Protective effects of central leptin on whole-body energy homeostasis following acute olanzapine exposure.

Antipsychotics represent mainstay treatment of schizophrenia and are also prescribed on- and off-label in other severe mental illnesses. Newer antipsychotic use is associated with severe metabolic side effects such as obesity and type 2 diabetes. Leptin is a hormone secreted by adipose tissue, and it acts on the brain to decrease body weight by reducing food intake and stimulating energy expenditure. Leptin also improves glucose and lipid metabolism. In this study, we examined the short-term impact of olanzapine, a commonly used second-generation antipsychotic, on the central leptin-mediated regulation of energy balance, glucose and lipid metabolism, and hypothalamic kinase activity. Male SD rats were given an acute intracerebroventricular (ICV) injection of either leptin or vehicle, combined with subcutaneous olanzapine or vehicle. As expected, ICV leptin decreased food intake and, importantly, olanzapine did not block this effect. Administration of leptin, olanzapine, or their combination reduced the average respiratory exchange ratio (RER) during the light-cycle, indicating increased fat oxidation. In the dark-cycle, leptin decreased the average RER regardless of olanzapine administration, and in the presence of leptin, olanzapine did not affect the average RER. Olanzapine treatment produced transient glucose intolerance during the IPGTT, an effect no longer observed with leptin co-treatment, though no significant differences in AUC, fasting serum glucose, insulin, or HOMA-IR were observed between any groups. Olanzapine and leptin treatment differentially activated hypothalamic kinases. In conclusion, the regulation of food intake and fuel preference by central leptin remains intact despite acute olanzapine administration, and leptin may transiently attenuate olanzapine-induced glucose intolerance.