An exercise-inducible metabolite that suppresses feeding and obesity

Authors: LI, VERONICA - Stanford University School Of Medicine; HE, YANG - Children'S Nutrition Research Center (CNRC); CONTREPOIS, KEVIN - Stanford University School Of Medicine; LIU, HAILAN - Children'S Nutrition Research Center (CNRC); KIM, JOON - Stanford University School Of Medicine; WIGGENHORN, AMANDA - Stanford University School Of Medicine; TANZO, JULIA - Stanford University School Of Medicine; TUNG, ALAN SHENG-HWA - Stanford University School Of Medicine; LYU, XUCHAO - Stanford University School Of Medicine; ZUSHIN, PETER-JAMES - University Of California Berkeley; JANSEN, ROBERT - Netherlands Cancer Institute; MICHAEL, BASIL - Stanford University School Of Medicine; LOH, KANG YONG - Stanford University; YANG, ANDREW - University Of California San Francisco (UCSF); CARL, CHRISTIAN - University Of Copenhagen; VOLDSTEDLUND, CHRISTIAN - University Of Copenhagen; WEI, WEI - Stanford University School Of Medicine; TERRELL, STEPHANIE - Stanford University School Of Medicine; MOELLER, BENJAMIN - University Of California, Davis; ARTHUR, RICK - University Of California, Davis; WALLIS, GARETH - University Of Birmingham; WETERING, KOEN VAN DE - Netherlands Cancer Institute; STAHL, ANDREAS - University Of California Berkeley; KIENS, BENTE - University Of Copenhagen; RICHTER, ERIK - University Of Copenhagen; BANIK, STEVEN - Stanford University; SNYDER, MICHAEL - Stanford University School Of Medicine; XU, YONG - Children'S Nutrition Research Center (CNRC); LONG, JONATHAN - Stanford University School Of Medicine

Submitted to: Nature
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/3/2022
Publication Date: 6/15/2022
Citation: Li, V., He, Y., Contrepois, K., Liu, H., Kim, J., Wiggenhorn, A., Tanzo, J., Tung, A., Lyu, X., Zushin, P., Jansen, R., Michael, B., Loh, K., Yang, A., Carl, C., Voldstedlund, C., Wei, W., Terrell, S., Moeller, B., Arthur, R., Wallis, G., Wetering, K., Stahl, A., Kiens, B., Richter, E., Banik, S., Snyder, M., Xu, Y., Long, J. 2022. An exercise inducible metabolite that suppresses feeding and obesity. Nature. https://doi.org/10.1038/s41586-022-04828-5.
DOI: https://doi.org/10.1038/s41586-022-04828-5

Interpretive Summary: There is a common phenomenon that people lose appetite after an intense exercise, like a running sprint. However, the biological mechanisms underlying this phenomenon is unknown. In this work, we discovered that one molecule, named Lac-Phe, increases much more than any others in the bloodstream. Mice treated with Lac-Phe decreased their food consumption. Moreover, mice failed to produce as much Lac-Phe as in the control group are still ballooned, eating more food and gaining much more weight even though they exercise. Overall, Lac-Phe is a key to how intense exercise helped the mice avoid weight gain. A failure of the animal to produce it, even with the same amount of exercise, resulted in overeating.

Technical 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.