TY - JOUR

T1 - An exercise-inducible metabolite that suppresses feeding and obesity

AU - Li, Veronica L

AU - He, Yang

AU - Contrepois, Kévin

AU - Liu, Hailan

AU - Kim, Joon T

AU - Wiggenhorn, Amanda L

AU - Tanzo, Julia T

AU - Tung, Alan Sheng Hwa

AU - Lyu, Xuchao

AU - Zushin, Peter James H

AU - Jansen, Robert S

AU - Michael, Basil

AU - Loh, Kang Yong

AU - Yang, Andrew C.

AU - Carl, Christian Strini

AU - Voldstedlund, Christian Thomas

AU - Wei, Wei

AU - Terrell, Stephanie M

AU - Moeller, Benjamin C

AU - Arthur, Rick M

AU - Wallis, Gareth A

AU - van de Wetering, Koen

AU - Stahl, Andreas

AU - Kiens, Bente

AU - Richter, Erik A.

AU - Banik, Steven M

AU - Snyder, Michael P.

AU - Xu, Yong

AU - Long, Jonathan Z

N1 - Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Faculty of Science

KW - Metabolomics

KW - Obesity

KW - Proteases

KW - Lac-Phe

U2 - 10.1038/s41586-022-04828-5

DO - 10.1038/s41586-022-04828-5

M3 - Journal article

C2 - 35705806

AN - SCOPUS:85131943233

VL - 606

SP - 785

EP - 790

JO - Nature

JF - Nature

SN - 0028-0836

ER -