An exercise-inducible metabolite that suppresses feeding and obesity

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  • Veronica L Li
  • Yang He
  • Kévin Contrepois
  • Hailan Liu
  • Joon T Kim
  • Amanda L Wiggenhorn
  • Julia T Tanzo
  • Alan Sheng Hwa Tung
  • Xuchao Lyu
  • Peter James H Zushin
  • Robert S Jansen
  • Basil Michael
  • Kang Yong Loh
  • Andrew C. Yang
  • Wei Wei
  • Stephanie M Terrell
  • Benjamin C Moeller
  • Rick M Arthur
  • Gareth A Wallis
  • Koen van de Wetering
  • Andreas Stahl
  • Steven M Banik
  • Michael P. Snyder
  • Yong Xu
  • Jonathan Z Long

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases1–5. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear6. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2+ cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.

Original languageEnglish
JournalNature
Volume606
Pages (from-to)785-790
Number of pages6
ISSN0028-0836
DOIs
Publication statusPublished - 2022

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Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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