Regulation of Adipose Tissue Function by Grb10

Grb10 对脂肪组织功能的调节

基本信息

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
项目类别：
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

项目摘要

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）：脂肪组织在响应环境和激素刺激的响应中，在储存，释放和扩散中起关键作用，以维持生物体的能量稳态。脂肪组织功能障碍与肥胖和各种代谢疾病有关。我们的初步研究表明，在小鼠中，生长因子受体结合蛋白10（GRB10）的脂肪特异性敲除大大增加了MTORC1信号传导，极大地促进了脂肪以及将蝙蝠转化为WAT样组织，从而极大地抑制了UNCOLPLING蛋白1（UCP1）的表达（UCP1），并增强了较高的脂肪，并强大的脂肪量增强了较高的脂肪，并抑制了较高的脂肪。根据这些发现，我们假设GRB10通过MTORC1的反馈调节来调节脂肪组织中脂质代谢和热活性。为了检验这一假设，我们将首先表征GRB10在调节脂质代谢和体内热发生。然后，我们将确定抑制MTORC1信号通路是否提供了一种机制，该机制通过该机制调节脂肪组织中脂质代谢和热功能。最后，我们将阐明GRB10在脂肪细胞中负面调节MTORC1信号的分子机制。我们的研究将确定脂肪组织中脂质代谢和热发生的新的重要调节剂。这项研究还将提供有关响应寒冷和肾上腺素能刺激的褐变作用的信号传导机制的新见解。将GRB10鉴定为脂肪细胞功能的关键调节剂并阐明潜在的信号传导机制可能会揭示有希望的新的抗肥胖药物靶标，并导致肥胖相关代谢性疾病的新型治疗方法。