Role of BMPs in Adipogenesis, Mitochondrial Function and Energy Homeostasis

描述（由申请人提供）：肥胖是一个全球性的公共卫生问题，其原因是能量摄入和消耗之间的不平衡。脂肪组织在能量平衡的调节中起着重要的作用。哺乳动物中存在两种功能不同类型的脂肪组织：白色脂肪组织是甘油三酯储存和脂肪酸释放的主要部位，棕色脂肪组织专门用于通过产热消耗能量。长期目标是确定这两种脂肪细胞类型的分化命运和功能不同的因素。这些因素可能有助于调节全身能量平衡和肥胖的发展。我们的初步研究表明，骨形态发生蛋白（BMP）-7在棕色脂肪形成和线粒体生物合成的调节中起重要作用。基于这些发现和之前关于BMP对白色脂肪细胞分化影响的知识，我们假设BMP家族的不同成员在决定棕色与白色脂肪组织的差异发育命运、调节这些细胞的产热功能方面发挥着关键作用，从而有助于调节全身能量稳态。拟议的研究将确定BMP影响脂肪细胞命运决定，脂肪细胞分化和线粒体活性的分子机制，在体外和体内设置。具体目标是： (1)确定BMP-7在指定棕色脂肪细胞命运和调节定向棕色和白色前脂肪细胞、多能间充质细胞、分选的原代脂肪祖细胞和人前脂肪细胞中的产热功能中的作用。(2)剖析不同BMP，特别是BMP-7，调节棕色与白色脂肪生成和线粒体功能的分子机制。(3)通过用BMP处理瘦小鼠和肥胖小鼠并表征其对脂肪生理学和全身能量代谢的影响，确定BMP在调节脂肪细胞分化、线粒体功能和全身能量平衡中的体内作用。BMP信号传导在脂肪发育中的发育作用将通过表征组成型和诱导型脂肪特异性BMP受体敲除小鼠来进一步研究。这些研究将增加我们对脂肪细胞分化、能量平衡和BMP作用的理解，并可能有助于开发肥胖和相关疾病的潜在治疗方法。

DESCRIPTION (provided by applicant): Obesity is a public health problem worldwide, which results from an imbalance between energy intake and expenditure. Adipose tissues play an important role in regulation of energy balance. Two functionally different types of fat tissue are present in mammals: white adipose tissue is the primary site of triglyceride storage and release of fatty acids, and brown adipose tissue is specialized for energy expenditure via thermogenesis. The long-term goal is to determine factors that underlie the divergent differentiation fates and functions of these two adipose cell types. These factors may contribute to regulation of whole-body energy balance and development of obesity. Our preliminary studies have suggested an important role for bone morphogenetic protein (BMP)-7 in regulation of brown adipogenesis and mitochondrial biogenesis. Based on these findings and previous knowledge of the effects of BMPs on white adipocyte differentiation, we hypothesize that different members of the BMP family play crucial roles in determining the differential developmental fate of brown vs. white adipose tissue, modulating thermogenic function in these cells, and thereby contributing to regulation of whole-body energy homeostasis. The proposed studies will determine the molecular mechanisms by which BMPs influence adipose cell fate determination, adipocyte differentiation and mitochondrial activity in both in vitro and in vivo settings. The specific aims are to: (1) Define the role of BMP-7 in specifying brown adipose cell fate and modulating thermogenic function in committed brown and white preadipocytes, pluripotent mesenchymal cells, sorted primary adipose progenitors and human preadipocytes. (2) Dissect the molecular mechanisms by which different BMPs, particularly BMP-7, regulate brown vs. white adipogenesis and mitochondrial function. (3) Define the in vivo role of BMPs in regulation of adipocyte differentiation, mitochondrial function and whole-body energy balance by treatment of lean and obese mice with BMPs and characterization of their effects on adipose physiology and whole-body energy metabolism. The developmental role of BMP signaling in fat development will be further investigated by characterization of constitutive and inducible adipose-specific BMP receptor knockout mice. These studies will increase our understanding of adipocyte differentiation, energy balance, and BMP actions, and may help to develop potential therapeutic approaches for obesity and related diseases.