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

• Published in: The 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
• Language: English
• 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
• DOI: 10.1172/JCI148852
• ISSN: 0021-9738

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.