Inhibition and mechanism of olanzapine on white adipose tissue beiging in mice

As one of the first-line antipsychotic drugs, olanzapine(OLA)inducing insulin resistance and metabolic disorder has become a serious clinical concern. This study aimed at investigating the effect of OLA on white adipose tissue(WAT)beiging as a potential mechanism behind its metabolism-disturbing effects. C57BL6/J mice were orally administered with low and high-dose OLA(4, 8 mg/kg, once daily)for 28 consecutive days; body weight and food intake were recorded every other day. Mice were subjected to glucose-tolerance test(GTT)and a cohort from each group was challenged with cold stress for 36 h before sacrifice. The perirenal, epididymal and inguinal WAT were carefully dissected, weighed and processed separately for hematoxylin-eosin staining, UCP-1 immunohistochemical and Western blot analysis. The results showed that OLA induced significant impairment in basal heat generation and glucose regulation. There were fewer beige adipocytes in the inguinal WAT after OLA treatment. The beiging of inguinal WAT in response to cold stress was significantly inhibited in OLA-treated mice. Mechanistically, OLA induced the activation of mTOR-Notch pathway, as evidenced by a significant increase in phosphorylated mammalian target of rapamycin(p-mTOR)and intracellular domain of Notch1(N1ICD)expression. Together, our study reveals that the inhibitory effects on WAT beiging may explain the propensity of OLA to induce metabolic disturbance, and mTOR-Notch pathway activation could play key roles in this effect. Future validation and elucidation of these novel findings are expected to provide novel insights into the metabolic risks of OLA and related second generation antipsychotics, which may lead to innovative intervention strategies in the clinic.