Regulation of Adipose Tissue Function by Grb10

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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.