Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance

Abstract

Brown adipose tissue (BAT), a crucial heat-generating organ, regulate 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 describe that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from dietinduced 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.

Chronic Intermittent Hypoxia during Sleep Causes Browning of Interscapular Adipose Tissue Accompanied by Local Insulin Resistance in Mice

“…Increased thermogenesis and UCP1 expression have also been linked to increased fatty acid oxidation by BAT [ 52 ], similar to what is suggested by the transcriptomic findings in the IH-exposed mice in the current study. However, it has also been shown, that thermogenesis may not necessarily be associated with improved BAT nutrient handling and insulin tolerance [ 53 ] and some metabolic function of BAT is independent of UCP1-linked thermogenesis [ 54 , 55 ]. Thus, the peripheral insulin resistance we observed in BAT under chronic IH conditions is not in line with the brown phenotype in BAT and may stem from other pathophysiological processes.…”

The Single-Cell Revelation of Thermogenic Adipose Tissue

“…Likewise, the computer algorithm MEBOCOST combining scRNA-seq transcriptome with the Human Metabolome Database has recently shown to be a promising tool in interrogating intercellular metabolite-sensor communication in BAT ( Zheng et al, 2022 ). Furthermore, despite the relatively scant discussion on BAT immunometabolism, recent report has strikingly laid out the divergence between thermogenesis and metabolic health, where the inflamed BAT promotes systemic insulin sensitivity through enhancing glucose uptake by other metabolic organs, while protecting against lipotoxicity and DIO at the expense of its energy-burning capacity ( Huang et al, 2022 ). Additionally, there is emerging recognition on the central involvement in BAT thermogenesis, where the oestrogen receptor-expressing or heat-sensing neurons has shown to modulate BAT activity and whole-body metabolic rates ( Makwana et al, 2021 ; Ye et al, 2022 ).…”

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

“…NLRP3 can recognize both PAMPs and danger-associated molecular patterns (DAMPs), and activate NLRP3 inflammasome, which consists of NLRP3 receptor protein, apoptosis-associated speck-like protein (ASC) and caspase-1 precursor protein (pro-caspase-1). A recent study found that mtDNA leaking into the cytoplasm activated NLRP3 inflammasome in brown adipose tissue, which is engaged in obesity-induced insulin resistance and impaired thermogenesis [ 46 ]. The double-stranded DNA receptor AIM2 also recognizes mtDNA released through BAK/BAX pores, and triggers IL-1β secretion and pyroptosis [ 47 ].…”