Methods for inhibiting adipogenesis and for treating type 2 diabetes

A method for identifying an agent that increases Fxr expression comprising contacting a plurality of cells that contain a Fxr promoter operably linked to a coding sequence for Fxr or a reporter gene with a candidate agent;

• assaying for expression of Fxr or the reporter in the presence and absence of the candidate agent;
• and comparing Fxr or reporter expression in the presence and absence of the candidate agent, whereby an increase in Fxr or reporter expression in the presence of the candidate agent is indicative of the identification of an agent that increases Fxr expression.

A method of identifying an agent that activates Fxr comprising contacting a plurality of cells that contain Fxr with a candidate agent;

• assaying for activation of Fxr in the presence and absence of the candidate agent;
• and comparing activation of Fxr in the presence and absence of the candidate agent, wherein an increase in activation in the presence of the agent is indicative of the identification of an agent that activates Fxr.

A method for inhibiting adipogenesis comprising contacting a cell capable of adipogenesis with an agent selected from the group consisting of an agent that increases levels of Foxa-2 mRNA, an agent that increases levels of Foxa-2 protein, an agent that increases levels of Fxr mRNA, an agent that increases levels of Fxr protein, and an agent that activates Fxr.

A method for treating obesity, metabolic syndrome or Type 2 diabetes comprising administering to a subject in need of such treatment a composition comprising an agent selected from the group consisting of an agent that increases levels of Foxa-2 mRNA, an agent that increases levels of Foxa-2 protein, an agent that increases levels of Fxr mRNA, an agent that increases levels of Fxr protein, and an agent that activates Fxr.

A method of identifying an agent that inhibits the phosphorylation of Foxa-2 comprising combining a candidate agent with a polypeptide having Akt kinase activity and a substrate comprising the phosphorylation domain of Foxa-2;

• assaying for phosphorylation of the substrate in the presence and absence of the candidate agent;
• and comparing phosphorylation in the presence and absence of the candidate agent, whereby a decrease in phosphorylation of the substrate in the presence of the candidate agent is indicative of the identification of an agent that inhibits phosphorylation of Foxa-2.

A method of identifying an agent that inhibits the nuclear exclusion of Foxa-2 in hepatocytes comprising contacting a plurality of hepatocytes, under conditions whereby Foxa-2 exhibits nuclear exclusion, with a candidate agent;

• determining the intracellular location of Foxa-2 in the presence and absence of the candidate agent;
• and comparing the intracellular location of Foxa-2 in the presence and absence of the agent, whereby an increase in nuclear localization of Foxa-2 in the presence of the candidate agent is indicative of the identification of an agent that inhibits nuclear exclusion of Foxa-2 in hepatocytes.