Novel PGC-1 Isoforms and Uses Therefor

Abstract

The invention provides isolated nucleic acid molecules, designated PGC-1b and PGC-1c nucleic acid molecules, which encode novel isoforms of PGC-1 family members. The invention also provides antisense nucleic acid molecules, recombinant expression vectors containing PGC-1 nucleic acid molecules, host cells into which the expression vectors have been introduced, and nonhuman transgenic animals in which a PGC-1 gene has been introduced or disrupted. The invention still further provides isolated PGC-1 proteins, fusion proteins, antigenic peptides and anti-PGC-1 antibodies. Diagnostic methods utilizing compositions of the invention are also provided.

1 - 24 . (canceled) 
     
     
         25 . A method for identifying a compound which binds to an isolated polypeptide selected from the group consisting of:
 a) a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16, wherein the fragment comprises at least 10 contiguous amino acids of SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16;   b) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 60% identical to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:17; and   c) a polypeptide comprising an amino acid sequence which is at least 60% identical to the amino acid sequence of SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16 comprising:   i) contacting the polypeptide, or a cell expressing the polypeptide with a test compound; and   ii) determining whether the polypeptide binds to the test compound.   
     
     
         26 . The method of  claim 25 , wherein the binding of the test compound to the polypeptide is detected by a method selected from the group consisting of:
 a) detection of binding by direct detection of test compound/polypeptide binding;   b) detection of binding using a competition binding assay;   c) detection of binding using an assay for PGC-1b activity; and   d) detection of binding using an assay for PGC-1c activity.   
     
     
         27 . The method of  claim 26 , wherein PGC-1b activity is selected from the group consisting of:
 a) interaction, with a nuclear receptor;   b) modulation of UCP-2 expression;   c) modulation of Acyl Co-A Oxidase expression;   d) modulation of thermogenesis in adipose cells;   e) modulation of differentiation of adipose cells; and   f) modulation of insulin sensitivity of adipose cells.   
     
     
         28 . The method of  claim 26 , wherein PGC-1c activity is selected from the group consisting of:
 a) interaction with a nuclear receptor;   b) modulation of UCP-2 expression;   c) modulation of Acyl Co-A Oxidase expression;   d) modulation of thermogenesis in adipose cells;   e) modulation of differentiation of adipose cells; and   f) modulation of insulin sensitivity of adipose cells.   
     
     
         29 - 30 . (canceled) 
     
     
         31 . A method for identifying a compound which modulates the activity of an isolated polypeptide selected from the group consisting of:
 a) a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:7 SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16, wherein the fragment comprises at least 10 contiguous amino acids of SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16;   b) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 60% identical to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:17; and   c) a polypeptide comprising an amino acid sequence which is at least 60% identical to the amino acid sequence of SEQ ID NO:7, SEQ ID NO:10, SEQ ID NO:13, or SEQ ID NO:16 comprising:
 i) contacting the polypeptide with a test compound; and 
 ii) determining the effect of the test compound on the activity of the polypeptide to thereby identify a compound which modulates the activity of the polypeptide. 
   
     
     
         32 . The method of  claim 31 , wherein the activity of the polypeptide is selected from the group consisting of:
 a) interaction with a nuclear receptor;   b) modulation of UCP-2 expression;   c) modulation of Acyl Co-A Oxidase expression;   d) modulation of thermogenesis in adipose cells;   e) modulation of differentiation of adipose cells; and   f) modulation of insulin sensitivity of adipose cells.