Language

English

Publication Date

10-1-2025

Journal

Nature Metabolism

DOI

10.1038/s42255-025-01377-9

PMID

40957996

PMCID

PMC13063381

PubMedCentral® Posted Date

4-10-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Lactate-derived N-lactoyl-phenylalanine (Lac-Phe) was recently identified as an lactate-derived circulating metabolite that reduces feeding and obesity, but mechanisms that underlie the metabolic benefits of Lac-Phe remain unknown. Here we demonstrated 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). We also found that both AgRP inhibition and PVH activation are required to mediate Lac-Phe-induced hypophagia. Further, we show that Lac-Phe inhibits AgRP neurons via activating the ATP-sensitive potassium (KATP) channel, and inhibition of the KATP channel blunts effects of Lac-Phe to suppress feeding. Together, these results reveal the molecular and neurobiological mechanisms by which Lac-Phe mediates exercise-induced metabolic benefits and further suggest therapeutic effects of this exercise-induced metabolite in a broad range of human diseases.

Keywords

Animals, Agouti-Related Protein, Mice, Neurons, Male, Phenylalanine, Mice, Inbred C57BL, Paraventricular Hypothalamic Nucleus, Lactates, KATP Channels, Hypothalamus, Lac-Phe, AgRP, KATP channel, LDH, feeding

Published Open-Access

yes

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