Regulators of PPARdelta (beta) and their use in the treatment of obesity and insulin resistance

Abstract

Obesity is a common clinical problem in most developed nations and is also rapidly becoming a major health concern in developing nations. Overweight individuals frequently suffer from several metabolic disorders such as insulin resistance, type 2 diabetes and dyslipidemia. This invention discloses proof of principle for the role PPARδ (also known as β) plays in the development of diet-induced obesity. In accordance with the present invention, a new method for treating obesity, insulin resistance and hyperlipidemia through administration of a pharmaceutical composition containing a chemical agent that antagonizes the function of PPARδ(β) protein, decreases PPARδ(β) gene expression and or transactivation of PPARδ(β) target gene expression is disclosed. This invention also proposes that obese, insulin resistant hyperlipidemic patients can be effectively treated with a combination of a PPARδ(β) antagonist with either an anti-diabetic agent or a lipid-lowering agent (or both).

What is claimed is:  
     
         1 . A method for treating obesity in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition that inhibits PPARδ(β) activity.  
     
     
         2 . A method according to  claim 1 , wherein said mammal is a human.  
     
     
         3 . A method for treating obesity in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition that modulates PPARδ(β) activity.  
     
     
         4 . A method according to  claim 3 , wherein said animal is a human.  
     
     
         5 . A method for treating obesity, insulin resistance and dyslipidemia in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition that inhibits PPARδ(β) activity in combination with an antidiabetic agent and/or a lipid-lowering agent.  
     
     
         6 . A method according to  claim 5 , wherein said mammal is a human.  
     
     
         7 . A method for treating obesity, insulin resistance and dyslipidemia in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or pharmaceutical composition that modulates PPARδ(β) activity in combination with an antidiabetic agent and/or a lipid-lowering agent.  
     
     
         8 . A method according to  claim 7 , wherein said mammal is a human.  
     
     
         9 . A method of screening compounds with an assay to identify inhibitors or regulators of PPARδ(β) activity, wherein the assay is selected from the following group: in vitro binding assay, cell based transactivation assay, adipocyte differentiation assay, and in vivo obese animal model assay.  
     
     
         10 . A method for treating osteoarthritis in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition that inhibits PPARδ(β) activity.  
     
     
         11 . A method according to  claim 10 , wherein said animal is a human.  
     
     
         12 . A method for treating osteoarthritis in a mammal comprising administering to a host in need of such treatment a therapeutically effective amount of a compound or a pharmaceutical composition that modulates PPARδ(β) activity.  
     
     
         13 . A method according to  claim 12 , wherein said animal is a human.  
     
     
         14 . A method according to any one of claims  3 ,  7  or  12 , wherein PPARδ(β) activity modulation is effected by regulating any one of the following: expression of the PPARδ(β) gene, PPARδ(β) protein activity, and transactivation of PPARδ(β) target gene expression.  
     
     
         15 . A pharmaceutical composition for the treatment of obesity and insulin resistance comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound which inhibits or modulates PPARδ(β) activity.