Role of BMPs in Adipogenesis, Mitochondrial Function and Energy Homeostasis

BMP 在脂肪生成、线粒体功能和能量稳态中的作用

基本信息

批准号：
7268223
负责人：
Yu-Hua Tseng
金额：
$ 31.96万
依托单位：
JOSLIN DIABETES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7268223
关键词：
Address Adenoviruses Adipocytes Adipose tissue Biogenesis Bone Morphogenetic Proteins Brown Fat Cell Separation Cells Commit Development Diabetes Mellitus Energy Intake Energy Metabolism Expenditure Family Fatty Acids Fatty acid glycerol esters Gene Targeting Goals Homeostasis Hormones Human In Vitro Insulin Resistance Knockout Mice Knowledge Lipids Mammals Mediating Mesenchymal Mitochondria Molecular Nutrient Obese Mice Obesity Obesity associated disease Outcome Pathway interactions Phenotype Physiology Play Pluripotent Stem Cells Process Protein Family Proteins Public Health Recombinants Regulation Research Research Personnel Role Signal Transduction Site Specific qualifier value Stem cells System Testing Therapeutic Thermogenesis Tissues Triglycerides Work adipocyte biology adipocyte differentiation base bone morphogenetic protein 2 bone morphogenetic protein 7 bone morphogenetic protein receptors cell type energy balance glucose metabolism human MAPK14 protein in vivo innovation lipid biosynthesis member mitogen-activated protein kinase p38 mouse model novel progenitor programs uncoupling protein 1

项目摘要

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.

描述（由申请人提供）：肥胖是世界范围内的一个公共健康问题，是由能量摄入和支出不平衡造成的。脂肪组织在能量平衡调节中发挥着重要作用。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场所，而棕色脂肪组织专门通过产热作用消耗能量。长期目标是确定这两种脂肪细胞类型不同的分化命运和功能背后的因素。这些因素可能有助于调节全身能量平衡和肥胖的发生。我们的初步研究表明骨形态发生蛋白 (BMP)-7 在调节棕色脂肪生成和线粒体生物合成中发挥重要作用。基于这些发现以及 BMP 对白色脂肪细胞分化影响的先前知识，我们假设 BMP 家族的不同成员在确定棕色脂肪组织与白色脂肪组织的差异发育命运、调节这些细胞的生热功能方面发挥着至关重要的作用，从而有助于调节全身能量稳态。拟议的研究将确定 BMP 在体外和体内环境中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) 定义 BMP-7 在指定棕色脂肪细胞命运和调节定型棕色和白色前脂肪细胞、多能间充质细胞、分选的初级脂肪祖细胞和人类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作用。通过对组成型和诱导型脂肪特异性 BMP 受体敲除小鼠的表征，将进一步研究 BMP 信号在脂肪发育中的发育作用。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及相关疾病的潜在治疗方法。