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An exercise-inducible metabolite that suppresses feeding and obesity.
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.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Publication Date: 2022-06-15 PubMed ID: 35705806PubMed Central: PMC9767481DOI: 10.1038/s41586-022-04828-5Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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This research focused on the discovery of a metabolite called N-lactoyl-phenylalanine (Lac-Phe) which is produced during exercise and has been found to suppress hunger and obesity, highlighting its potential crucial role in managing obesity and related metabolic disorders.
About the Research
In this study, researchers aimed to investigate the molecular and cellular mechanisms influenced by physical activity that could potentially offer protection against obesity and other metabolic disorders. The primary finding was the identification of the metabolite N-lactoyl-phenylalanine (Lac-Phe), which is produced during exercise and found to be effective in suppressing hunger and obesity.
- The research team discovered that the production of Lac-Phe from lactate and phenylalanine occurs in CNDP2-positive cells, which include macrophages, monocytes, and other immune and epithelial cells based in various organs.
- They further observed that in mice suffering from diet-induced obesity, increases in Lac-Phe due to pharmacological intervention led to reduced food intake, without affecting their movement or energy expenditure.
- The team also discovered that long-term administration of Lac-Phe can result in decreased body weight and improved glucose homeostasis, implying better control of diabetes-related factors.
- On the other hand, mouse models that underwent genetic removal of Lac-Phe biosynthesis showed an increase in food intake and obesity.
Implications and Future Directions
- The discovery of Lac-Phe’s role in appetite regulation and obesity prevention offers critical insights into potential strategies for managing obesity-related metabolic disorders.
- The observation that increases in circulating Lac-Phe are related to physical activity in different mammalian species, including humans and racehorses, highlights the metabolite’s universal role in energy balance.
- In the future, further research could focus on leveraging the properties of Lac-Phe as a therapeutic approach for chronic metabolic conditions such as obesity and type 2 diabetes.
Cite This Article
APA
Li VL, He Y, Contrepois K, Liu H, Kim JT, Wiggenhorn AL, Tanzo JT, Tung AS, Lyu X, Zushin PH, Jansen RS, Michael B, Loh KY, Yang AC, Carl CS, Voldstedlund CT, Wei W, Terrell SM, Moeller BC, Arthur RM, Wallis GA, van de Wetering K, Stahl A, Kiens B, Richter EA, Banik SM, Snyder MP, Xu Y, Long JZ.
(2022).
An exercise-inducible metabolite that suppresses feeding and obesity.
Nature, 606(7915), 785-790.
https://doi.org/10.1038/s41586-022-04828-5 Publication
Researcher Affiliations
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
- Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA.
- Netherlands Cancer Institute, Amsterdam, Netherlands.
- Department of Microbiology, Radboud University, Nijmegen, Netherlands.
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Anatomy and the Bakar Aging Research Institute, University of California San Francisco, San Francisco, CA, USA.
- August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
- August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Biology, Stanford University, Stanford, CA, USA.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Maddy Equine Analytical Chemistry Laboratory, California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California at Davis, Davis, CA, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA.
- School of Sport, Exercise, and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK.
- Netherlands Cancer Institute, Amsterdam, Netherlands.
- Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA.
- Department of Nutrition and Toxicology, University of California Berkeley, Berkeley, CA, USA.
- August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
- August Krogh Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
- Department of Chemistry, Stanford University, Stanford, CA, USA.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
- Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. yongx@bcm.edu.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. yongx@bcm.edu.
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
- Sarafan ChEM-H, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
- Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
- Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
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
Grant Funding
- DK130541 / NIH HHS
- R01 DK124265 / NIDDK NIH HHS
- P01 DK113954 / NIDDK NIH HHS
- R01 DK120858 / NIDDK NIH HHS
- R01 DK118940 / NIDDK NIH HHS
- T32 GM113854 / NIGMS NIH HHS
- R01 DK115761 / NIDDK NIH HHS
- DP1 DK130641 / NIDDK NIH HHS
- R01 DK117281 / NIDDK NIH HHS
- 20POST35120600 / American Heart Association-American Stroke Association
- P30 DK020579 / NIDDK NIH HHS
- GM113854 / NIH HHS
- DK113954 / NIH HHS
- R01 AR072695 / NIAMS NIH HHS
- R01 DK126830 / NIDDK NIH HHS
Conflict of Interest Statement
Competing interest declaration. The authors declare the following competing interests: a provisional patent application has been filed by Stanford University on lactoyl amino acids for the treatment of metabolic disease.
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