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Obesity Studies

Muscular G9a Regulates Muscle-Liver-Fat Axis by Musclin Under Overnutrition in Female Mice

  1. Wenquan Zhang1,
  2. Dong Yang2,
  3. Yangmian Yuan1,
  4. Chong Liu1,
  5. Hong Chen2,
  6. Yu Zhang2,
  7. Qing Wang1,
  8. Robert B. Petersen3,
  9. Kun Huang2⇑ and
  10. Ling Zheng1,4⇑
  1. 1Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China
  2. 2Tongji School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  3. 3Foundational Sciences, Central Michigan University College of Medicine, Mount Pleasant, MI
  4. 4Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China
  1. Corresponding authors: Ling Zheng, lzheng{at}whu.edu.cn, and Kun Huang, kunhuang{at}hust.edu.cn
Diabetes 2020 Dec; 69(12): 2642-2654. https://doi.org/10.2337/db20-0437
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Abstract

Cross talk among different tissues and organs is a hotspot in metabolic research. Recent studies have revealed the regulatory roles of a number of myokines in metabolism. Here, we report that female mice lacking muscle-specific histone methylase G9a (Ehmt2Ckmm knockout [KO] or Ehmt2HSA KO) are resistant to high-fat diet (HFD)-induced obesity and hepatic steatosis. Furthermore, we identified a significantly upregulated circulating level of musclin, a myokine, in HFD-fed Ehmt2Ckmm KO or Ehmt2HSA KO female mice. Similarly, upregulated musclin was observed in mice injected with two structurally different inhibitors for G9a methylase activity: BIX01294 and A366. Moreover, injection of recombinant full-length musclin or its functional core domain inhibited the HFD-induced obesity and hepatic steatosis in wild-type female and male mice. Mechanistically, G9a methylase activity-dependently regulated muscular musclin level by binding to its promoter, also by regulating phosphorylated-FOXO1/FOXO1 levels in vivo and in vitro. Collectively, these data suggest a critical role for G9a in the muscle-liver-fat metabolic axis, at least for female mice. Musclin may serve as a potential therapeutic candidate for obesity and associated diseases.

Footnotes

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12990842.

  • Received April 28, 2020.
  • Accepted September 21, 2020.
  • © 2020 by the American Diabetes Association
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December 2020, 69(12)
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Muscular G9a Regulates Muscle-Liver-Fat Axis by Musclin Under Overnutrition in Female Mice
Wenquan Zhang, Dong Yang, Yangmian Yuan, Chong Liu, Hong Chen, Yu Zhang, Qing Wang, Robert B. Petersen, Kun Huang, Ling Zheng
Diabetes Dec 2020, 69 (12) 2642-2654; DOI: 10.2337/db20-0437

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Muscular G9a Regulates Muscle-Liver-Fat Axis by Musclin Under Overnutrition in Female Mice
Wenquan Zhang, Dong Yang, Yangmian Yuan, Chong Liu, Hong Chen, Yu Zhang, Qing Wang, Robert B. Petersen, Kun Huang, Ling Zheng
Diabetes Dec 2020, 69 (12) 2642-2654; DOI: 10.2337/db20-0437
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