MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue.

Summary

Across species, MTCH2 acts as a brake on thermogenesis. Adipose-specific MTCH2 depletion increases UCP1, mitochondrial biogenesis, lipolysis, and browning of scWAT, boosting energy expenditure and protecting mice from HFD-induced obesity and metabolic dysfunction. Integrated RNA-seq and proteomics indicate MTCH2 suppresses thermogenesis by negatively regulating autophagy via a Bcl‑2–dependent mechanism.

Key Findings

• MTCH2 identified as a conserved negative regulator of energy homeostasis in flies, rodents, and humans.
• Adipose-specific MTCH2 knockout protects mice from HFD-induced obesity and metabolic disorders by increasing energy expenditure.
• Upregulation of UCP1, mitochondrial biogenesis, and lipolysis in BAT and scWAT with enhanced browning of scWAT.
• Integrated RNA-seq/proteomics reveal MTCH2 suppresses thermogenesis by negatively regulating autophagy via a Bcl-2–dependent mechanism.

Clinical Implications

Therapeutic inhibition of MTCH2 or modulation of its Bcl-2–autophagy axis could enhance brown/beige fat thermogenesis to treat obesity and metabolic disease, pending human mechanistic validation and safety studies.

Limitations

• Lack of interventional human studies; causal roles inferred without pharmacologic MTCH2 modulation in humans.
• Long-term safety of enhancing autophagy/thermogenesis remains unknown.

Future Directions

Develop selective MTCH2 modulators, map downstream autophagy nodes amenable to drugging, and test efficacy/safety in human adipocyte systems and early-phase trials.