Role of BMPs in Adipogenesis, Mitochondrial Function and Energy Metabolism

BMP 在脂肪形成、线粒体功能和能量代谢中的作用

• 批准号: 8664365
• 负责人: Yu-Hua Tseng
• 金额: $ 40.26万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664365
• 关键词: Adipocytes; Adipose tissue; Adult; BMP7 gene; Blood Vessels; Brown Fat; Cell Separation; Cell surface; Cells; Commit; Cues; Data; Defect; Development; Differentiation and Growth; Disease; Dyslipidemias; Eating; Employee Strikes; Energy Metabolism; Epidemic; Equilibrium; Event; Fatty Liver; Fatty acid glycerol esters; Food Energy; Gene Targeting; Genes; Genomics; Goals; Grant; Hypertension; Image; Impairment; Insulin Resistance; Intrinsic factor; Knock-out; Knowledge; Lead; Link; Mediating; Metabolic; Metabolic syndrome; MicroRNAs; Microspheres; Mission; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Nanosphere; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Physiological; Play; Progress Reports; Public Health; Quality of life; Regulation; Research; Response Elements; Risk Factors; Role; Signal Transduction; Signaling Molecule; Silk; Site; Skeletal Muscle; Smooth Muscle Myocytes; Specific qualifier value; Staging; Stem cells; System; Testing; Therapeutic; Thermogenesis; Tissues; Transcriptional Regulation; Triglycerides; Weight Gain; Work; adipocyte differentiation; age related; bone morphogenetic protein 7; bone morphogenetic protein receptors; cardiovascular disorder risk; established cell line; gain of function; improved; in vivo; indexing; inhibitor/antagonist; insight; insulin signaling; knock-down; lipid biosynthesis; loss of function; meetings; member; mouse model; novel; novel therapeutic intervention; obesity treatment; overexpression; progenitor; promoter; single cell analysis; subcutaneous

DESCRIPTION (provided by applicant): We are in the midst of a worldwide epidemic of obesity, which is a major risk factor for type 2 diabetes and is closely linked to other components of metabolic syndrome, including insulin resistance, dyslipidemia, hypertension, fatty liver, and increased risk of cardiovascular disease. The development of obesity not only depends on the balance between food intake and energy utilization but also on the balance between white adipose tissue, which is the primary site of triglyceride storage, and brown adipose tissue, which is specialized for energy expenditure. Recently, compelling evidence reveals that brown fat is present and active in adult humans, and its presence and activity are inversely associated with adiposity and indexes of metabolic syndrome. Thus, inducing brown fat differentiation and function becomes a very attractive way to counteract obesity. Our long-term goal is to gain fundamental knowledge of the cellular lineage specification of brown fat and the inductive signals determining brown adipose formation, and to use this knowledge to develop potential therapeutic approaches to treat obesity. Recently, we and others have gained insight into the cellular origin of brown fat cells and the factors that underlie the divergent differentiation fates and functions of different adipose depots. Combining cellular, molecular and physiological approaches, we have discovered that the developmental signaling molecule bone morphogenetic protein (BMP) 7 specifically promotes brown adipocyte differentiation and function. In addition, we have identified and isolated a subpopulation of endogenous progenitors residing in murine brown fat, white fat, and skeletal muscle. The developmental fate of these progenitors is regulated by BMP7. Therefore, we hypothesize that BMP7 functions as an inductive signal providing instructive cues to progenitors to differentiate into brown fat lineage, thereby playing a significant role in whole body energy metabolism. In this grant, we propose to directly test this hypothesis by determining the interplay between tissue resident progenitors and niche factor BMP7 in determining brown fat cell fate using conditional knockout models and cell isolation approaches. At the molecular level, we will determine the role of microRNAs in mediating BMP7's brown adipogenic effect. Finally, we will delineate the physiological role of BMP7 signaling in the regulation of brown adipogenesis and whole body energy metabolism using murine models with specific impairments of BMP7 signaling in the niche cell, the progenitors, and the mature brown adipocytes and determine whether increasing the availability of BMP7 in proximity to adipose progenitors in vivo can lead to increased brown fat-mediated energy expenditure. Accomplishing the proposed studies will not only improve our current understanding of brown fat development and energy metabolism, but also suggest a novel pathway in the regulation of energy expenditure, and ultimately help to develop potential therapeutic approaches to treat obesity and its many related disorders.

描述（由申请人提供）：我们正处于肥胖症的全球流行之中，肥胖症是2型糖尿病的主要危险因素，并与代谢综合征的其他组成部分密切相关，包括胰岛素抵抗、血脂异常、高血压、脂肪肝和心血管疾病的风险增加。肥胖的发生不仅取决于食物摄入和能量利用之间的平衡，还取决于甘油三酯主要储存部位白色脂肪组织和专门用于能量消耗的棕色脂肪组织之间的平衡。最近，令人信服的证据表明，棕色脂肪在成年人中存在并活跃，其存在和活动与肥胖和代谢综合征指标呈负相关。因此，诱导棕色脂肪的分化和功能成为对抗肥胖的一种非常有吸引力的方法。我们的长期目标是获得棕色脂肪的细胞谱系规范和确定棕色脂肪形成的诱导信号的基本知识，并利用这些知识开发潜在的治疗方法来治疗肥胖。最近，我们和其他人已经深入了解了棕色脂肪细胞的细胞起源，以及不同脂肪库不同分化命运和功能的因素。结合细胞、分子和生理学方法，我们发现发育信号分子骨形态发生蛋白（BMP） 7特异性地促进棕色脂肪细胞的分化和功能。此外，我们已经鉴定并分离了一个内源性祖细胞亚群，它们存在于小鼠棕色脂肪、白色脂肪和骨骼肌中。这些祖细胞的发育命运受BMP7调控。因此，我们假设BMP7作为一种诱导信号，为祖细胞分化为棕色脂肪谱系提供指导性线索。