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

基本信息

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
项目类别：
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

项目摘要

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病中，这是2型糖尿病的主要危险因素，与代谢综合征的其他成分紧密相关，包括胰岛素抵抗，包括胰岛素性血症，低血压，高血压，脂肪，脂肪肝和心血管疾病的风险增加。肥胖的发展不仅取决于食物摄入量和能量利用之间的平衡，还取决于白脂肪组织（是甘油三酸酯储存的主要部位）和棕色脂肪组织的平衡，该组织是专门用于能量消耗的棕色脂肪组织。最近，令人信服的证据表明，棕色脂肪存在于成年人中，其存在和活性与代谢综合征的肥胖和指标成反比。因此，诱导棕色脂肪分化和功能成为抵消肥胖症的一种非常有吸引力的方式。我们的长期目标是获得有关棕色脂肪的细胞谱系规范的基本知识以及决定棕色脂肪形成的电感信号，并利用这些知识来开发潜在的治疗方法来治疗肥胖症。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仓库分化命运和功能的因素。结合了细胞，分子和生理方法，我们发现发育信号分子骨形态发生蛋白（BMP）7专门促进棕色脂肪细胞的分化和功能。此外，我们已经确定并隔离了居住在鼠棕色脂肪，白脂肪和骨骼肌中的内源祖细胞的亚群。这些祖细胞的发育命运受BMP7的调节。因此，我们假设BMP7充当电感信号，为祖细胞提供有指导的提示，以区分为棕色脂肪谱系，从而在全身能量代谢中发挥了重要作用。在这笔赠款中，我们建议通过确定组织居民祖细胞和小裂因子BMP7之间的相互作用直接检验该假设，以使用条件敲除模型和细胞分离方法来确定棕色脂肪细胞命运。在分子水平上，我们将确定microRNA在介导BMP7的棕色成脂作用中的作用。 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支出。完成拟议的研究不仅会改善我们对棕色脂肪发展和能量代谢的当前理解，而且还暗示了能源消耗调节的新途径，最终有助于开发潜在的治疗方法来治疗肥胖症及其许多相关疾病。