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

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 (Ehmt2 Ckmm knockout [KO] or Ehmt2 HSA 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 Ehmt2 Ckmm KO or Ehmt2 HSA 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.