Role of BMPs in Adipogenesis, Mitochondrial Function and Energy Homeostasis

描述(申请人提供)：肥胖是一个世界性的公共健康问题，它是由能量摄入和消耗不平衡引起的。脂肪组织在调节能量平衡方面起着重要作用。哺乳动物体内存在两种功能不同的脂肪组织：白色脂肪组织是甘油三酯储存和释放脂肪酸的主要部位，棕色脂肪组织专门用于通过产热来消耗能量。长期目标是确定导致这两种脂肪细胞分化分化、命运和功能差异的因素。这些因素可能有助于调节全身能量平衡，促进肥胖的发生。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发生中起着重要的调节作用。基于这些发现和先前对BMP对白色脂肪细胞分化影响的了解，我们推测BMP家族的不同成员在决定棕色和白色脂肪组织的不同发育命运，调节这些细胞的生热功能，从而有助于调节全身能量平衡方面发挥着至关重要的作用。拟议的研究将确定BMPs在体外和体内环境下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。具体目标是： (1)明确BMP-7在棕色和白色前脂肪细胞、多能间充质细胞、分选的原代脂肪前体细胞和人前脂肪细胞中决定棕色脂肪细胞命运和调节生热功能中的作用。(2)剖析不同的BMP，尤其是BMP-7，调节棕色和白色脂肪生成和线粒体功能的分子机制。(3)通过BMPs对瘦身和肥胖小鼠的治疗，明确BMPs在体内对脂肪细胞分化、线粒体功能和全身能量平衡的调节作用，并研究其对脂肪生理和全身能量代谢的影响。BMP信号在脂肪发育中的发育作用将通过结构性和可诱导的脂肪特异性BMP受体基因敲除小鼠的特征进一步研究。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，并可能有助于开发潜在的肥胖和相关疾病的治疗方法。

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.