The TNF ‐α– FABP4 –Dhhc7 Axis Mediates Olanzapine‐Induced Insulin Resistance in Rats and Humans

A rapid increase in the incidence of insulin resistance (IR) induced by long-term olanzapine treatment has been observed; however, there are no more efficient ways to prevent IR. Our study aimed to demonstrate the mechanism underlying olanzapine-induced insulin resistance. In this study, we first analysed the data of 120 schizophrenia patients who had been taking olanzapine for at least 3 months. Eventually, it was found that an increase in circulating tumour necrosis factor-α (TNF-α, p < 0.05). Subsequently, we verified this finding in a rat model. We detected the expression levels of the target genes fatty acid binding protein 4 (FABP4) and the palmitoyltransferase Dhhc7 in both rats and three T3-L1 adipocytes by using Western blotting and polymerase chain reaction (p < 0.05). Exposure to olanzapine increased the expression of FABP4 while decreasing the expression of Dhhc7. Additionally, we demonstrated that it may affect metabolism by inhibiting glucose transporter 4 (GLUT4) membrane transport. Finally, we improved olanzapine-induced insulin resistance by injecting FABP4 adenovirus and elucidating its underlying mechanism. In summary, our study demonstrated that long-term exposure to olanzapine increases circulating plasma levels of TNF-α, thus leading to increased expression of FABP4 protein in white adipose tissue and subsequently inhibiting Dhhc7expression, which correspondingly leads to reduced membrane translocation of GLUT4 and consequent insulin resistance. In conclusion, this study elucidated the signalling pathway through which olanzapine inhibits GLUT4 membrane transport via the TNF-α/FABP4/Dhhc7 axis, thus ultimately leading to insulin resistance.