent.

18. The method of claim 13, wherein the second agent is a weight gain-promoting agent.

21. The method of claim 13, wherein the subject a human.

22. A method for preventing fat accumulation in a cell with lipogenic capacity, comprising contacting the cell with an agent that increases the activity or protein level of a sirtuin.

24. The method of claim 22, wherein the cell with lipogenic capacity is a liver, pancreas or muscle cells.

23. A method for enhancing fat accumulation in, or adipogenesis of, a cell, comprising contacting a cell with an agent that decreases the activity or protein level of a sirtuin.

25. The method of claim 23, wherein the cell is an adipocyte.

26. A method for preventing the differentiation of a pre-adipocyte, comprising contacting the pre-adipocyte with an agent that increases the activity or protein level of a sirtuin in a cell, such that the differentiation of the pre-adipocyte is inhibited.

27. The method of claim 26, wherein the cell is in vitro.

28. A method for identifying an agent that modulates weight or weight gain, comprising:

(i) identifying an agent that modulates a sirtuin; and

(ii) determining the effect of the agent on weight gain, wherein the presence of an effect of the agent on weight or weight gain indicates that the agent modulates weight or weight gain.

29. A method for identifying an agent for treating or preventing obesity, insulin resistance, metabolic syndrome or diabetes in a subject, comprising:

(i) identifying an agent that activates a sirtuin; and

(ii) determining the effect of the agent on obesity, insulin resistance, metabolic syndrome or diabetes, wherein a decrease in the presence, degree or occurrence of obesity, insulin resistance, metabolic syndrome or diabetes indicates that the agent is an agent for treating or preventing these conditions.