Children’s Nutrition Research Center Staff Publications
Publication Date
6-1-2022
Journal
Nature
DOI
10.1038/s41586-022-04828-5
PMID
35705806
PMCID
PMC9767481
PubMedCentral® Posted Date
12-20-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Adiposity, Animals, Body Weight, Diabetes Mellitus, Type 2, Disease Models, Animal, Eating, Energy Metabolism, Feeding Behavior, Glucose, Lactic Acid, Mice, Obesity, Phenylalanine, Physical Conditioning, Animal
Abstract
Exercise confers robust 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 unclear.6 Here we show that exercise stimulates production of Lac-Phe, a blood-borne signaling metabolite that suppresses feeding and obesity. Lac-Phe biosynthesis from lactate occurs in CNDP2+ cells including immune cells, epithelial cells, and mesenchymal stem cells localized to diverse organs. In diet-induced obese mice, pharmacological elevation of circulating 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. Lastly, dramatic activity-inducible elevations of circulating Lac-Phe levels are also observed in humans and racehorses, establishing this metabolite to be a robust 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.
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Dietetics and Clinical Nutrition Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Nutrition Commons