An exercise-inducible metabolite that suppresses feeding and obesity
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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.
|Status||Udgivet - 2022|
CURIS 2022 NEXS 161
We thank members of the Long, Xu, Snyder, Richter and Svensson laboratories, and L. Sylow for helpful discussions. This work was supported by the NIH (DK124265 and DK130541 to J.Z.L.; DK113954, DK115761, DK117281 and DK120858 to Y.X.; GM113854 to V.L.L.; and AR072695 to K.v.d.W), the Ono Pharma Foundation (research grant to J.Z.L.), BASF (research grant to J.Z.L.), the USDA (51000-064-01S to Y.X.), the American Heart Association (20POST35120600 to Y.H.), the Novo Nordisk Foundation (NNF17OC0027274 and NNF18OC00334072 to E.A.R.) and PXE International (research grant to K.v.d.W.).
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
- Det Natur- og Biovidenskabelige Fakultet