MOLECULAR BASIS OF ADIPOGENESIS

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DESCRIPTION: (Adapted from the applicant's abstract) In the proposed studies, the applicant's goal will be to identify and characterize mammalian genes involved in the regulation of early stages of adipocyte differentiation. Currently, there are no morphological or molecular markers to identify adipocyte precursors in mammals. The molecular switches that permit the adipogenic programming of these cells are not well understood. Therefore, the applicant will focus on molecules that have been implicated in comparable processes in the fruit fly, Drosophila Melanogaster, and test whether homologues of these genes play similar roles in mammalian systems. The fruit fly carries a structure called fat body that appears to be the functional homologue of mammalian adipose tissue and liver. Earlier studies have identified genes that play a crucial role in the formation of precursor cells of the Drosophila fat body. One such gene is the Drosophila serpent (srp) gene. Serpent is an interesting gene since it is a member of the GATA family and has been demonstrated to be an essential factor for the development of Drosophila fat body and the hemapoietic system. Serpent is also required for endodermal development and differentiation and morphogenesis of the gut. The applicant hypothesizes that the mammalian homologue(s) of serpent, GATA family of transcription factors, is also expressed in mammalian adipose tissue and plays an important role in adipogenesis. The applicant's preliminary experiments have demonstrated that at least two members of the GATA family of transcription factors, GATA-2 and GATA-3, are expressed highly in the adipose tissue of adult mice. Interestingly, GATA-3 expression is restricted to white and not brown adipose tissue. Furthermore, expression was not detected in isolated mature adipocytes suggesting that the primary source of GATA-3 expression in adipose tissue is adipocyte precursors. In strong support of this, these factors are also expressed in cultured 3T3-F442A and 3T3-L1 preadipocytes but their expression is diminished very early during differentiation. When expressed constitutively, they block the differentiation of adipocytes. Specific aims are to (a) characterize the expression and biology of GATA factors in adipocytes, b) study the mechanisms by which GATA factors regulate differentiation of adipocytes by focusing on potential crosstalk with adipogenic transcription factors, and c) generate gain of function transgenic mice to test the biology of GATA on adipogenesis in vivo. Through this line of investigation, the applicant hopes to obtain novel and important information on a key biological process involving adipogenesis.