Abstract
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, including the 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 Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT, uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.
Highlights
Some studies suggest that brown adipose tissue (BAT) activation promotes adaptive thermogenesis and increases EE, protecting against obesity, insulin resistance, and hyperlipidemia [5–7], whereas other studies indicate that the defective adaptive thermogenesis in BAT is an adaptation to metabolic stress with metabolic benefits [8, 9]
Enlarged interscapular BAT (iBAT) was attributed to steatotic hypertrophy, as we observed in the accumulation of larger and more unilocular lipid droplets (LDs) in adipocytes from Trx2BATKO mice compared with those in WT (Supplemental Figure 1H)
These data suggest that TRX2 deficiency in BAT induces BAT steatotic hypertrophy without metabolic disorder under normal chow diet (NCD), in contrast to the diabetic and hyperlipidemic phenotype observed in Trx2ADKO mice [29]
Summary
Obesity related to overnutrition is driven by energy intake and energy expenditure (EE) imbalance. White adipose tissue (WAT), having small numbers of mitochondria, plays a major role in energy storage, but does not contribute substantially to EE [1]. Brown adipose tissue (BAT), characterized by densely packed mitochondria, is a major contributor to EE that produces heat via adaptive thermogenesis to maintain body temperature [2–4]. The role of BAT in maintaining whole-body metabolism homeostasis under metabolic stress remains controversial. Some studies suggest that BAT activation promotes adaptive thermogenesis and increases EE, protecting against obesity, insulin resistance, and hyperlipidemia [5–7], whereas other studies indicate that the defective adaptive thermogenesis in BAT is an adaptation to metabolic stress with metabolic benefits [8, 9]. Since substantial amounts of metabolically active BAT have been
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