HORMONAL CONTROL OF ADIPOSE GENE EXPRESSION

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The LONG-TERM GOAL of this research is to understand how insulin and counter-regulatory agents control the expression of genes involved in insulin action and energy storage in the adipocyte. We have cloned, determined the structures and studied the regulation of a family of mouse differentially-expressed adipocyte genes that encode proteins important for energy storage and insulin action. These include the genes for: the insulin receptor; the insulin-responsive glucose transporter, GLUT4 (and also GLUT1); 422(aP2) protein; two stearoyl-CoA desaturases (SCD1 and SCD2); CCAAT/enhancer binding protein (C/EBPalpha) and C/EBPbeta (LAP). We now plan to investigate the mechanisms by which certain of these genes (the GLUT4, SCD2 and C/EBPalpha genes) are regulated using the 3T3-L1 preadipocyte/adipocyte model system. This subset of genes was selected for further study because of the importance of their gene products in insulin action an/or in preadipocyte differentiation and because of the substantial progress we have made in characterizing their regulation. The SPECIFIC AIMS of this research are: 1. to elucidate the molecular basis of the regulation of GLUT4 gene: by hormones whose effects are mediated through cAMP in the fully- differentiated adipocyte, and by the transcription factor, C/EBPalpha (and its homologues) during differentiation of preadipocytes into adipocytes. An impaired expression of the GLUT4 gene would be expected to cause resistance of glucose uptake to insulin similar to that which accompanies Type 2 (NIDDM) diabetes. 2. to investigate the mechanism by which a nuclear factor, expressed in preadipocytes but not adipocytes, represses transcription of the SCD2 gene. The "preadipocyte factor" will be purified sequenced and its role in differentiation-induced expression of the SCD2 gene (and possibly other genes) will be determined. 3. to determine the mechanism(s) by which expression of the C/EBPalpha gene is activated during differentiation of preadipocytes into adipocytes. The roles of the C/EBP binding site (a possible site of autoactivation) and a putative repressor binding site in the gene will be investigated. We have obtained compelling evidence that C/EBPalpha serves an essential role in the coordinate activation of a group of adipose-specific genes during adipose conversion.