Brown adipose TRX2 deficiency activates mtDNA-NLRPB to impair thermogenesis and protect against diet-induced insulin resistance

Brown adipose tissue (BAT), a crucial heat-generating organ, regulates whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabo...

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Published inThe Journal of clinical investigation Vol. 132; no. 9
Main Authors Huang, Yanrui, Zhou, Jenny H, Zhang, Haifeng, Canfran-Duque, Alberto, Singh, Abhishek K, Perry, Rachel J, Shulman, Gerald I, Fernandez-Hernando, Carlos, Min, Wang
Format Journal Article
LanguageEnglish
Published American Society for Clinical Investigation 01.05.2022
Subjects
Brown adipose tissue
Development and progression
Health aspects
Inflammation
Insulin resistance
Medical research
Medicine, Experimental
Mitochondrial DNA
Obesity
Physiological aspects
Thermogenesis
Thioredoxin
United States
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Summary:Brown adipose tissue (BAT), a crucial heat-generating organ, regulates whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results show that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, indudingthe cGAS/STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific 7rx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT, uncovering an adaptive mechanism underlyingthe link between BAT inflammation and systematic metabolism.
ISSN:0021-9738
DOI:10.1172/JCI148852