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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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Items 301–332 of 332
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“Lac-Phe has gained increasing attention due to its role as a signaling metabolite that is inducible by exercise and has been implicated in appetite regulation and energy homeostasis [31–33, 34 ].”
Clements, C. M., Udovich, C. C., Ludwig, K. R., Cendali, F. I., Dzieciątkowska, M., Fortis, S. P., Schütz, U. H. W., Schmidt‐Trucksäss, A., Klenk, C., D’Alessandro, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.12.711477
“…is a microbial metabolite (in addition to p-cresol 71 , indole-3-acetate 72 , and TMAO that is associated with cardiovascular pathology 73 in part due to its role in arterial stiffening 74 ), which is produced by the condensation of lactate and phenylalanine 75 in response to exercise 33,34 .”
Hsu, J. C.-N., Chen, C.-H., Chen, M.-W., Chen, W., & Lee, T. (2026) · Antioxidants · doi:10.3390/antiox15040441
“One such molecule, N-lactoyl-phenylalanine (Lac-Phe), has garnered significant attention since its identification in 2022 as an exercise-inducible metabolite [1].”
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Exercise and aging: Unlocking health beyond 65 years old
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Exercise benefits in metabolism on cardiovascular disease
Guo, Y., Zheng, Q., Wang, X., Zhang, B. X., & Yan, T. (2026) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2026.1781202
“Plasma Lac-Phe is a top metabolite in exercise mice.”
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Tissue-dependent enzymatic control of N-acetyl-β-alanine by PTER
Li, R., Fu, S., Lyu, Z., Wang, B., Hassman, R., Shuster, J. T., Kizzar, T., Simcox, J., & Wei, W. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113191
“A recent example is the CNDP2-catalyzed condensation of lactate and phenylalanine to form Lac-Phe (47), as well as β -hydroxybutyrate and phenylalanine to produce BHB-Phe (46).”
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“Work over the past decade has established that exercise can elicit systemic effects via circulating molecules termed ‘exerkines’ (8), as well as exercise-inducible metabolites with systemic effects on feeding and energy balance (9, 10).”
The Metabolome of Drosophila Reveals Exercise-Induced Stress and Anti-Inflammatory ResponsePreprint
Mabayoje, T. R., Backlund, A. E., Albrecht, J. E., Chamberlain, M. S., Tremblay, S. S., Myers, A., Koehler, A., Maisonet-Nieves, M. A., Hogland, C., Bicanovsky, G. N., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.26.734830
Practical Synthesis of N-Lactoyl-Phenylalanine and Its Isotopically Deuterated Variant Lac-Phe-d 5
Touaibia, M. (2026) · Letters in Organic Chemistry · doi:10.2174/0115701786492436260617164313
AAV delivered lysosome-targeting chimeras mediate sustained antibody depletion in vivoPreprint
Yang, J. L., Loh, K. Y., Espinoza, C. R. S., Schuster, D., Yamada‐Hunter, S. A., Labanieh, L., Sotillo, E., Mackall, C. L., Deisseroth, K. A., & Bertozzi, C. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.05.736665
Self-citationCai, H., He, Y. F., Wang, C., Zhao, Y., & Yang, C. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2026.1885022 · Cited by 1
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InfluentialSelf-citationMuñoz-López, M., Quesada-Fernández, G., Sancho-Haro, E. S., Viúdez, X. R. D. L. P., Baz-Valle, E., López‐Gil, J. F., & Tornero-Aguilera, J. F. (2026) · Metabolites · doi:10.3390/metabo16070483
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InfluentialLac-Phe: An Exercise Hormone for Metabolic Regulation
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MCT6 is an intestinal Lac-Phe exporter required for metformin-associated weight loss
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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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