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MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue

Xin-Yuan Zhao1, Ben-Chi Zhao1, Hui-Lin Li1

  • 1Laboratory of Metabolism and Aging, School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, 518107, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|March 7, 2025
PubMed

Insights

Mitochondrial carrier homolog 2 (MTCH2) negatively regulates energy expenditure. Depleting MTCH2 in mice combats obesity by boosting adipose tissue thermogenesis and improving metabolic health, revealing a new therapeutic target.

Area of Science:

  • Metabolic disease research
  • Adipose tissue biology
  • Obesity mechanisms

Background:

  • Adipose tissue thermogenesis, regulated by uncoupling protein 1 (UCP1), is crucial for energy expenditure and obesity management.
  • Mechanisms suppressing thermogenesis in obesity remain incompletely understood.
  • Mitochondrial carrier homolog 2 (MTCH2) is an obesity susceptibility gene with an unclear role in energy homeostasis.

Purpose of the Study:

  • To investigate the role of MTCH2 in regulating energy homeostasis and adipose tissue thermogenesis.
  • To identify MTCH2 as a potential therapeutic target for obesity and related metabolic disorders.

Main Methods:

  • Utilized a combination of genetic manipulation (adipose-specific MTCH2 depletion in mice), high-fat diet (HFD) models, and integrated multi-omics analyses (RNA sequencing and proteomics).
  • Assessed metabolic parameters, thermogenesis markers (UCP1), mitochondrial biogenesis, and lipolysis in brown adipose tissue (BAT) and subcutaneous white adipose tissue (scWAT).
  • Investigated the molecular mechanism linking MTCH2 to thermogenesis regulation, focusing on autophagy and Bcl-2 interactions.

Main Results:

  • Adipose-specific MTCH2 depletion in mice conferred protection against HFD-induced obesity and metabolic dysfunction.
  • MTCH2 deficiency enhanced energy expenditure by stimulating BAT thermogenesis and promoting scWAT browning.
  • Key findings include upregulated UCP1, increased mitochondrial biogenesis, enhanced lipolysis, and MTCH2's role as a negative regulator of autophagy via a Bcl-2-dependent pathway.

Conclusions:

  • MTCH2 acts as a critical suppressor of thermogenesis and energy homeostasis.
  • MTCH2 negatively regulates autophagy through a Bcl-2-dependent mechanism, impacting adipose tissue function.
  • MTCH2 represents a novel therapeutic target for enhancing energy expenditure and treating obesity and metabolic diseases.
Keywords:
adipose tissueautophagymitochondrial carrier homolog 2 (MTCH2)obesitythermogenesis

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