journal article·2025-05Open access

MTCH2 Suppresses Thermogenesis by Regulating Autophagy in Adipose Tissue

Xin‐Yuan Zhao, Ben‐Chi Zhao, Hui‐Lin Li, Ying Liu, Bei Wang, An‐Qi Li, Tian‐Shu Zeng, Hannah Xiaoyan Hui, Jia Sun, Domagoj Cikes, Nele Gheldof, Jorg Hager, Jian‐Xun Mi, D. Ross Laybutt, Yin‐Yue Deng, Yan‐Chuan Shi, G. Gregory Neely, Qiao‐Ping Wang

Advanced Science· Volume 12· Issue 17

Abstract

Abstract 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.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Adipose Tissue and Metabolism · Lipid metabolism and biosynthesis · Mitochondrial Function and Pathology

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Laboratory of Metabolism and Aging School of Pharmaceutical Sciences (Shenzhen) Shenzhen Campus of Sun Yat‐sen University Shenzhen 518107 China

Wuhan Union Hospital Huazhong University of Science and Technology Wuhan 430022 China

School of Biomedical Sciences The Chinese University of Hong Kong Hong Kong 999077 China

Department of Endocrinology Zhujiang Hospital Southern Medical University Guangzhou 510280 China

Institute of Physiology and Pathophysiology Johannes Kepler University Linz Linz 4020 Austria

Ecole Polytechnique de Lausanne (EPFL) Lausanne CH‐1015 Switzerland

Nestlé Institute of Health Sciences Lausanne CH‐1015 Switzerland

Key Laboratory of Big Data Intelligent Computing Chongqing University of Posts and Telecommunications Chongqing 400065 China

Chongqing Key Laboratory of Image Cognition Chongqing University of Posts and Telecommunications Chongqing 400065 China

College of Computer Science and Technology Chongqing University of Posts and Telecommunications Chongqing 400065 China

Garvan Institute of Medical Research St Vincent's Clinical School UNSW Sydney Darlinghurst Sydney NSW 2010 Australia

School of Pharmaceutical Sciences (Shenzhen) Sun Yat‐sen University Shenzhen 518107 China

Neuroendocrinology Group Garvan Institute of Medical Research Darlinghurst Sydney NSW 2010 Australia

St Vincent's Clinical School Faculty of Medicine University of New South Wales Sydney NSW 2010 Australia

The Dr. John and Anne Chong Laboratory for Functional Genomics Charles Perkins Centre and School of Life & Environmental Sciences The University of Sydney Sydney NSW 2006 Australia

Guangdong Provincial Key Laboratory of Diabetology Guangzhou Key Laboratory of Mechanistic and Translational Obesity Research The Third Affiliated Hospital of Sun Yat‐sen University Guangzhou 510630 China

State Key Laboratory of Anti‐Infective Drug Discovery and Development School of Pharmaceutical Sciences Sun Yat‐sen University Guangzhou 510006 China

Funding

National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities

References (74)

Show source-provided references
1. 10.1002/mco2.20710.1002/mco2.207 ↗
2. 10.1002/ptr.808310.1002/ptr.8083 ↗
3. 10.1016/j.cell.2021.12.01610.1016/j.cell.2021.12.016 ↗
4. 10.1093/lifemeta/loae00310.1093/lifemeta/loae003 ↗
5. 10.1038/s41580-021-00350-010.1038/s41580-021-00350-0 ↗
6. 10.1093/lifemeta/loac00310.1093/lifemeta/loac003 ↗
7. 10.1016/j.cmet.2012.01.01910.1016/j.cmet.2012.01.019 ↗
8. 10.1016/j.cell.2013.12.01210.1016/j.cell.2013.12.012 ↗
9. 10.1038/s41576-021-00414-z10.1038/s41576-021-00414-z ↗
10. 10.1016/S2213-8587(17)30200-010.1016/S2213-8587(17)30200-0 ↗
11. 10.1038/sj.ijo.080135810.1038/sj.ijo.0801358 ↗
12. 10.3945/ajcn.2010.2980810.3945/ajcn.2010.29808 ↗
13. 10.3945/ajcn.2009.2808510.3945/ajcn.2009.28085 ↗
14. 10.3945/ajcn.114.08970610.3945/ajcn.114.089706 ↗
15. 10.3945/ajcn.117.15621610.3945/ajcn.117.156216 ↗
16. 10.1016/j.celrep.2016.01.04610.1016/j.celrep.2016.01.046 ↗
17. 10.1038/s41467-021-22925-310.1038/s41467-021-22925-3 ↗
18. 10.1016/j.cmet.2013.01.00610.1016/j.cmet.2013.01.006 ↗
19. 10.1093/nar/gkaa101110.1093/nar/gkaa1011 ↗
20. 10.2174/138161282966623031311131410.2174/1381612829666230313111314 ↗
21. 10.1101/2023.06.27.54668310.1101/2023.06.27.546683 ↗
22. 10.1016/j.jbc.2023.10545810.1016/j.jbc.2023.105458 ↗
23. 10.1016/j.febslet.2011.01.03110.1016/j.febslet.2011.01.031 ↗
24. 10.1016/j.cmet.2023.01.01110.1016/j.cmet.2023.01.011 ↗
25. 10.1080/15548627.2022.204843210.1080/15548627.2022.2048432 ↗
26. 10.1128/MCB.25.11.4579-4590.200510.1128/MCB.25.11.4579-4590.2005 ↗
27. 10.1038/ncb205710.1038/ncb2057 ↗
28. 10.1038/nrendo.2014.3510.1038/nrendo.2014.35 ↗
29. 10.1038/s41580-022-00542-210.1038/s41580-022-00542-2 ↗
30. 10.1038/s41574-018-0009-110.1038/s41574-018-0009-1 ↗
31. 10.1093/lifemeta/load01810.1093/lifemeta/load018 ↗
32. 10.1080/15548627.2018.147431410.1080/15548627.2018.1474314 ↗
33. 10.1016/j.celrep.2022.11169010.1016/j.celrep.2022.111690 ↗
34. 10.1126/science.add185610.1126/science.add1856 ↗
35. 10.1016/j.mito.2023.10183710.1016/j.mito.2023.101837 ↗
36. 10.1016/j.celrep.2017.09.05210.1016/j.celrep.2017.09.052 ↗
37. 10.1210/jc.2010-305010.1210/jc.2010-3050 ↗
38. 10.1002/oby.2175110.1002/oby.21751 ↗
39. 10.1096/fj.201801393RRR10.1096/fj.201801393RRR ↗
40. 10.1038/srep4440110.1038/srep44401 ↗
41. 10.1016/j.tem.2015.01.00310.1016/j.tem.2015.01.003 ↗
42. 10.1093/lifemeta/loac00210.1093/lifemeta/loac002 ↗
43. 10.1002/oby.2059210.1002/oby.20592 ↗
44. 10.1038/s44318-024-00335-710.1038/s44318-024-00335-7 ↗
45. 10.1016/j.cmet.2014.12.00910.1016/j.cmet.2014.12.009 ↗
46. 10.1038/s41467-018-07519-w10.1038/s41467-018-07519-w ↗
47. 10.1038/s44319-023-00009-110.1038/s44319-023-00009-1 ↗
48. 10.1038/s41467-021-26999-x10.1038/s41467-021-26999-x ↗
49. 10.1080/15548627.2022.211108110.1080/15548627.2022.2111081 ↗
50. 10.1038/s42255-021-00493-610.1038/s42255-021-00493-6 ↗
51. 10.1007/s13105-019-00708-110.1007/s13105-019-00708-1 ↗
52. 10.1080/15548627.2024.233857610.1080/15548627.2024.2338576 ↗
53. 10.1016/j.cmet.2019.07.01010.1016/j.cmet.2019.07.010 ↗
54. 10.1016/j.cell.2005.07.00210.1016/j.cell.2005.07.002 ↗
55. 10.3389/fcell.2021.75010010.3389/fcell.2021.750100 ↗
56. 10.1210/en.2015-118410.1210/en.2015-1184 ↗
57. 10.1038/sj.cdd.440075910.1038/sj.cdd.4400759 ↗
58. 10.1038/s41419-021-03722-810.1038/s41419-021-03722-8 ↗
59. 10.4161/auto.2403910.4161/auto.24039 ↗
60. 10.1016/j.bbrc.2018.12.10310.1016/j.bbrc.2018.12.103 ↗
61. 10.1038/emboj.2011.4910.1038/emboj.2011.49 ↗
62. 10.1016/j.lfs.2019.11670710.1016/j.lfs.2019.116707 ↗
63. 10.1186/s13073-021-00890-210.1186/s13073-021-00890-2 ↗
64. 10.1016/j.cell.2020.04.03410.1016/j.cell.2020.04.034 ↗
65. 10.1016/j.celrep.2020.03.04410.1016/j.celrep.2020.03.044 ↗
66. 10.1038/ijo.2016.20110.1038/ijo.2016.201 ↗
67. 10.1016/j.ajhg.2017.01.02710.1016/j.ajhg.2017.01.027 ↗
68. 10.2337/db11-150810.2337/db11-1508 ↗
69. 10.1038/s41467-017-00624-210.1038/s41467-017-00624-2 ↗
70. 10.1016/j.ymgme.2017.04.00110.1016/j.ymgme.2017.04.001 ↗
71. 10.1002/imt2.22810.1002/imt2.228 ↗
72. 10.1038/s42255-021-00362-210.1038/s42255-021-00362-2 ↗
73. 10.1038/s41467-023-37714-310.1038/s41467-023-37714-3 ↗
74. 10.1016/j.cmet.2021.02.00710.1016/j.cmet.2021.02.007 ↗