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

Crosstalk 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.