Histone H3 methyltransferase Ezh2 promotes white adipocytes but inhibits brown and beige adipocyte differentiation in mice

Obesity is a disease characterized by imbalance between energy intake and expenditure, excessive energy store in white adipocytes, but brown and beige adipocytes consume energy to relieve obesity. In this study, we want to explore the role of the histone H3 methyltransferase EZH2 in the differentiation of white, brown and beige adipocytes with EZH2 conditional knockout mice (EZH2^flox/floxPrx1-cre) and mouse embryonic fibroblasts (MEFs). The results showed that Ezh2-deficient mice have a leaner phenotype and less white adipose tissues. The morphological changes in the adipose tissue included smaller white adipose tissue depots, white adipocytes with smaller diameter, smaller lipid droplets inside the brown adipocytes and more beige adipocytes in the Ezh2-deficient mice compared with the control. The differentiation markers of white adipocytes in EZH2 knockout mice decreased; Ucp1 and other browning markers increased in brown and beige adipocytes. The EZH2 knockout mice could better tolerate cold stimulation, and they can also resist obesity and Insulin resistance induced by a high-fat diet. The EZH2 Inhibitor GSK126 could inhibit the differentiation of MEFs into white adipocytes but promote their differentiation into brown/beige adipocytes. The H3K27me3 demethylase Jmjd3/UTX inhibitor GSKJ4 inhibited MEFs' differentiation into brown/beige adipocytes. These results showed that EZH2 promotes the differentiation of white adipocytes and inhibits the differentiation of brown and beige adipocytes in vivo and in vitro through its methylase activity and this may represent new knowledge for obesity therapeutic strategy.