Compositions for treating obesity and insulin resistance disorders
View Patent ↗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.
1. A method of treating an insulin resistance disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of a non-naturally occurring compound that increases the activity and/or protein level of SIRT1.
2. The method of claim 1 , wherein the non-naturally occurring compound is a sirtuin-activating compound, or a salt thereof.
3. The method of claim 1 , wherein the insulin resistance disorder is diabetes.
4. The method of claim 1 , wherein the insulin resistance disorder is obesity.
5. The method of claim 1 , wherein the insulin resistance disorder is metabolic syndrome.
6. The method of claim 2 , wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 5.
7. The method of claim 6 , wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 10.
8. The method of claim 7 , wherein the non-naturally occurring compound activates the deacetylase activity of SIRT1 by a factor of at least about 20.
9. The method of claim 2 , wherein the non-naturally occurring compound has an EC 50 for activating SIRT1 that is less than about 100 μM.
10. The method of claim 9 , wherein the non-naturally occurring compound has an EC 50 for activating SIRT1 that is less than about 10 μM.
11. The method of claim 10 , wherein the non-naturally occurring compound has an EC 50 for activating SIRT1 that is less than about 1 μM.
12. The method of claim 1 , further comprising administering to the subject a second agent that: increases the activity or protein level of a sirtuin in a cell; increases the activity or protein level of 5′-AMP-activated protein kinase (AMPK) in a cell; is an anti-diabetic agent; or is an anti-obesity agent.
13. The method of claim 12 , wherein the second agent is an anti-diabetic agent.
14. The method of claim 12 , wherein the second agent is an anti-obesity agent.
15. The method of claim 2 , wherein the non-naturally occurring compound does not substantially inhibit the catalytic activity of cyclooxygenase.
16. The method of claim 2 , wherein the non-naturally occurring compound does not substantially inhibit PI3-kinase.
17. The method of claim 2 , wherein the non-naturally occurring compound does not substantially inhibit tyrosine protein kinase.