Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

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

doi:10.1038/s42255-025-01377-9

Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

Nat Metab. 2025 Oct;7(10):2004-2017. doi: 10.1038/s42255-025-01377-9. Epub 2025 Sep 16.

Authors

Hailan Liu^#^{1

2}, Veronica L Li^#^{3

4

5

6}, Qingzhuo Liu^#^{1

2}, Yao Liu⁷, Cunjin Su⁸, Hueyxian Wong⁷, Na Yin¹, Hesong Liu¹, Xing Fang¹, Kristine M McDermott^{1

2}, Hueyzhong Wong¹, Meng Yu¹, Longlong Tu^{1

2}, Jonathan C Bean¹, Yongxiang Li^{1

2}, Mengjie Wang^{1

2}, Yue Deng^{1

2}, Yuhan Shi¹, Olivia Z Ginnard¹, Yuxue Yang^{1

2}, Junying Han¹, Megan E Burt¹, Sanika V Jossy¹, Chunmei Wang¹, Yongjie Yang^{1

2}, Benjamin R Arenkiel⁷, Dong Kong⁹, Yang He^{10

11}, Jonathan Z Long^{12

13

14

15}, Yong Xu^{16

17

18

19}

Affiliations

¹ USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
² Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁵ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁶ The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
⁷ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
⁸ Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Center at Houston, Houston, TX, USA.
⁹ Division of Endocrinology, F.M. Kirby Neurobiology Center, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁰ Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA. yang.he@bcm.edu.
¹¹ Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. yang.he@bcm.edu.
¹² Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
¹³ Sarafan ChEM-H, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
¹⁴ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
¹⁵ The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
¹⁶ USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. yongxu@usf.edu.
¹⁷ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. yongxu@usf.edu.
¹⁸ Department of Medicine, Baylor College of Medicine, Houston, TX, USA. yongxu@usf.edu.
¹⁹ Department of Psychiatry and Behavioral Neurosciences, University of South Florida, Tampa, FL, USA. yongxu@usf.edu.

^# Contributed equally.

Abstract

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_ATP) channel, whereas inhibition of the K_ATP 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.

MeSH terms

Agouti-Related Protein* / antagonists & inhibitors
Agouti-Related Protein* / metabolism
Animals
Hypothalamus / drug effects
Hypothalamus / metabolism
KATP Channels / metabolism
Lactates* / pharmacology
Male
Mice
Mice, Inbred C57BL
Neurons* / drug effects
Neurons* / metabolism
Paraventricular Hypothalamic Nucleus / drug effects
Paraventricular Hypothalamic Nucleus / metabolism
Phenylalanine* / analogs & derivatives
Phenylalanine* / pharmacology

Substances

Agouti-Related Protein
Phenylalanine
Agrp protein, mouse
Lactates
KATP Channels
N-lactoyl-phenylalanine

Abstract

MeSH terms

Substances

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