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
USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA.
Nat Metab. 2025 Sep 16. doi: 10.1038/s42255-025-01377-9.
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 (K) channel, whereas inhibition of the K 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.
N-乳酰苯丙氨酸（Lac-Phe）是一种源自乳酸的循环代谢产物，可减少进食和肥胖，但Lac-Phe代谢益处背后的分子机制仍不清楚。在这里，我们表明Lac-Phe直接抑制表达刺鼠相关蛋白（AgRP）的下丘脑神经元，从而间接激活下丘脑室旁核（PVH）中的厌食神经元。AgRP抑制和PVH激活都是介导Lac-Phe诱导的摄食减少所必需的。Lac-Phe介导的对AgRP神经元的抑制是通过激活ATP敏感性钾（K）通道实现的，而抑制该K通道会减弱Lac-Phe抑制进食的作用。这些结果共同揭示了Lac-Phe介导代谢改善的分子和神经生物学机制，并表明这种运动诱导的代谢产物可能对多种人类疾病具有治疗益处。
