Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.
Mills, Evanna L
Jedrychowski, Mark P
Gruszczyk, Anja V
Bradshaw, Gary A
Gygi, Steven P
Spiegelman, Bruce M
Chouchani, Edward T
MetadataShow full item record
Mills, E. L., Harmon, C., Jedrychowski, M. P., Xiao, H., Gruszczyk, A. V., Bradshaw, G. A., Tran, N., et al. (2022). Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation.. Cell Metab https://doi.org/10.1016/j.cmet.2021.11.003
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.
UCP1, cysteine, inflammation, metabolism, reactive oxygen species, sex differences
This work was supported by the Claudia Adams Barr Program (E.T.C), the Lavine Family Fund (E.T.C), the Pew Charitable Trust (E.T.C), NIH DK123095 (E.T.C) , NIH DK123321 (E.M.), the National Cancer Center (H.X.), R01DK078081 (N.N.D.). We thank the Nikon Imaging Center at Harvard Medical School for assistance with microscopy, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core (NIH-5-P30-CA06516) for preparing histology slides and the Harvard Digestive Disease Center, Core D for assistance with thermal imaging. Cartoon illustrations were created with BioRender.com.
Medical Research Council (MC_U105663142)
Wellcome Trust (110159/Z/15/Z)
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External DOI: https://doi.org/10.1016/j.cmet.2021.11.003
This record's URL: https://www.repository.cam.ac.uk/handle/1810/331645
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/