G9a-musclin_supplemental_information-0816终版.pdf (1.26 MB)
Download fileMuscular G9a regulates muscle-liver-fat axis by musclin under overnutrition in female mice
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posted on 2020-09-29, 19:32 authored by Ada AdminAda Admin, Wenquan Zhang, Dong Yang, Yangmian Yuan, Chong Liu, Hong Chen, Yu Zhang, Qing Wang, Robert B. Petersen, Kun Huang, Ling ZhengCrosstalk 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 muscle-specific lacking histone methylase G9a (Ehmt2Ckmm KO or Ehmt2HSA
KO) are resistant to high-fat-diet (HFD) induced obesity and hepatic steatosis.
Furthermore, we identified 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 wildtype female and
male mice. Mechanistically, G9a methylase activity-dependently regulated
muscular musclin level by binding to its promoter,
also by regulating p-Foxo1/Foxo1
level in vivo and in vitro. Collectively, these data
suggested 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.