Role of BMPs on Brown Adipogenesis and Thermogenesis

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DESCRIPTION (provided by applicant): Obesity is a major public health problem in the US and is associated with many serious illnesses, such as diabetes, heart diseases and cancer. Obesity develops when energy intake exceeds energy expenditure. Recently, there has been a great deal of interest in adaptive thermogenesis as a physiological defense system against obesity. Brown adipose tissue (BAT) is specialized in thermogenic energy expenditure through the expression of peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) and uncoupling protein-1 (UCP-1). As part of a long-term goal to investigate the regulation of adipocyte differentiation and energy homeostasis by various hormones and nutrients, we have begun to examine the effect of the bone morphogenetic proteins (BMPs) on BAT. Our preliminary data have suggested a potential role of BMPs on differentiation of brown preadipocytes and expression of PGC-1 and UCP-1. Here, we propose to elucidate the molecular mechanisms by which BMPs influence adipocyte cell fate decision and regulate adaptive thermogenesis in BAT. We will initially determine whether BMPs may serve as a molecular switch between brown and white fat cell differentiation in pluripotent stem cells as well as in committed preadipocytes. In addition, we will also examine the effect of BMPs on regulation of adaptive thermogenesis by measuring cellular respiration and mitochondria! biogenesis. Once these are characterized, we will further investigate the signaling pathways used by BMPs to regulate brown adipogenesis and adaptive thermogenesis, with emphasis on regulation of PGC-1 and UCP-1 expression. The data from this research will increase our understanding of adipocyte differentiation, energy balance, and BMP actions, and may help to define a potential target for therapeutic intervention in the management of obesity and related diseases.