Journal Article

An exercise-inducible metabolite that suppresses feeding and obesity

Snyder, Michael P., Loh, Kang Yong, Wallis, Gareth A., Arthur, Rick M., Zushin, Peter-James H., Kiens, Bente, He, Yang, Moeller, Benjamin C., Terrell, Stephanie M., Stahl, Andreas, Michael, Basil, Xu, Yong, Carl, Christian S., Long, Jonathan Z., Wei, Wei, Lyu, Xuchao, Tanzo, Julia T., Banik, Steven M., Jansen, Robert S., Li, Veronica L., Voldstedlund, Christian T., Contrepois, Kévin, Richter, Erik A., Yang, Andrew C., Tung, Alan Sheng-Hwa, van de Wetering, Koen, Liu, Hailan, Kim, Joon T., Wiggenhorn, Amanda L.

2022

Overview

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 unclear 6 . 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. A newly identified exercise-induced signalling metabolite—an amidated conjugate of lactate and phenylalanine—can reduce food intake and improve blood glucose homeostasis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/95 / 631/443/319/1642/393 / 631/45/320 / 631/92/607/468 / 64/60 / 82/58 / Ablation / Adipose tissue / Adiposity - drug effects / Amino acids / Animals / Biosynthesis / Body weight / Body Weight - drug effects / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 / Disease Models, Animal / Eating - physiology / Energy / Energy balance / Energy expenditure / Energy Metabolism / Enzymes / Epithelial cells / Epithelium / Exercise / Feeding Behavior - physiology / Food / Food intake / Glucose / Glucose - metabolism / Homeostasis / Humanities and Social Sciences / Lactic acid / Lactic Acid - metabolism / Macrophages / Metabolism / Metabolites / Mice / Monocytes / multidisciplinary / Obesity / Obesity - metabolism / Obesity - prevention & control / Organs / Peptides / Phenylalanine / Phenylalanine - administration & dosage / Phenylalanine - analogs & derivatives / Phenylalanine - metabolism / Phenylalanine - pharmacology / Physical activity / Physical Conditioning, Animal - physiology / Physical fitness / Physical training / Physiology / Plasma / Science / Science (multidisciplinary)