Nature metabolism · 2025
Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice.
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Liu Hailan, Li Veronica L, Liu Qingzhuo, Liu Yao, Su Cunjin, Wong Hueyxian, Yin Na, Liu Hesong, Fang Xing, McDermott Kristine M, Wong Hueyzhong, Yu Meng, Tu Longlong, Bean Jonathan C, Li Yongxiang, Wang Mengjie, Deng Yue, Shi Yuhan, Ginnard Olivia Z, Yang Yuxue, Han Junying, Burt Megan E, Jossy Sanika V, Wang Chunmei, Yang Yongjie, Arenkiel Benjamin R, Kong Dong, He Yang, Long Jonathan Z, Xu Yong
Аннотация
N-Lactoyl-phenylalanine (Lac-Phe) is a lactate-derived circulating metabolite that reduces feeding and obesity, but the molecular mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we show that Lac-Phe directly inhibits hypothalamic neurons that express Agouti-related protein (AgRP), resulting in an indirect activation of anorexigenic neurons in the paraventricular nucleus of the hypothalamus (PVH). Both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Lac-Phe-mediated inhibition of AgRP neurons occurs through activation of the ATP-sensitive potassium (KATP) channel, whereas inhibition of the KATP channel blunts the effects of Lac-Phe to suppress feeding. Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates metabolic improvements and suggest this exercise-induced metabolite might have therapeutic benefits in various human diseases.