MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue
Stimulating adipose tissue thermogenesis has emerged as a promising strategy for combating obesity, with uncoupling protein 1 (UCP1) playing a central role in this process. However, the mechanisms that suppress adipose thermogenesis and energy dissipation in obesity are not fully understood. This study identifies mitochondrial carrier homolog 2 (MTCH2), an obesity susceptibility gene, as a negative regulator of energy homeostasis across flies, rodents, and humans. Notably, adipose-specific MTCH2 depletion in mice protects against high-fat-diet (HFD)-induced obesity and metabolic disorders. Mechanistically, MTCH2 deficiency promotes energy expenditure by stimulating thermogenesis in brown adipose tissue (BAT) and browning of subcutaneous white adipose tissue (scWAT), accompanied by upregulated UCP1 protein expression, enhanced mitochondrial biogenesis, and increased lipolysis in BAT and scWAT. Using integrated RNA sequencing and proteomic analyses, this study demonstrates that MTCH2 is a key suppressor of thermogenesis by negatively regulating autophagy via Bcl-2-dependent mechanism. These findings highlight MTCH2's critical role in energy homeostasis and reveal a previously unrecognized link between MTCH2, thermogenesis, and autophagy in adipose tissue biology, positioning MTCH2 as a promising therapeutic target for obesity and related metabolic disorders. This study provides new opportunities to develop treatments that enhance energy expenditure.
Authors
- Yan‐Chuan Shi (ORCID: https://orcid.org/0000-0002-8368-6735)
- G. Gregory Neely (ORCID: https://orcid.org/0000-0002-1957-9732)
- Yanhong Deng (ORCID: https://orcid.org/0000-0001-6873-8026)
- Qiao‐Ping Wang (ORCID: https://orcid.org/0000-0003-2809-6457)
- Ben‐Chi Zhao
- Xiaoyan Hui (ORCID: https://orcid.org/0000-0002-7525-5812)
- Jia Sun (ORCID: https://orcid.org/0000-0001-9617-5865)
- Jian‐Xun Mi (ORCID: https://orcid.org/0000-0002-7531-4341)
- Nele Gheldof (ORCID: https://orcid.org/0000-0001-8922-7372)
- Jörg Hager (ORCID: https://orcid.org/0000-0002-6634-9294)
- D. Ross Laybutt (ORCID: https://orcid.org/0009-0005-1943-8859)
- Tianshu Zeng (ORCID: https://orcid.org/0000-0001-9171-7151)
- Domagoj Cikes (ORCID: https://orcid.org/0000-0003-0350-5672)
- Bei Wang (ORCID: https://orcid.org/0000-0003-3002-3302)
- Anqi Li (ORCID: https://orcid.org/0000-0003-1409-1858)
- Ying Liu (ORCID: https://orcid.org/0000-0003-1405-5419)
- Huilin Li (ORCID: https://orcid.org/0000-0002-7261-5675)
- Xinyuan Zhao (ORCID: https://orcid.org/0000-0003-2388-5967)
Institutions
- Chongqing University of Posts and Telecommunications (CN)
- Johannes Kepler University of Linz (AT)
- The University of Sydney (AU)
- Garvan Institute of Medical Research (AU)
- Sun Yat-sen University (CN)
- Chinese University of Hong Kong (HK)
- UNSW Sydney (AU)
- Nestlé (Switzerland) (CH)
- Zhujiang Hospital (CN)
- St Vincent's Clinic (AU)
- Wuhan Union Hospital (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- École Polytechnique Fédérale de Lausanne (CH)
- Southern Medical University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1002/advs.202416598
- Citations
- 9
- Primary Topic
- Adipose Tissue and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- National Natural Science Foundation of China
- Fundamental Research Funds for the Central Universities