bioRxiv : the preprint server for biology · 2026
THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons.
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Liu Qingzhuo, Bean Jonathan C, Jian Jinjing, Zhou Tong, Yang Yuxue, Sun Meixin, Li Yongxiang, Conde Kristine M, Wang Mengjie, Deng Yue, Qiu Jiamin, Wang Fuhui, Liu Xinming, Liu Yutian, Cheng Jingjing, Wu Xi, Xue Lamei, Chen Chunling, Meng Chenling, Zhu Yi, Yang Yongjie, Tu Longlong, Liu Hailan, Xu Yong
Аннотация
Microglia play essential roles in maintaining energy homeostasis, and their dysfunction contributes to metabolic disease. Although high-fat diet (HFD) exposure induces microglial activation, the underlying mechanisms remain poorly defined. Here, we identified a previously unrecognized role for THIK-1 channel in mediating glucose sensing of microglia in arcuate nucleus of the hypothalamus (ARH), during HFD-induced obesity. Pharmacological inhibition of THIK-1 channel with tetrapentylammonium (TPA) suppresses feeding and attenuates body-weight gain in diet induced obese mice. Mechanistically, inhibition of agouti-related peptide (AgRP) neurons is indispensable for TPA-induced hypophagia. Moreover, THIK-1 inhibition promotes microglial phagocytosis of perineuronal nets (PNNs), leading to reduced AgRP neuronal activity and feeding suppression. Together, these findings establish THIK-1 as a critical glucose sensor in hypothalamic microglia and uncover a microglia-dependent pathway through which overnutrition modulates AgRP neuronal activity via PNN remodeling to regulate energy balance, highlighting THIK-1 as a potential therapeutic target for treatment of diet-induced obesity.