An exercise-inducible metabolite that suppresses feeding and obesity

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

doi:10.1038/s41586-022-04828-5

An exercise-inducible metabolite that suppresses feeding and obesity

Nature. 2022 Jun;606(7915):785-790. doi: 10.1038/s41586-022-04828-5. Epub 2022 Jun 15.

Authors

Veronica L Li^#^{1

2

3

4}, Yang He^#⁵, Kévin Contrepois^{6

7

8}, Hailan Liu⁵, Joon T Kim^{1

3}, Amanda L Wiggenhorn^{1

2

3}, Julia T Tanzo^{1

3}, Alan Sheng-Hwa Tung^{1

3}, Xuchao Lyu^{1

3

4}, Peter-James H Zushin⁹, Robert S Jansen^{10

11}, Basil Michael⁶, Kang Yong Loh^{2

3}, Andrew C Yang¹², Christian S Carl¹³, Christian T Voldstedlund¹³, Wei Wei^{1

3

14}, Stephanie M Terrell^{1

3}, Benjamin C Moeller^{15

16}, Rick M Arthur¹⁶, Gareth A Wallis¹⁷, Koen van de Wetering^{10

18}, Andreas Stahl⁹, Bente Kiens¹³, Erik A Richter¹³, Steven M Banik^{2

3}, Michael P Snyder^{6

7

8

4}, Yong Xu^{19

20}, Jonathan Z Long^{21

22

23

24

25}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Chemistry, Stanford University, Stanford, CA, USA.
³ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁴ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁵ Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
⁸ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁹ Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA.
¹⁰ Netherlands Cancer Institute, Amsterdam, Netherlands.
¹¹ Department of Microbiology, Radboud University, Nijmegen, Netherlands.
¹² Department of Anatomy and the Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA.
¹³ August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
¹⁴ Department of Biology, Stanford University, Stanford, CA, USA.
¹⁵ Maddy Equine Analytical Chemistry Laboratory, California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California at Davis, Davis, CA, USA.
¹⁶ Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
¹⁷ School of Sport, Exercise, and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK.
¹⁸ Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
¹⁹ Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. [email protected].
²⁰ Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. [email protected].
²¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
²² Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
²³ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. [email protected].
²⁴ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. [email protected].
²⁵ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Adiposity / drug effects
Animals
Body Weight / drug effects
Diabetes Mellitus, Type 2
Disease Models, Animal
Eating* / physiology
Energy Metabolism
Feeding Behavior* / physiology
Glucose / metabolism
Lactic Acid / metabolism
Mice
Obesity* / metabolism
Obesity* / prevention & control
Phenylalanine* / administration & dosage
Phenylalanine* / analogs & derivatives
Phenylalanine* / metabolism
Phenylalanine* / pharmacology
Physical Conditioning, Animal* / physiology

Substances

Lactic Acid
Phenylalanine
Glucose

Abstract

MeSH terms

Substances

Grants and funding