Follistatin promotes browning and influences energy metabolism

卵泡抑素促进褐变并影响能量代谢

• 批准号: 8740378
• 负责人: RAJAN SINGH
• 金额: $ 28.7万
• 依托单位: CHARLES R. DREW UNIVERSITY OF MED & SCI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740378
• 关键词: Activins; Adipocytes; Adipose tissue; Adrenergic Receptor; Affinity; Age; Agonist; Area; BMP7 gene; Bioenergetics; Biogenesis; Biological Assay; Body Composition; Brown Fat; Burn injury; Calories; Cardiovascular Diseases; Cells; Consultations; Data; Development; Diabetes Mellitus; Diet; Disease; Doctor of Philosophy; Drug Design; Embryo; Energy Intake; Energy Metabolism; Enzyme-Linked Immunosorbent Assay; Epidemic; Exercise; Expenditure; Extracellular Protein; FGF21 gene; Fatty acid glycerol esters; Fibroblasts; Follistatin; Gene Expression; Gene Expression Profiling; Genus Hippocampus; Gifts; Glucose; Glucose tolerance test; Grant; Health; In Vitro; Inflammatory; Insulin Receptor; Insulin Resistance; Knock-out; Knowledge; Link; Lipids; Mediator of activation protein; Metabolic; Metabolic Diseases; Minority; Mission; Mitochondria; Molecular; Molecular Profiling; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PTGS2 gene; Pathway interactions; Play; Population; Process; Protein Binding; Proteins; Reagent; Receptor Signaling; Recruitment Activity; Regulation; Regulatory Element; Reporting; Research Personnel; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Skeletal Muscle; Small Interfering RNA; Subcutaneous Tissue; Symptoms; Testing; Testosterone; Time; Tissues; Transforming Growth Factors; Transgenes; Transgenic Mice; Transgenic Mouse Facility; Triglycerides; United States National Institutes of Health; Western Blotting; Wild Type Mouse; Work; X-Ray Computed Tomography; adipocyte biology; adiponectin; base; burden of illness; disability; energy balance; experience; extracellular; fatty acid oxidation; glucose disposal; glucose metabolism; glucose tolerance; improved; in vitro Model; in vivo; in vivo Model; insulin sensitivity; knock-down; lipid metabolism; male; muscle form; myostatin; novel; novel therapeutics; obesity treatment; prevent; programs; promoter; protein expression; response; treatment program

DESCRIPTION (provided by applicant): Obesity is a major health problem spreading at an epidemic pace throughout the world without any sign of abatement. Development of obesity, which is often associated with insulin resistance and diabetes, results from an excess of energy intake over expenditure. Brown adipose tissues (BAT) have the unique ability to burn excess calories, and facilitate triglyceride clearance and glucose disposal. Previously, we identified Follistatin (Fst) as a direct target of testosterone that regulates skeletal muscle mass and inhibits transforming growth factor-β (TGF-β) signaling. Based on our preliminary findings, we hypothesize that Fst promotes overall thermogenic program and improves symptoms of obesity and metabolic disorder by regulating overall Mst/TGF-β /BMP/Myf5/PRDM16- signaling pathways. We will test our hypothesis with the following Specific Aims- Aim 1: We will demonstrate the essential role of Fst during brown fat differentiation and the regulation of thermogenic program in vitro and in vivo. Aim 2: We will determine the molecular mechanisms by which Fst regulates the overall thermogenic program and Aim 3: We will generate mice expressing Fst under the control of adiponectin or UCP1 regulatory elements, and compare their metabolic parameters and response to high fat chow diet with control littermates. We will determine the effect of endogenous and exogenous Fst on protein and gene expression profiles of key thermogenic markers, and overall cellular bioenergetics using both in vitro and in vivo models under basal and β-adrenoceptor agonist (CL316,248) stimulated conditions. Involvement of Myf5/PRDM16, Mst/pSmad2/3/BMP/COX 2, insulin receptor and AMPK/PGC-1α signaling pathway in in vitro models as well as in adiponectin-Fst and UCP1-Fst transgenic mice will be analyzed by Affymetrix gene expression and quantitative western blot analysis. Expression levels of Fst, Myf5 and Smad3 in mouse preadipocytes and MEF cultures will be inhibited by siRNAs and their thermogenic capabilities will be determined. We will generate Fst-transgenic mice using adiponectin (Adipoq) and UCP1-specific promoters, and test the effect of high fat diet on their body composition (Micro CT), energy expenditure (indirect calorimetric analysis), insulin sensitivity and glucose tolerance under both basal and β-adrenoceptor agonist (CL 316,248) stimulated conditions. Serum levels of Fst, adiponectin and lipid profiles will be analyzed by ELISA. Evaluating the critical role of Fst during its regulation of overall thermogenic process will provide rationale for novel therapeutic drug design for the treatment of obesity and related metabolic diseases.

描述（由适用提供）：肥胖是在全世界流行病空间中传播的主要健康问题，而没有任何减少迹象。肥胖的发展通常与胰岛素抵抗和糖尿病有关，这是由于超过支出的能量摄入过量而导致的。棕色脂肪组织（BAT）具有独特的燃烧能力超过卡路里，并促进甘油三酸酯清除和葡萄糖处置。以前，我们将卵泡蛋白（FST）确定为调节骨骼肌质量的睾丸激素的直接靶标，并抑制转化生长因子-β（TGF-β）信号传导。根据我们的初步发现，我们假设FST通过调节总体MST/TGF-β/BMP/MyF5/PRDM16信号途径来促进整体热生效计划并改善肥胖和代谢障碍的症状。我们将以以下特定目标来检验我们的假设1：我们将证明FST在棕色脂肪分化过程中的基本作用以及体外和体内的热计划调节。 AIM 2：我们将确定FST调节整体热程序程序的分子机制，AIM 3：我们将在脂联素或UCP1调节元件的控制下产生表达FST的小鼠，并比较其代谢参数，并将其对高脂饮食的反应与对照中心脉的响应。我们将确定内源性和外源性FST对关键热标记的蛋白质和基因表达谱的影响，以及在碱性和β-肾上腺素受体激动剂（CL316,248）下，使用体外和体内模型都使用体外和体内模型的总体细胞生物能力。在体外模型以及在脂联蛋白-FST和UCP1-FST中，将通过AffyMetrix Gene Centrient Crancers anderative Werternitative Werternitative Werternitative Werternitative Werternitative sallys分析，在体外模型以及UCP1-FST中的MyF5/PRDM16，MST/PSMAD2/3/BMP/COX 2，胰岛素受体和AMPK/PGC-1α信号通路的参与。 siRNA将抑制小鼠前脂肪细胞和MEF培养物中FST，MYF5和SMAD3的表达水平及其热能力。我们将使用脂联素（ADIPOQ）和UCP1特异性启动子生成FST-转基因小鼠，并测试高脂肪饮食对其身体成分（微CT），能量支出（间接calolimetric分析），胰岛素敏感性和glucose耐受性和glucose耐受性的影响。 ELISA将分析FST，脂联素和脂质谱的血清水平。评估FST在调节总体热过程中的关键作用将为肥胖症和相关代谢疾病的治疗提供新型热药设计的基本原理。