Epigenetic regulation role of SUV420H in sexual dimorphism of adipose tissue and obesity

Obesity is a worldwide health crisis linked to numerous harmful medical conditions. It arises from complex interactions between behavioral, environmental, and genetic factors. Interestingly, there is evidence of sexual dimorphism in the function of mitochondrial activity and metabolic flexibility of adipose tissue in obesity. Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a critical factor in the formation of fat cells, glucose processing, and fat production, plays an essential role in the onset of obesity. Recently, it has been implicated in sex-based differences in adipose tissue gene expression and fat distribution. Epigenetic modifications mediate the effects of environmental factors by controlling the activity of genes related to metabolism. SUV420H1 and SUV420H2, histone methyltransferases that catalyze the addition of di- and trimethyl groups to lysine 20 of histone H4, suppress gene expression. Previous research has shown that SUV420H proteins respond to environmental signals by directly repressing PPAR-γ activity. In this study, we demonstrated that SUV420H1 and SUV420H2 are expressed differently between sexes in both human and mouse models. Interestingly, mice with a double knockout of Suv420h1 and Suv420h2 exhibit a sex-specific difference in their resistance to diet-induced obesity. Gene expression analysis of adipose tissue samples from obese humans reveals a significant inverse relationship between SUV420H and PPAR-γ expression in females, while no such correlation is observed in males. These findings highlight a potentially novel role for SUV420H proteins in modulating PPAR-γ activity, metabolic function, and the risk of obesity, with a clear sexual dimorphism in their effects.