Cited by 262Adipose Tissue and MetabolismLipid metabolism and biosynthesisPeroxisome Proliferator-Activated Receptors

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The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

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Long, Jonathan Z., Svensson, Katrin J., Bateman, Leslie A., Lin, Hua, Kamenecka, Theodore, Lokurkar, Isha A., Lou, Jesse, Rao, Rajesh R., Chang, Mi Ra, Jedrychowski, Mark P., Paulo, Joao A., Gygi, Steven P., Griffin, Patrick R., Nomura, Daniel K., Spiegelman, Bruce M.·2016·Cell

DOI 10.1016/j.cell.2016.05.071PMC PMC4947008

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Abstract

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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Additional file 6 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 3 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 7 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 1 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 5 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 4 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 2 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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Additional file 8 of Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression
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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: Long, Jonathan Z.
Svensson, Katrin J.
Lin, Hua
Kamenecka, Theodore
Chang, Mi Ra
Gygi, Steven P.
Griffin, Patrick R.
Nomura, Daniel K.
Spiegelman, Bruce M.
Venue: Cell
Publisher: Elsevier BV
Published: 2016-07
Volume: 166
Issue: 2
Pages: 424-435
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2016.05.071
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 378 d)
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 (medical) › 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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The Secreted Enzyme PM20D1 Regulates Lipidated Amino Acid Uncouplers of Mitochondria

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