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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. [ABSTRACT FROM AUTHOR]