Hypothalamic Grb10 enhances leptin signaling and promotes weight loss

Authors: LIU, HAILAN - Children'S Nutrition Research Center (CNRC); HE, YANG - Children'S Nutrition Research Center (CNRC); BAI, JULI - Central South University; ZHANG, CHUANHAI - University Of Texas At San Antonio; ZHANG, FENG - Central South University; YANG, YONGJIE - Children'S Nutrition Research Center (CNRC); LUO, HAIRONG - Central South University; YU, MENG - Children'S Nutrition Research Center (CNRC); LIU, HESONG - Children'S Nutrition Research Center (CNRC); TU, LONGLONG - Children'S Nutrition Research Center (CNRC); ZHANG, NAN - Children'S Nutrition Research Center (CNRC); YIN, NA - Children'S Nutrition Research Center (CNRC); HAN, JUNYING - Children'S Nutrition Research Center (CNRC); YAN, ZILI - Children'S Nutrition Research Center (CNRC); SCARCELLI, NIKOLAS - Children'S Nutrition Research Center (CNRC); CONDE, KRISTINE - Children'S Nutrition Research Center (CNRC); WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); BEAN, JONATHAN - Children'S Nutrition Research Center (CNRC); POTTS, CAMILLE - Children'S Nutrition Research Center (CNRC); WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC); HU, FANG - Central South University; LIU, FENG - Central South University; XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/19/2022
Publication Date: 1/2/2023
Citation: Liu, H., He, Y., Bai, J., Zhang, C., Zhang, F., Yang, Y., Luo, H., Yu, M., Liu, H., Tu, L., Zhang, N., Yin, N., Han, J., Yan, Z., Scarcelli, N., Conde, K., Wang, M., Bean, J., Potts, C., Wang, C., Hu, F., Liu, F., Xu, Y. 2023. Hypothalamic Grb10 enhances leptin signaling and promotes weight loss. Nature Metabolism. 5:147–164. https://doi.org/10.1038/s42255-022-00701-x.
DOI: https://doi.org/10.1038/s42255-022-00701-x

Interpretive Summary: Leptin is a hormone that tells the brain to stop eating and start burning calories. Scientists are still figuring out how it works in the brain. In this study, researchers found that a protein called Grb10 can interact with the leptin receptor and enhance leptin signaling. When Grb10 was removed from certain neurons in mice, they gained weight, while adding more Grb10 helped them lose weight. Grb10 made the anorexic (appetite-suppressing) effects of leptin stronger in some neurons and the weight-reducing effects stronger in others. Grb10 did this by affecting the way certain channels in the neurons worked. Overall, the study shows that Grb10 is important for maintaining a healthy energy balance by making neurons more responsive to leptin.

Technical Abstract: 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.