Abstract: Objective To investigate how histone demethylase inhibitor GSK-J4 could reduce body weight in obese mice fed high-fat diet(HFD). Methods After 16 weeks of feeding C57/BL6 mice with a HFD, GSK-J4 was injected intraperitoneally for 16 days, during which time the body weight and body temperature were monitored. The serum leptin expression was measured using ELISA kits. Direction of macrophage polarization in epididymis and subcutaneous adipose tissue was detected by flow cytometry. The browning degree of white fat in adipose tissue of epididymis and subcutaneous adipose tissue was evaluated by HE staining microscopy and immunohistochemistry.Quantitative PCR was used to analyze the levels of related cytokines and the expression levels of genes related to oxidative phosphorylation in macrophages. Results Compared with solvent control group, GSK-J4 reduced body weight in a time-dependent manner. Serum leptin expression was significantly decreased (P＜0.01); The surface marker CD11c⁺ decreased in epididymal and subcutaneous adipose tissue macrophages. The degree of browning of subcutaneous white fat was increased; The mRNA level of oxidative phosphorylation related genes was stimulated in brown adipose tissue, and the expression of IL-1β was decreased. Conclusions The histone demethylase inhibitor GSK-J4 can reduce M1 polarization of macrophages. After treatment with GSK-J4, the body weight of obese mice induced by HFD is significantly decreased and the energy consumption is increased.

Key words: obesity, adipose tissue macrophage, GSK-J4, histone lysine demethylases 6