Methods for treating obesity by inhibiting expression of obese gene product receptor variant

Abstract

The present invention relates to a variant form of the receptor for the obese gene product. In particular, the invention relates to methods of detecting this receptor variant in cells and tissues of obese individuals. In addition, it relates to methods of inhibiting or down-regulating expression of this variant in cells to augment their responsiveness to weight regulation by leptin as well as methods of using compounds to directly activate signal transduction pathways associated with this ligand-receptor system.

1 . A method for detecting a defective OB-R in cells comprising: 
 (a) extracting RNA from a cell population;    (b) contacting the RNA with an oligonucleotide derived from a portion of the sequence depicted in  FIG. 1A-1E ; and    (c) detecting hybridization of the RNA with the oligonucleotide.    
     
     
         2 . The method of  claim 1  in which the cell population is obtained from the brain.  
     
     
         3 . The method of  claim 1  in which the cell population is obtained from the lung.  
     
     
         4 . The method of  claim 1  in which the cell population is obtained from the kidney.  
     
     
         5 . The method of  claim 1  in which the oligonucleotide is derived from nucleotide residue #2770 and beyond in the sequence depicted in  FIG. 1A-1E .  
     
     
         6 . A method for treating obesity, comprising administering to an individual an effective amount of an agent capable of inhibiting expression of an OB-R variant gene.  
     
     
         7 . The method of  claim 6  in which the OB-R variant gene further comprises the sequence of  FIG. 1A-1E  or which is capable of selectively hybridizing to it.  
     
     
         8 . The method of  claim 7  in which the agent is an antisense molecule complementary to mRNA encoded by the sequence of  FIG. 1A-1E .  
     
     
         9 . The method of  claim 7  in which the agent is a ibozyme molecule specific for mRNA encoded by the sequence of  FIG. 1A-1E .  
     
     
         10 . The method of  claim 7  in which the agent is a riple helix component.  
     
     
         11 . A method for identifying a compound capable of supplementing biological activity of leptin, comprising: 
 (a) incubating host cell expressing an OB-R variant with leptin;    (b) incubating a portion of the leptin-treated cells with a test compound; and    (c) comparing activation signal in the cells treated in step (b) with cells treated in step (a);    thereby determining whether the compound augments activation of the OB-R variant by leptin.    
     
     
         12 . The method of  claim 11  in which the OB-R variant is encoded by the sequence depicted in  FIG. 1A-1E .