Txnip deficiency causes a susceptibility to acute cold stress with brown fat dysfunction in mice.

Mammals adaptively regulate energy metabolism in response to environmental changes such as starvation and cold circumstances. Thioredoxin-interacting protein (Txnip), known as a redox regulator, serves as a nutrient sensor regulating energy homeostasis. Txnip is essential for mice to adapt to starvation, but its role in adapting to cold circumstances remains unclear. Here, we identified Txnip as a pivotal factor for maintaining nonshivering thermogenesis in mice. Txnip protein levels in brown adipose tissue (BAT) were upregulated by the acute cold exposure. Txnip-deficient (Txnip) mice acclimated to thermoneutrality (30 °C) exhibited significant BAT enlargement and triglyceride accumulation with downregulation of BAT signature and metabolic gene expression. Upon acute cold exposure (5 °C), Txnip mice showed a rapid decline in BAT surface temperatures with the failure of increasing metabolic respiration, developing lethal hypothermia. The BAT dysfunction and cold susceptibility in Txnip mice were corrected by acclimation to 16 °C, protecting the mice from life-threatening hypothermia. Transcriptomic and metabolomic analysis using dissected BAT revealed that despite preserving glycolysis, the BAT of Txnip mice failed to activate the catabolism of branched-chain amino acids and fatty acids in response to acute cold stress. These findings illustrate that Txnip is required for maintaining basal BAT function and ensuring cold-induced thermogenesis.