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

被引:36
作者
Mills, Evanna L. [1 ,2 ]
Harmon, Cathal [4 ,5 ,6 ]
Jedrychowski, Mark P. [1 ,2 ]
Xiao, Haopeng [1 ,2 ]
Gruszczyk, Anja, V [8 ]
Bradshaw, Gary A. [3 ]
Tran, Nhien [1 ]
Garrity, Ryan [1 ]
Laznik-Bogoslavski, Dina [1 ]
Szpyt, John [2 ]
Prendeville, Hannah [7 ]
Lynch, Lydia [4 ,5 ,6 ,7 ]
Murphy, Michael P. [8 ,9 ]
Gygi, Steven P. [2 ]
Spiegelman, Bruce M. [1 ,2 ]
Chouchani, Edward T. [1 ,2 ]
机构
[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[2] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA
[3] Harvard Med Sch, Harvard Program Therapeut Sci, Boston, MA 02115 USA
[4] Harvard Med Sch, Dept Immunol, Boston, MA USA
[5] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA
[6] Harvard Med Sch, Boston, MA 02115 USA
[7] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin, Ireland
[8] Univ Cambridge, Med Res Council, Mitochondria Biol Unit, Cambridge CB2 0XY, England
[9] Univ Cambridge, Dept Med, Cambridge CB2 0QQ, England
基金
英国惠康基金; 英国医学研究理事会;
关键词
DIET-INDUCED OBESITY; COLD-ACTIVATED BROWN; INDUCED THERMOGENESIS; MITOCHONDRIAL-DNA; MICE LACKING; SYMPATHETIC INNERVATION; MACROPHAGE RECRUITMENT; INSULIN-RESISTANCE; FAT; PROTEIN;
D O I
10.1016/j.cmet.2021.11.003
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:140 / +
页数:27
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