An exercise-inducible metabolite that suppresses feeding and obesity

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, Christian Strini Carl, Christian Thomas Voldstedlund, Wei Wei, Stephanie M Terrell, Benjamin C Moeller, Rick M ArthurGareth A Wallis, Koen van de Wetering, Andreas Stahl, Bente Kiens, Erik A. Richter, Steven M Banik, Michael P. Snyder, Yong Xu*, Jonathan Z Long*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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

Bibliographical note

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

Keywords

  • Faculty of Science
  • Metabolomics
  • Obesity
  • Proteases
  • Lac-Phe

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