Secreted ap2 and methods of inhibiting same

Abstract

A method of reducing a symptom of a clinical disorder characterized by aberrantly elevated circulating aP2 is carried out by administering to a subject an inhibitor of secreted aP2, secretion of aP2, or a serum aP2 blocking agent. For example, glucose intolerance is reduced following administration of such an inhibitor or agent. Exemplary compositions inhibit cellular secretion of aP2 or bind to circulating aP2, thereby reducing the level or activity of aP2 in blood or serum.

1 . A method of treating or reducing the severity of an aP2-mediated disorder, comprising administering to a subject an inhibitor of secreted aP2 or an inhibitor of aP2 secretion. 
     
     
         2 . The method of  claim 1 , wherein said subject is identified as comprising an elevated level of circulating aP2. 
     
     
         3 . The method of  claim 1 , wherein said disorder is selected from the group consisting of metabolic syndrome, obesity, diabetes, fatty liver disease, glucose intolerance, atherosclerosis, asthma, hypertension, stroke, neurodegenerative disease, chronic haemodialysis (CD), obstructive sleep apnea, lipodystrophy in HIV-infected patients, and lipolysis. 
     
     
         4 . The method of  claim 1 , wherein said inhibitor of secreted aP2 comprises a soluble aP2 blocking agent. 
     
     
         5 . The method of  claim 4 , wherein said blocking agent is an aP2-specific antibody or aP2-binding fragment thereof. 
     
     
         6 . A method of preventing or reducing the severity of metabolic disease, comprising administering to a subject a composition that reduces serum aP2 concentration. 
     
     
         7 . The method of  claim 6 , wherein said serum aP2 concentration is reduced by at least 10%. 
     
     
         8 . The method of  claim 6 , wherein said composition is an aP2-specific antibody. 
     
     
         9 . The method of  claim 6 , wherein said composition is an antibody that binds to a discontinuous epitope of aP2. 
     
     
         10 . The method of  claim 9 , wherein said epitope is surface exposed on a 3-dimensional structure of aP2 in solution. 
     
     
         11 . The method of  claim 9 , comprising at least one of the following sequences: residues 1-5, residue 22, residues 36-37, residues 46-47, residue 57, residues 59-60, residue 78, residue 80, residue 89, residues 97-101, residues 110-112, or residue 122 of SEQ ID NO:3. 
     
     
         12 . A method of reducing a symptom of metabolic disease, comprising administering to a subject an inhibitor of aP2 secretion by a cell. 
     
     
         13 . The method of  claim 12 , wherein said symptom is glucose intolerance. 
     
     
         14 . The method of  claim 12 , wherein said cell is an adipocyte. 
     
     
         15 . A method of treating diabetes, comprising administering to a subject diagnosed as having or at risk of developing Type II diabetes an inhibitor of aP2 secretion. 
     
     
         16 . A method of identifying an inhibitor of aP2 secretion, comprising contacting an aP2-secreting cell with a candidate compound and detecting a level of extracellular aP2, wherein a decrease in said extracellular aP2 in the presence of said compound compared to in the absence of said compound indicates that said compound inhibits aP2 secretion. 
     
     
         17 . The method of  claim 16 , wherein said cell is an adipocyte or a macrophage.