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

## TL;DR

This study shows that Txnip is essential for brown fat to function properly in cold conditions, and its absence makes mice vulnerable to hypothermia.

## Contribution

The study reveals Txnip's novel role in cold-induced thermogenesis and brown fat function in mice.

## Key findings

- Txnip deficiency leads to brown fat dysfunction and cold susceptibility in mice.
- Txnip−/− mice fail to activate fatty acid and amino acid catabolism during acute cold stress.
- Acclimation to moderate cold (16 °C) rescues BAT function and prevents lethal hypothermia in Txnip−/− mice.

## Abstract

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.