Mechanistic Study On How G9a Affects Lipid Metabolism Through Regulating Musclin

Glucose and lipid metabolism are important life processes that provide energy and biological macromolecules for the cell.Thus,disorders of glucose and lipid metabolism seriously threaten human health and result in obesity,type 2 diabetes,non-alcoholic fatty liver disease（NAFLD）and other metabolic diseases.As important exercise and metabolic organ,muscle plays an important role in maintaining glucose and lipid homeostasis and energy balance.Recent years,the function of various myokines secreted by muscle on metabolic regulation have been revealed.Since myokines mediated interaction and crosstalk between different tissues and organs,research on them have become the hotspot in the field of metabolism.G9a,an important histone methyltransferase,is widely expressed in many mammalian tissues and has been reported to have a role in metabolic diseases.However,whether muscular G9a has regulatory effects on metabolic diseases remains unknown.In this paper,the author constructed muscle-specific G9a knockout mice(Ehmt2^Ckmm or Ehmt2^HSA)to study the role of muscular G9a in high-fat diet（HFD）-induced metabolic diseases.The Ehmt2^Ckmm or Emmt2^HSA female mice,but not male mice,alleviated the HFD-induced obesity and NAFLD.Increased type I myofibers in muscle,increased energy expenditure,and increased thermogenesis-related genes in adipose tissue were found in the knockout female mice under HFD stimulation.In addition,both the m RNA and protein levels of muscular Musclin,and serum Musclin were significantly increased in female Ehmt2^Ckmm or Emmt2^HSAmice under HFD stress.In vitro and in vivo experiments have confirmed that G9a negatively regulated Musclin depending on its methyltransferase activity.Specifically,G9a directly bound to the promoter region of Musclin and mediated H3K9me2 modification to inhibit its transcription.G9a also indirectly inhibited the expression of Musclin by regulating the level of p-Foxo1/Foxo1.In addition,exogenous injection of full-length Musclin（Mus-F）or its 33-residue core domain（Mus33）significantly prevented the weight gain and NAFLD caused by HFD in wildtype mice,regardless of gender.Taken together,our results indicate that muscular G9a plays a key role in the sex-dependent regulation of Musclin,and Musclin is a regulator for the“muscle-liver/fat”metabolic axis.The effects of Musclin in regulating HFD-induced obesity and NAFLD,suggesting that it might be a potential drug to treat obesity and its related diseases.