Methods and compositions for treating obesity and/or diabetes and for identifying candidate treatment agents

Abstract

Provided are methods and compositions for identifying candidate agents for treatment of obesity, liver disease, and/or diabetes. Such methods include, e.g., contacting a mammalian cell or cell population with a test agent, and measuring an expression level and/or activity level of ClpP in the mammalian cell or in cells of the cell population. Also provided are methods and compositions for treating an individual (e.g., one who is obese and/or has diabetes). Treatment methods include administering an inhibitor of ClpP to the individual (e.g., to prevent or reduce weight gain, to increase insulin sensitivity, and/or to increase glucose tolerance).

What is claimed is: 
     
         1 . A method of treating an individual with obesity, liver disease, and/or diabetes, the method comprising:
 administering an inhibitor of ClpP to the individual in an amount effective for decreasing an amount of fat tissue in the individual, preventing or reducing weight gain of the individual, increasing insulin sensitivity of the individual, and/or increasing glucose tolerance of the individual.   
     
     
         2 . The method according to  claim 1 , wherein the inhibitor of ClpP is an RNAi agent or a gene editing agent that specifically reduces expression of ClpP. 
     
     
         3 . The method according to  claim 1 , wherein the inhibitor of ClpP is administered such that reduction of ClpP expression is substantially liver-specific, and the amount administered is effective for increasing insulin sensitivity of the individual. 
     
     
         4 . The method according to  claim 1 , wherein the inhibitor of ClpP is a small molecule. 
     
     
         5 . The method according to  claim 4 , wherein the small molecule is a β-Lactone. 
     
     
         6 . The method according to  claim 5 , wherein the β-Lactone is (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridin-3-yl)ethyl)oxetan-2-one or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method according to  claim 1 , wherein the inhibitor of ClpP is delivered directly to the individual's liver, and the amount administered is effective for increasing insulin sensitivity of the individual. 
     
     
         8 . The method according to  claim 1 , wherein the administering comprises local injection. 
     
     
         9 . The method according to  claim 1 , further comprising a step of measuring insulin sensitivity of the individual.