Methods and Compositions for Modulating Gluconeogenesis Using PGC-1

Abstract

The invention provides novel methods and compositions for modulating gluconeogenesis through modulation of PGC-1 activity or expression. Also provided are methods for identifying compounds that modulate gluconeogenesis through modulation of PGC-1 activity or expression, as well as methods for identifying compounds that modulate the interaction of PGC-1 with PGC-1 target molecules. Further provided are methods for treating disorders characterized by aberrant gluconeogenesis.

1 - 33 . (canceled) 
     
     
         34 . A method for identifying a compound capable of modulating gluconeogenesis comprising:
 a) contacting a cell with a compound; and   b) assaying the ability of the compound to modulate the activity of a PGC-1 polypeptide by determining whether expression of at least one of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase is modulated
 to thereby identify a compound that modulates gluconeogenesis. 
   
     
     
         35 . The method of  claim 34 , wherein expression of the at least one of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase activity is increased. 
     
     
         36 . The method of  claim 34 , wherein expression of the at least one of phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase activity is decreased. 
     
     
         37 - 39 . (canceled) 
     
     
         40 . The method of  claim 34 , wherein expression is measured by measuring the expression or activity of a reporter construct comprising the promoter/enhancer region from at least one of the phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase genes, operatively linked to a nucleic acid molecule encoding a reporter gene. 
     
     
         41 . The method of  claim 34 , wherein determining whether PGC-1 activity is modulated comprises determining whether glucose output from the cell is modulated. 
     
     
         42 . The method of  claim 34 , wherein the cell is a hepatocyte. 
     
     
         43 . The method of  claim 42 , wherein the hepatocyte is selected from the group consisting of a primary hepatocyte and a Fao hepatoma cell. 
     
     
         44 - 77 . (canceled)