An exercise-inducible metabolite that suppresses feeding and obesity

  • Nature. 2022 Jun;606(7915):785-790. doi: 10.1038/s41586-022-04828-5.
Veronica L Li   #  1  2  3  4 ,  Yang He   #  5 ,  Kévin Contrepois  6  7  8 ,  Hailan Liu  5 ,  Joon T Kim  1  3 ,  Amanda L Wiggenhorn  1  2  3 ,  Julia T Tanzo  1  3 ,  Alan Sheng-Hwa Tung  1  3 ,  Xuchao Lyu  1  3  4 ,  Peter-James H Zushin  9 ,  Robert S Jansen  10  11 ,  Basil Michael  6 ,  Kang Yong Loh  2  3 ,  Andrew C Yang  12 ,  Christian S Carl  13 ,  Christian T Voldstedlund  13 ,  Wei Wei  1  3  14 ,  Stephanie M Terrell  1  3 ,  Benjamin C Moeller  15  16 ,  Rick M Arthur  16 ,  Gareth A Wallis  17 ,  Koen van de Wetering  10  18 ,  Andreas Stahl  9 ,  Bente Kiens  13 ,  Erik A Richter  13 ,  Steven M Banik  2  3 ,  Michael P Snyder  6  7  8  4 ,  Yong Xu  19  20 ,  Jonathan Z Long  21  22  23  24  25
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Department of Chemistry, Stanford University, Stanford, CA, USA.
  • 3. Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 4. Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • 5. Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 6. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 7. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
  • 8. Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • 9. Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA.
  • 10. Netherlands Cancer Institute, Amsterdam, Netherlands.
  • 11. Department of Microbiology, Radboud University, Nijmegen, Netherlands.
  • 12. Department of Anatomy and the Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 13. August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
  • 14. Department of Biology, Stanford University, Stanford, CA, USA.
  • 15. Maddy Equine Analytical Chemistry Laboratory, California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California at Davis, Davis, CA, USA.
  • 16. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
  • 17. School of Sport, Exercise, and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK.
  • 18. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
  • 19. Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 20. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
  • 21. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 22. Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
  • 23. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. [email protected].
  • 24. Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. [email protected].
  • 25. Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. [email protected].
  • # Contributed equally.
PMID: 35705806 DOI: 10.1038/s41586-022-04828-5
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.

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