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 S. Carl, Christian T. Voldstedlund, Wei Wei, Stephanie M. Terrell, Benjamin C. Moeller, Rick M. Arthur, Gareth A. Wallis, Koen Wetering, Andreas Stahl, Bente Kiens, Erik A. Richter, Steven M. Banik, Michael P. Snyder, Yong Xu () and Jonathan Z. Long ()
Additional contact information
Veronica L. Li: Stanford University School of Medicine
Yang He: Baylor College of Medicine
Kévin Contrepois: Stanford University School of Medicine
Hailan Liu: Baylor College of Medicine
Joon T. Kim: Stanford University School of Medicine
Amanda L. Wiggenhorn: Stanford University School of Medicine
Julia T. Tanzo: Stanford University School of Medicine
Alan Sheng-Hwa Tung: Stanford University School of Medicine
Xuchao Lyu: Stanford University School of Medicine
Peter-James H. Zushin: University of California Berkeley
Robert S. Jansen: Netherlands Cancer Institute
Basil Michael: Stanford University School of Medicine
Kang Yong Loh: Stanford University
Andrew C. Yang: University of California San Francisco
Christian S. Carl: University of Copenhagen
Christian T. Voldstedlund: University of Copenhagen
Wei Wei: Stanford University School of Medicine
Stephanie M. Terrell: Stanford University School of Medicine
Benjamin C. Moeller: University of California at Davis
Rick M. Arthur: University of California
Gareth A. Wallis: University of Birmingham
Koen Wetering: Netherlands Cancer Institute
Andreas Stahl: University of California Berkeley
Bente Kiens: University of Copenhagen
Erik A. Richter: University of Copenhagen
Steven M. Banik: Stanford University
Michael P. Snyder: Stanford University School of Medicine
Yong Xu: Baylor College of Medicine
Jonathan Z. Long: Stanford University School of Medicine

Nature, 2022, vol. 606, issue 7915, 785-790

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04828-5

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