Compositions for treating or preventing obesity and insulin resistance disorders

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.

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 a gent 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.  
     
     
         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.  
     
     
         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.  
     
     
         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.  
     
     
         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.  
     
     
         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.  
     
     
         19 . The method of  claim 1 , wherein the subject is human.  
     
     
         20 . The method of  claim 7 , wherein the subject is human.  
     
     
         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.  
     
     
         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.  
     
     
         24 . The method of  claim 22 , wherein the cell with lipogenic capacity is a liver, pancreas or muscle cells.  
     
     
         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.