下丘脑在能量代谢调控中发挥了重要作用，Grb10是与受体酪氨酸激酶结合的接头蛋白和胰岛素信号通路负调控因子。我们发现Grb10高表达于小鼠下丘脑，并建立了下丘脑POMC神经元Grb10特异性敲除小鼠模型。预实验发现在正常饮食喂养下，与对照小鼠相比，Grb10敲除小鼠的体重减轻，能量消耗增加，皮下脂肪组织产热基因的表达增加。但导致这种表型的机制还不清楚。进一步研究发现Grb10能够与瘦素受体结合，敲低神经细胞中Grb10的表达增强了胰岛素和瘦素信号通路的敏感性，提示Grb10可能同时参与了胰岛素与瘦素信号通路的调控。本项目我们计划通过“loss-of-function”以及“gain-of-function”的研究策略，利用POMC神经元Grb10特异性敲除或过表达的多种小鼠模型结合细胞实验，深入研究POMC神经元Grb10对机体能量代谢的调控作用和机制。为抗肥胖药物靶点开发提供理论依据。

The hypothalamic neurons play key roles in coordinating appropriate endocrine, autonomic and behavioral responses to maintain energy homeostasis. Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that has previously been shown to negatively modulate insulin signaling. Our preliminary data showed that Grb10 is abundantly expressed in hypothalamic neurons. In addition, specific deletion of Grb10 in hypothalamic POMC neurons leads to profound lean phenotypes in mice, including lower body weight, higher energy expenditure and increased thermogenic gene expression in subcutaneous white adipose tissues. Furthermore, we found that Grb10 binds to leptin receptor and deletion of Grb10 in neuron cells enhances insulin and leptin signaling pathways. Based on these, we hypothesized that Grb10 negatively regulates leptin and insulin signaling in hypothalamic neurons to promote body weight gain. In the proposed studies, by using“loss- of-function” and “gain-of- function” strategies with multiple animal and cellular models, we aim to determine roles and mechanisms of Grb10 in POMC neurons on the regulation of browning and energy homeostasis. Our studies will help to identify a novel target to combat against obesity pandemic.