Our laboratory is continuing studies on the molecular mechanisms responsible for transcriptional regulation in the adipose cell and the molecular biology of energy expenditure and of obesity. One focus has been on leptin, a hormone made in adipose cells that is important for adaptation to starvation and in feedback regulation of energy expenditure and adiposity. Mice without functional leptin develop massive obesity and diabetes mellitus due to overeating and decreased metabolic expenditure. One goal is an understanding of the signals controlling transcription of the leptin gene. We have defined C/EBP, Sp1, and TATA elements, in addition to a novel motif, as contributing to leptin promoter function. Humans express leptin in the placenta and we have elucidated the molecular basis for this. The same promoter is used in adipose and placental cells, but a placenta-selective enhancer is present upstream of the gene. The enhancer's functional motifs have been identified. Characterization of the interacting transcription factors is in progress. While studying leptin expression in mice, we observed that circulating leptin levels increase approximately 40-fold during pregnancy. We have now shown that the circulating leptin is bound to a soluble form of the leptin receptor. This variant of the leptin receptor is encoded by a mRNA splice isoform that contains a stop codon before the transmembrane region of the receptor. The secreted form of the leptin receptor is made by the placenta. This is the first characterization of a leptin binding protein. Studies are in progress to address the physiological significance of bound versus free leptin. We are also producing genetically modified mice expected to have altered 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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