Olanzapine-induced decreases of FGF21 in brown adipose tissue via histone modulations drive UCP1-dependent thermogenetic impairment

Long-term olanzapine treatment has been associated with serious metabolism disorders, such as abnormal body weight gain, hyperglycemia, and dyslipidemia. Recently, accumulated evidence points to a link between the metabolic disorders caused by olanzapine and thermogenetic impairment. Fibroblast growth factor 21 (FGF21), a pleiotropic protein, is a potent stimulator of thermogenesis in brown adipose tissue (BAT). However, the relationship between autocrine FGF21 in BAT and thermogenetic impairment induced by olanzapine has not been investigated. In this study, C57BL/6 mice and C3H10T1/2 (a brown adipocyte cell line) were used to investigate the role of FGF21 in modulating thermogenetic impairments caused by olanzapine. Our data found a fall in BAT temperature, with a decrease in the protein levels of uncoupling protein 1 (UCP1) and FGF21 in olanzapine-treatment mice. Olanzapine-induced deficits of mitochondrial activity and the expression of UCP1 and related thermogenetic factors could be improved by FGF21-overexpression in brown adipocytes. Furthermore, ChIP-sequencing showed the H3K9me3 modification in Fgf21 was dramatically increased in BAT of mice with olanzapine treatment. Lysine-specific demethylase 4a (KDM4a), a histone demethylase responsible for site-specific erasure of H3K9me3, was decreased in olanzapine-treated C3H10T1/2 cells, whereas FGF21 and UCP1 expression and thermogenesis were upregulated in KMD2a-overexpressing brown adipocyte. We concluded that FGF21 was a crucial regulator mediating UCP1-dependent thermogenetic impairments by olanzapine-modulating histone methylations. Our results also provide novel insights into identifying a new therapeutic target for treating metabolic side effects caused by the antipsychotic drug.