N-acetylaspartate from fat cells regulates postprandial body temperature
Open accessPublished version of a preprint
Abstract
Abstract N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.
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- Authors
- Felix, J. B., Saha, P. K., de Groot, E. L., Tan, L., Sharp, R., Anaya, E. S., Li, Y., Quang, H., Saidi, N., Abushamat, L., Ballantyne, C. M., Amos, C. I., Lorenzi, P. L., Klein, S., Gao, X., & Hartig, S. M.
- Affiliations
- Baylor College of Medicine (US)
- The University of Texas MD Anderson Cancer Center (US)
- University of New Mexico (US)
- Washington University in St. Louis (US)
- Corresponding author
- Hartig, Sean M.
- ORCID
- Venue
- Nature Metabolism
- Published
- 2025-07-23
- Volume
- 7
- Issue
- 8
- Pages
- 1524-1535
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC12373498
- OpenAlex
- W4412589489
- Cited by
- 6
- References
- 7
- Citations by year
- 2026: 4 · 2025: 2
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Metabolism (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01DK138018, R01DK139397, R01DK114356, F31DK130596)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R00CA237618)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- N-acetylaspartate, aspartoacylase, white adipose tissue, adipocytes, pyrimidine metabolism, glucose disposal, adipose tissue endocrine function, metabolic homeostasis, body mass index
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