Role of BMPs on Brown Adipogenesis and Thermogenesis

描述(申请人提供)：在美国，肥胖是一个主要的公共健康问题，与许多严重的疾病有关，如糖尿病、心脏病和癌症。当能量摄入超过能量消耗时，肥胖就会发生。最近，适应性产热作为一种抵抗肥胖的生理防御系统引起了人们极大的兴趣。棕色脂肪组织(BAT)通过表达过氧化物酶体增殖物激活受体-1(PGC-1)和解偶联蛋白-1(UCP-1)，专门负责热能消耗。作为研究各种激素和营养物质对脂肪细胞分化和能量平衡调节的长期目标的一部分，我们已经开始研究骨形态发生蛋白(BMPs)对蝙蝠的影响。我们的初步数据表明，BMPs在棕色前脂肪细胞的分化以及PGC-1和UCP-1的表达方面具有潜在的作用。在此，我们拟阐明BMPs影响BAT脂肪细胞命运决定和调节适应性产热的分子机制。我们将初步确定BMPs是否可能在多能干细胞和定向前脂肪细胞中作为棕色和白色脂肪细胞分化的分子开关。此外，我们还将通过测量细胞呼吸和线粒体来研究BMPs在适应性产热调节中的作用！生物发生学。一旦这些特征被确定，我们将进一步研究BMPs用来调节棕色脂肪生成和适应性产热的信号通路，重点是PGC-1和UCP-1的表达调控。这项研究的数据将增加我们对脂肪细胞分化、能量平衡和BMP作用的理解，并可能有助于确定肥胖和相关疾病治疗干预的潜在靶点。

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.