Leucine catabolic enzyme AUH regulates BAT thermogenesis via PPARγ HMGylation and RNA-binding function in male mice.

Summary

This mechanistic study identifies AUH as a dual-function regulator of thermogenesis: via metabolite-driven HMGylation of PPARγ (K386) that boosts UCP1 transcription and via RNA-binding that stabilizes Ucp1 mRNA. AUH overexpression promotes browning and protects male mice from diet-induced obesity, linking leucine catabolism to adipose thermogenesis.

Key Findings

• HMG-CoA mediates PPARγ HMGylation at lysine 386, enhancing UCP1 transcription and thermogenesis.
• AUH binds and stabilizes Ucp1 mRNA, providing a second, RNA-mediated mechanism to increase UCP1.
• AUH overexpression induces browning and protects male mice from high-fat diet–induced obesity; AUH expression in human WAT inversely correlates with adiposity.

Clinical Implications

While preclinical, modulating AUH activity or PPARγ HMGylation could be explored to enhance brown/beige fat function and energy expenditure in obesity and metabolic disease.

Limitations

• Predominant use of male mice may limit generalizability to females.
• Translational applicability and safety of targeting AUH/PPARγ HMGylation remain untested in humans.

Future Directions

Validate PPARγ HMGylation in human thermogenic adipocytes, define sex-specific effects, and develop pharmacologic modulators of AUH/HMG-CoA flux to test metabolic efficacy and safety.