Regulation of Adipose Tissue Function by Grb10

描述（由申请人提供）：脂肪组织在高能量分子的储存、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多种代谢疾病有关。我们的初步研究表明，在小鼠中，脂肪特异性敲除生长因子受体结合蛋白-10 （Grb10）显著增加了mTORC1信号，极大地促进了肥胖和BAT向wat样组织的转化，显著抑制了解偶联蛋白1 （UCP1）的表达和能量消耗，并显著增强了高脂肪饮食（HFD）诱导的胰岛素抵抗。基于这些发现，我们假设Grb10通过反馈调节mTORC1调节脂肪组织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Grb10在脂质代谢调节中的作用

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.