2. Academic Validation
  3. An exercise-inducible metabolite that suppresses feeding and obesity

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

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. yongx@bcm.edu.
  • 20 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. yongx@bcm.edu.
  • 21 Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
  • 22 Sarafan ChEM-H, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
  • 23 Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
  • 24 Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
  • 25 Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
  • # 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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