Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

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.

PMID: 40957996
DOI: 10.1038/s42255-025-01377-9

Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

Hailan Liu et al. Nat Metab. 2025 Oct.

. 2025 Oct;7(10):2004-2017.

doi: 10.1038/s42255-025-01377-9. Epub 2025 Sep 16.

Authors

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.

PMID: 40957996
DOI: 10.1038/s42255-025-01377-9

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.

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Conflict of interest statement

Competing interests: V.L.L., Y.H., J.Z.L. and Y.X. are listed as inventors on a patent covering lactoyl amino acids for the treatment of metabolic diseases (E-160-2023-0-PC-01, N-lactoyl-phenylalanine [Lac-Phe] compound derivatives, Stanford University and Baylor College of Medicine). The other authors declare no conflict of interest.

References

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Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

Affiliations

Lac-Phe induces hypophagia by inhibiting AgRP neurons in mice

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases