Liu Hailan, He Yang, Bai Juli, Zhang Chuanhai, Zhang Feng, Yang Yongjie, Luo Hairong, Yu Meng, Liu Hesong, Tu Longlong, Zhang Nan, Yin Na, Han Junying, Yan Zili, Scarcelli Nikolas Anthony, Conde Kristine Marie, Wang Mengjie, Bean Jonathan Carter, Potts Camille Hollan Sidell, Wang Chunmei, Hu Fang, Liu Feng, Xu Yong
National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
Nat Metab. 2023 Jan;5(1):147-164. doi: 10.1038/s42255-022-00701-x. Epub 2023 Jan 2.
Leptin acts on hypothalamic neurons expressing agouti-related protein (AgRP) or pro-opiomelanocortin (POMC) to suppress appetite and increase energy expenditure, but the intracellular mechanisms that modulate central leptin signalling are not fully understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an adaptor protein that binds to the insulin receptor and negatively regulates its signalling pathway, can interact with the leptin receptor and enhance leptin signalling. Ablation of Grb10 in AgRP neurons promotes weight gain, while overexpression of Grb10 in AgRP neurons reduces body weight in male and female mice. In parallel, deletion or overexpression of Grb10 in POMC neurons exacerbates or attenuates diet-induced obesity, respectively. Consistent with its role in leptin signalling, Grb10 in AgRP and POMC neurons enhances the anorexic and weight-reducing actions of leptin. Grb10 also exaggerates the inhibitory effects of leptin on AgRP neurons via ATP-sensitive potassium channel-mediated currents while facilitating the excitatory drive of leptin on POMC neurons through transient receptor potential channels. Our study identifies Grb10 as a potent leptin sensitizer that contributes to the maintenance of energy homeostasis by enhancing the response of AgRP and POMC neurons to leptin.
瘦素作用于表达刺鼠相关蛋白（AgRP）或阿黑皮素原（POMC）的下丘脑神经元，以抑制食欲并增加能量消耗，但调节中枢瘦素信号传导的细胞内机制尚未完全了解。在这里，我们表明生长因子受体结合蛋白10（Grb10），一种与胰岛素受体结合并负向调节其信号通路的衔接蛋白，可与瘦素受体相互作用并增强瘦素信号传导。在AgRP神经元中敲除Grb10会促进体重增加，而在AgRP神经元中过表达Grb10会降低雄性和雌性小鼠的体重。同时，在POMC神经元中删除或过表达Grb10分别会加剧或减轻饮食诱导的肥胖。与其在瘦素信号传导中的作用一致，AgRP和POMC神经元中的Grb10增强了瘦素的厌食和减肥作用。Grb10还通过ATP敏感性钾通道介导的电流增强了瘦素对AgRP神经元的抑制作用，同时通过瞬时受体电位通道促进了瘦素对POMC神经元的兴奋驱动。我们的研究确定Grb10是一种有效的瘦素敏化剂，通过增强AgRP和POMC神经元对瘦素的反应来维持能量稳态。
