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<p><i>N</i>-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<sub>ATP</sub>) channel, whereas inhibition of the K<sub>ATP</sub> 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.</p>

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Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

  • 期刊论文

  • 发表日期：

    2025年9月16日

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  • Hailan Liu,
  • Veronica L. Li,
  • Qingzhuo Liu,
  • Yao Liu,
  • Cunjin Su,
  • Hueyxian Wong,
  • Na Yin,
  • Hesong Liu,
  • Xing Fang,
  • Kristine M. McDermott,
  • Hueyzhong Wong,
  • Meng Yu,
  • Longlong Tu,
  • Jonathan C. Bean,
  • Yongxiang Li,
  • Mengjie Wang,
  • Yue Deng,
  • Yuhan Shi,
  • Olivia Z. Ginnard,
  • Yuxue Yang,
  • Junying Han,
  • Megan E. Burt,
  • Sanika V. Jossy,
  • Chunmei Wang,
  • Yongjie Yang,
  • Benjamin R. Arenkiel,
  • Dong Kong,
  • Yang He,
  • Jonathan Z. Long,
  • Yong Xu

摘要

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.