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An exercise-inducible metabolite that suppresses feeding and obesity
Open accessAbstract
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.
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“A recent study revealed that lactate reduced appetite via N-lactoyl-phenylalanine (Lac-Phe) and exerted neuroplastic effects through the BDNF pathway [58].”
From High-intensity interval training or lactate administration combined with aerobic training enhances visceral fat loss while promoting VMH neuroplasticity in female rats (2024) · cites this paper as [58]
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“An increase in the levels of N-lactoyl-phenylalanine, which reduces appetite and obesity risk, has also been reported during exercise [144].”
Background
Metadata
- Authors
- Li, V. L., He, Y., Contrepois, K., Liu, H., Kim, J. T., Wiggenhorn, A. L., Tanzo, J. T., Tung, A. S.-H., Lyu, X., Zushin, P.-J. H., Jansen, R. S., Michael, B., Loh, K. Y., Yang, A. C., Carl, C. S., Voldstedlund, C. T., Wei, W., Terrell, S. M., Moeller, B. C., Arthur, R. M., Wallis, G. A., van de Wetering, K., Stahl, A., Kiens, B., Richter, E. A., Banik, S. M., Snyder, M. P., Xu, Y., & Long, J. Z.
- Affiliations
- Stanford Medicine (US)
- Baylor College of Medicine (US)
- University of California, Berkeley (US)
- Radboud University Nijmegen (NL)
- Stanford University (US)
- University of California, San Francisco (US)
- University of Copenhagen (DK)
- University of California, Davis (US)
- University of Birmingham (GB)
- Corresponding author
- Xu, Yong
- Long, Jonathan Z.
- ORCID
- Li, Veronica L.
- He, Yang
- Contrepois, Kévin
- Liu, Hailan
- Kim, Joon T.
- Wiggenhorn, Amanda L.
- Tanzo, Julia T.
- Tung, Alan Sheng-Hwa
- Lyu, Xuchao
- Zushin, Peter-James H.
- Jansen, Robert S.
- Michael, Basil
- Loh, Kang Yong
- Yang, Andrew C.
- Carl, Christian S.
- Voldstedlund, Christian T.
- Wei, Wei
- Terrell, Stephanie M.
- Moeller, Benjamin C.
- Wallis, Gareth A.
- van de Wetering, Koen
- Stahl, Andreas
- Kiens, Bente
- Richter, Erik A.
- Banik, Steven M.
- Snyder, Michael P.
- Xu, Yong
- Long, Jonathan Z.
- Venue
- Nature
- Published
- 2022-06-15
- Volume
- 606
- Issue
- 7915
- Pages
- 785-790
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9767481
- OpenAlex
- W4282972916
- Cited by
- 331
- References
- 31
- Citations by year
- 2026: 69 · 2025: 91 · 2024: 86 · 2023: 61 · 2022: 24
- FWCI
- 34.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Funders
- U.S. Department of Agriculture (51000-064-01S)
- American Heart Association (20POST35120600)
- Novo Nordisk
- Novo Nordisk Fonden (NNF18OC0034072, NNF17OC0027274)
- Ono Pharma Foundation
- National Institutes of Health (DK130541, 51000-064-01S, DK113954)
- National Institute of General Medical Sciences (T32GM113854)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124265, R01DK120858, R01DK118940, P01DK113954, R01DK126830, R01DK117281, R01DK115761, DP1DK130641, R01DK109934, P30DK020579)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR072695)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- physical activity, feeding inhibition, obesity, dietary intake, energy balance, lactate, phenylalanine, CNDP2, macrophages, monocytes, glucose homeostasis, diet-induced obesity, exercise training, racehorses
- MeSH terms
- Animals, Body Weight, Diabetes Mellitus, Type 2, Disease Models, Animal, Eating, Energy Metabolism, Feeding Behavior, Glucose, Obesity, Phenylalanine, Physical Conditioning, Animal, Lactic Acid, Adiposity, Mice
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