Voluntary physical activity protects against olanzapine-induced hyperglycemia

Olanzapine (OLZ) is used in the treatment of schizophrenia and a growing number of "off-label" conditions. Although effective in reducing psychoses, OLZ causes rapid impairments in glucose and lipid homeostasis. The purpose of this study was to investigate if voluntary physical activity via wheel running (VWR) would protect against the acute metabolic side effects of OLZ. Male C57BL/6J mice remained sedentary or were provided with running wheels overnight, before treatment with OLZ either at the beginning of the light cycle, or 7 or 24 h following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 h following a bout of overnight wheel running. Protection against, hyperglycemia immediately following VWR was associated with increased insulin tolerance and an attenuated OLZ-induced increase in the serum glucagon:insulin ratio. The protective effect of VWR against OLZ-induced increases in hyperglycemia and glucagon:insulin ratio was maintained in high-fat fed, and AMPK β1-deficient mice, models which display a potentiated OLZ-induced increase in blood glucose. Repeated OLZ treatment did not impair VWR performance and protection against the acute effects of OLZ on blood glucose was present after 1 wk of daily OLZ treatment in mice given access to running wheels. In contrast to the effects on glucose metabolism, VWR, for the most part, did not impact OLZ-induced perturbations in lipolysis, liver triglyceride accumulation, or whole body substrate oxidation. Collectively, our findings demonstrate the efficacy of voluntary physical activity as an approach to protect against OLZ-induced impairments in glucose metabolism.NEW & NOTEWORTHY The antipsychotic medication olanzapine causes rapid and large increases in blood glucose. We demonstrate that a prior bout of voluntary overnight wheel running can protect against this harmful side effect and is likely mediated by reductions in olanzapine-induced increases in the circulating glucagon to insulin ratio. This study highlights the powerful effects of voluntary activity in conditions of treatment with antipsychotic medications.