In the past year, our laboratory has become interested in the molecular mechanisms responsible for transcriptional regulation in the adipose cell and the molecular biology of the regulation of energy expenditure and of obesity. Our initial focus has been on a newly discovered hormone, leptin. Leptin is made in adipose cells and is important in the response to starvation and in feedback regulation of energy expenditure and adiposity. Mice homozygous for a nonfunctional leptin (previously denoted obese) or leptin receptor (previously denoted diabetes) gene become massively obese and develop diabetes mellitus due to overeating and decreased metabolic expenditure. Our goal is an understanding of the signals controlling transcription of the leptin gene. One line of investigation has been a detailed characterization of the leptin promoter, defining its structure and then studying protein-DNA ubteractions and their functional implications using transient expression. We have defined C/EBP, Sp1- like, and TATA sequence elements in the promoter, shown cognate factor binding, and demonstrated their functional contribution to transcription. A complimentary approach has been examination of the regulation of leptin in intact adipose cells. Our plan is that the studies of endogenous gene expression will converge with the promoter characterization work, leading to elucidation of the machanistic details. Out of a number of hormones tested, glucocordicoids specifically and selectively increased transcription of the endogenous leptin gene and were selected for further characterization. This result is consistent with the observation of elevated leptin levels in patients with Cushing's syndrome. In the past year we have begun generating genetically modified mice expected to have defects in adipose cell biology and in energy metabolism. These long-term studies will allow us to take the detailed knowledge of hormonal and promoter regulation and apply it in the complete organism.
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