The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria
Open accessAbstract
Brown and beige adipocytes are specialized cells that express uncoupling protein 1 (UCP1) and dissipate chemical energy as heat. These cells likely possess alternative UCP1-independent thermogenic mechanisms. Here, we identify a secreted enzyme, peptidase M20 domain containing 1 (PM20D1), that is enriched in UCP1(+) versus UCP1(-) adipocytes. We demonstrate that PM20D1 is a bidirectional enzyme in vitro, catalyzing both the condensation of fatty acids and amino acids to generate N-acyl amino acids and also the reverse hydrolytic reaction. N-acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. Mice with increased circulating PM20D1 have augmented respiration and increased N-acyl amino acids in blood. Lastly, administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure. These data identify an enzymatic node and a family of metabolites that regulate energy homeostasis. This pathway might be useful for treating obesity and associated disorders.
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Recent research demonstrates that UCP1 is not essential for non-shivering thermogenesis.
“However, recent research demonstrates that UCP1 is not essential for non‐shivering thermogenesis 93, 99, 100.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [100]
PM20D1, a secreted enzyme produced by brown and brite adipocytes, contributes to alternative thermogenesis by participating in the uncoupling of mitochondria in a UCP1-independent manner.
“Peptidase M20 domain‐containing 1 (PM20D1), a secreted enzyme produced by brown and brite adipocytes, has been recently discovered to contribute to this alternative thermogenesis by participating in the uncoupling of mitochondria in an UCP1‐independent manner 99, 100.”
From Inter‐organ communication: a gatekeeper for metabolic health (2019) · cites this paper as [100]
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- Authors
- Long, J. Z., Svensson, K. J., Bateman, L. A., Lin, H., Kamenecka, T., Lokurkar, I. A., Lou, J., Rao, R. R., Chang, M. R., Jedrychowski, M. P., Paulo, J. A., Gygi, S. P., Griffin, P. R., Nomura, D. K., & Spiegelman, B. M.
- Affiliations
- Harvard University (US)
- University of California, Berkeley (US)
- Scripps Research Institute (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Nomura, Daniel K.
- Spiegelman, Bruce M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 166
- Issue
- 2
- Pages
- 424-435
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4947008
- OpenAlex
- W2474050011
- Cited by
- 257
- References
- 31
- Citations by year
- 2026: 23 · 2025: 22 · 2024: 22 · 2023: 17 · 2022: 29 · 2021: 27 · 2020: 31 · 2019: 27 · 2018: 24 · 2017: 27 · 2016: 7
- FWCI
- 22.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (DK105203)
- American Cancer Society (DK31405, DK5447, R01CA172667, RSG14-242-01-TBE)
- JPB Foundation
- Vetenskapsrådet (DK098285, PE2013/613)
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- PM20D1, N-acyl amino acids, mitochondrial uncouplers, brown adipocytes, beige adipocytes, energy expenditure, glucose homeostasis, obesity, secreted enzymes, mitochondrial respiration
- MeSH terms
- Amidohydrolases, Amino Acids, Animals, Energy Metabolism, Fatty Acids, Glucose, Homeostasis, Male, Mice, Inbred C57BL, Mitochondria, Adipocytes, Cell Respiration, Thermogenesis, Mitochondrial Proteins, Mice, Metabolic Networks and Pathways
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