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.
Original language | English |
---|---|
Journal | Nature |
Volume | 606 |
Pages (from-to) | 785-790 |
Number of pages | 6 |
ISSN | 0028-0836 |
DOIs | |
Publication status | Published - 2022 |
Bibliographical note
Publisher Copyright:© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords
- Faculty of Science
- Metabolomics
- Obesity
- Proteases
- Lac-Phe