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An exercise-inducible metabolite that suppresses feeding and obesity.

ABSTRACT: Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases^1-5. 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.

SUBMITTER: Li VL

PROVIDER: S-EPMC9767481 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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An exercise-inducible metabolite that suppresses feeding and obesity.

Li Veronica L VL He Yang Y Contrepois Kévin K Liu Hailan H Kim Joon T JT Kim Joon T JT Wiggenhorn Amanda L AL Tanzo Julia T JT Tung Alan Sheng-Hwa AS Lyu Xuchao X Zushin Peter-James H PH Jansen Robert S RS Michael Basil B Loh Kang Yong KY Yang Andrew C AC Carl Christian S CS Voldstedlund Christian T CT Wei Wei W Terrell Stephanie M SM Moeller Benjamin C BC Arthur Rick M RM Wallis Gareth A GA van de Wetering Koen K Stahl Andreas A Kiens Bente B Richter Erik A EA Banik Steven M SM Snyder Michael P MP Xu Yong Y Long Jonathan Z JZ

Nature 20220615 7915

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, ...[more]

PMID: 35705806

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Project description:ObjectiveExercise training has several well-established health benefits, including many related to body weight, appetite control, and blood glucose homeostasis. However, the molecular mechanisms and, in particular, the hormonal systems that mediate and integrate these beneficial effects are poorly understood. In the current study, we aimed to investigate the role of the hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR; ghrelin receptor), in mediating the effects of exercise on food intake and blood glucose following exercise as well as in regulating exercise endurance capacity.MethodsWe used two mouse models of treadmill running to characterize the changes in plasma ghrelin with exercise. We also assessed the role of the ghrelin system to influence food intake and blood glucose after exercise, exercise endurance, and parameters potentially linked to responses to exercise. Mice lacking GHSRs (GHSR-null mice) and wild-type littermates were studied.ResultsAn acute bout of exercise transiently elevated plasma acyl-ghrelin. Without the action of this increased ghrelin on GHSRs (as in GHSR-null mice), high intensity interval exercise markedly reduced food intake compared to control mice. The effect of exercise to acutely raise blood glucose remained unmodified in GHSR-null mice. Exercise-induced increases in plasma ghrelin positively correlated with endurance capacity, and time to exhaustion was reduced in GHSR-null mice as compared to wild-type littermates. In an effort to mechanistically explain their reduced exercise endurance, exercised GHSR-null mice exhibited an abrogated sympathoadrenal response, lower overall insulin-like growth factor-1 levels, and altered glycogen utilization.ConclusionsExercise transiently increases plasma ghrelin. GHSR-null mice exhibit decreased food intake following high intensity interval exercise and decreased endurance when submitted to an exercise endurance protocol. These data suggest that an intact ghrelin system limits the capacity of exercise to restrict food intake following exercise, although it enhances exercise endurance.

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An exercise-inducible metabolite that suppresses feeding and obesity.

Publications

An exercise-inducible metabolite that suppresses feeding and obesity.

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