Regulation of Adipose Tissue Function by Grb10

Grb10 对脂肪组织功能的调节

• 批准号: 8884599
• 负责人: FENG LIU
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8884599
• 关键词: 1-Phosphatidylinositol 3-Kinase; Ablation; Adaptor Signaling Protein; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Affect; Animal Model; Anti-Obesity Agents; Binding; Binding Proteins; Brown Fat; Cells; Complex; Development; Diet; Drug Targeting; Energy Metabolism; Fatty acid glycerol esters; Feedback; Figs - dietary; Functional disorder; GRB10 gene; Gene Expression; Genetic Transcription; Health; Homeostasis; Hormonal; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Insulin-Like Growth Factor I; Knock-out; Knockout Mice; Lead; Leucine; Light; Mediating; Metabolic Diseases; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Phosphorylation; Physiological; Play; Process; Regulation; Role; Signal Pathway; Signal Transduction; Sirolimus; Stimulus; Stress; TSC1/2 gene; Testing; Thermogenesis; Tissues; Work; adrenergic; base; diabetic; human FRAP1 protein; in vivo; insight; insulin signaling; knockout animal; lipid biosynthesis; lipid metabolism; mTOR inhibition; mouse model; novel; novel therapeutic intervention; novel therapeutics; prevent; response; subcutaneous; uncoupling protein 1

DESCRIPTION (provided by applicant): Adipose tissues play key roles in the storage, release, and dispersal of highly energetic molecules to maintain energy homeostasis of the organism in response to environmental and hormonal stimuli. Adipose tissue dysfunction is associated with obesity and various metabolic diseases. Our preliminary studies showed that fat-specific knockout of the Growth factor receptor binding protein-10 (Grb10) in mice substantially increased mTORC1 signaling, greatly promoted adiposity and the conversion of BAT to a WAT-like tissue, drastically suppressed the expression of uncoupling protein 1 (UCP1) and energy expenditure, and significantly enhanced high fat diet (HFD)-induced insulin resistance. Based on these findings, we hypothesize that Grb10 regulates lipid metabolism and thermogenic activity in adipose tissues by feedback regulation of mTORC1. To test this hypothesis, we will first characterize the roles of Grb10 in the regulation of lipid metabolism and thermogenesis in vivo. We will then determine whether inhibiting the mTORC1 signaling pathway provides a mechanism by which Grb10 regulates lipid metabolism and thermogenic function in adipose tissues. Lastly, we will elucidate the molecular mechanism by which Grb10 negatively regulates mTORC1 signaling in adipocytes. Our study will identify a new important regulator of lipid metabolism and thermogenesis in adipose tissues. The study will also provide new insights into the signaling mechanisms underlying the browning effect in WAT in response to cold and adrenergic stimulation. Identification of Grb10 as a critical regulator of adipocyte function and elucidating the underlying signaling mechanisms may reveal promising new anti-obesity drug targets and lead to novel therapeutic approaches for obesity- associated metabolic diseases.

描述（由申请人提供）：脂肪组织在高能分子的储存、释放和分散中发挥关键作用，以维持生物体对环境和激素刺激的能量稳态。脂肪组织功能障碍与肥胖和各种代谢性疾病有关。我们的初步研究表明，脂肪特异性敲除小鼠生长因子受体结合蛋白-10（Grb 10）显著增加mTORC 1信号传导，极大地促进肥胖和BAT向WAT样组织的转化，显著抑制解偶联蛋白1（UCP 1）的表达和能量消耗，并显著增强高脂饮食（HFD）诱导的胰岛素抵抗。基于这些发现，我们推测Grb 10通过反馈调节mTORC 1来调节脂肪组织中的脂质代谢和产热活性。为了验证这一假设，我们将首先描述Grb 10在调节脂质代谢中的作用， 体内产热然后，我们将确定是否抑制mTORC 1信号通路提供了一种机制，Grb 10调节脂肪组织中的脂质代谢和产热功能。最后，我们将阐明Grb 10负调控脂肪细胞中mTORC 1信号的分子机制。我们的研究将确定一个新的重要调节脂肪组织的脂质代谢和产热。该研究还将提供新的见解的信号转导机制的布朗宁效应在WAT响应冷和肾上腺素能刺激。将Grb 10鉴定为脂肪细胞功能的关键调节因子并阐明潜在的信号传导机制可能揭示有希望的新的抗肥胖药物靶点，并导致肥胖相关代谢疾病的新治疗方法。