NRF2‐REGγ‐ACADM/KLF15 Signaling Pathway Regulates the Browning of White Adipose Tissue to Modulate Obesity

Abstract Obesity is a significant risk factor for diabetes, cardiovascular diseases, and certain cancers, and manifests as excessive fat accumulation. The browning of white adipose tissue (WAT) represents one of the most promising strategies for preventing and treating obesity and metabolic diseases. To date, an increasing number of studies have focused on key molecular mechanisms regulating fat thermogenesis, laying the foundation for effective intervention strategies. Here, REGγ expression is shown to be significantly upregulated in adipose tissue of obese individuals and in inguinal WAT (iWAT) of obese mice. Deficiency in REGγ expression reduces fat deposition, increases energy expenditure in adipose tissue, and protects mice from HFD‐induced obesity and insulin resistance. Mechanistically, REGγ expression regulates browning of WAT by modulating ACADM and KLF15‐UCP1 signaling in a ubiquitin‐independent degradation manner. Overactivation of the NRF2‐REGγ axis facilitates adipose tissue function to cause obesity. Notably, inhibition of REGγ in the iWAT alleviates HFD‐induced obesity, thereby identifying REGγ as a latent target for obesity treatment. Together, the findings provide new targets for intervening in obesity and might ultimately offer new options for treating obesity.