Regulation of Adipose Tissue Function by Grb10

描述(申请人提供)：脂肪组织在高能分子的储存、释放和扩散中发挥关键作用，以维持机体对环境和激素刺激的能量平衡。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，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信号转导，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，并显著增强了高脂饮食(HFD)诱导的胰岛素抵抗。基于这些发现，我们假设Grb10通过对mTORC1的反馈调节来调节脂肪组织中的脂代谢和生热活性。为了验证这一假说，我们将首先表征Grb10在调节脂质代谢和 体内生热作用。然后，我们将确定抑制mTORC1信号通路是否提供了Grb10调节脂肪组织中的脂肪代谢和生热功能的机制。最后，我们将阐明Grb10负性调控脂肪细胞mTORC1信号的分子机制。我们的研究将确定脂肪组织中脂代谢和产热的新的重要调节因子。这项研究还将为WAT响应寒冷和肾上腺素能刺激而产生褐变效应的信号机制提供新的见解。确定Grb10是脂肪细胞功能的关键调节因子，并阐明其潜在的信号机制，可能会揭示新的抗肥胖药物靶点，并导致肥胖相关代谢性疾病的新治疗方法。

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.