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Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.

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Title: Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.
Authors: Mills EL; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Harmon C; Department of Immunology, Harvard Medical School, Boston, MA, USA; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, USA., Jedrychowski MP; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Xiao H; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Gruszczyk AV; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK., Bradshaw GA; Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA., Tran N; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Garrity R; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Laznik-Bogoslavski D; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA., Szpyt J; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Prendeville H; School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland., Lynch L; Department of Immunology, Harvard Medical School, Boston, MA, USA; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, USA; School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland., Murphy MP; Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK; Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Spiegelman BM; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA., Chouchani ET; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. Electronic address: edwardt_chouchani@dfci.harvard.edu.
Source: Cell metabolism [Cell Metab] 2022 Jan 04; Vol. 34 (1), pp. 140-157.e8. Date of Electronic Publication: 2021 Dec 02.
Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Language: English
Journal Info: Publisher: Cell Press Country of Publication: United States NLM ID: 101233170 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-7420 (Electronic) Linking ISSN: 15504131 NLM ISO Abbreviation: Cell Metab Subsets: MEDLINE
Imprint Name(s): Original Publication: Cambridge, Mass. : Cell Press, c2005-
MeSH Terms: Adipose Tissue, Brown*/metabolism , Cysteine*/metabolism, Adipose Tissue/metabolism ; Inflammation/metabolism ; Thermogenesis/physiology ; Uncoupling Protein 1/genetics ; Uncoupling Protein 1/metabolism ; Animals ; Energy Metabolism ; Female ; Male ; Mice
Abstract: Uncoupling protein 1 (UCP1) is a major regulator of brown and beige adipocyte energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss-of-function model has recently been shown to have a severe deficiency in the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as a regulatory site on UCP1 that elevates protein activity upon covalent modification. Here, we examine the physiological importance of this site through the generation of a UCP1 cysteine-253-null (UCP1 C253A) mouse, a precise genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses in both males and females but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, we find that a lack of C253 results in adipose tissue redox stress, which drives substantial immune cell infiltration and systemic inflammatory pathology in adipose tissues and liver of male, but not female, mice. Elevation of systemic estrogen reverses this male-specific pathology, providing a basis for protection from inflammation due to loss of UCP1 C253 in females. Together, our results establish the UCP1 C253 activation site as a regulator of acute thermogenesis and sex-dependent tissue inflammation.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests E.T.C. is a founder, board member, and equity holder in EoCys Therapeutics. M.P.M. holds shares in Antipodean Pharmaceuticals who are commercializing MitoQ.
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Grant Information: R01 DK123095 United States DK NIDDK NIH HHS; 110159/A/15/Z United Kingdom WT_ Wellcome Trust; K99 DK123321 United States DK NIDDK NIH HHS; R01 DK123228 United States DK NIDDK NIH HHS; 110158/Z/15/Z United Kingdom WT_ Wellcome Trust; P30 DK135043 United States DK NIDDK NIH HHS; P30 CA006516 United States CA NCI NIH HHS; MC_UU_00015/3 United Kingdom MRC_ Medical Research Council; MC_U105663142 United Kingdom MRC_ Medical Research Council; R01 AI134861 United States AI NIAID NIH HHS; R00 DK123321 United States DK NIDDK NIH HHS
Contributed Indexing: Keywords: UCP1; cysteine; inflammation; metabolism; reactive oxygen species; sex differences
Substance Nomenclature: 0 (Ucp1 protein, mouse)
0 (Uncoupling Protein 1)
K848JZ4886 (Cysteine)
Entry Date(s): Date Created: 20211203 Date Completed: 20220407 Latest Revision: 20250530
Update Code: 20260130
PubMed Central ID: PMC8732317
DOI: 10.1016/j.cmet.2021.11.003
PMID: 34861155
Database: MEDLINE
Description
ISSN:1932-7420
DOI:10.1016/j.cmet.2021.11.003