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. While 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, prior to treatment with OLZ either at the beginning of the light cycle, or 7 or 24 hours following the cessation of VWR. Prior VWR protected against OLZ-induced hyperglycemia immediately and 7 hours 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 were maintained in high fat fed, and AMPK b1 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 week 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.