The Deletion of AMPK β1 Worsens Glucose Tolerance and Liver Lipid Accumulation, but Doesn’t Impact the Metabolic Effects of Olanzapine in Male Mice

Abstract

Second generation antipsychotic (SGA) medications, like olanzapine (OLZ), are an important component in the pharmacological management of many conditions including schizophrenia. These drugs, have been linked with a neuroendocrine signaling axis that, leads to weight gain, however, peripheral mechanisms and predictors are currently poorly understood. 5’AMP activated protein kinase (AMPK) is a ubiquitously expressed, energy‐sensing enzyme and significant associations between polymorphisms in AMPK subunit genes and OLZ‐induced weight gain have been demonstrated. Conversely, others have suggested that the central activation of AMPK mediates the deleterious metabolic effects of SGAs. The purpose of this study was to determine if reductions in AMPK activity, primarily in the liver, would impact the chronic effects of OLZ treatment. We hypothesized that the absence of AMPK β1, a subunit which is primarily found in the liver, at least in mice, would worsen the metabolic side effects of OLZ. To address this question, we housed male AMPK β1 knockout (KO) and wildtype (WT) mice at thermoneutrality (29°C) and fed them either a control diet (HFD, 45% kcal from fat) or a diet supplemented with OLZ (HFD+OLZ, 50mg/kg diet) for 10 weeks. OLZ treatment did not increase food intake or weight gain to a greater extent than the control diet in either genotype. There was a main effect of the OLZ containing diet to increase heat production, TEE and fat oxidation during the light and dark cycles. The OLZ‐fed mice also demonstrated suppressed RER during the dark cycle. Interestingly, the OLZ‐fed KO mice were more physically active during the light cycle than the OLZ‐fed WT mice. The AMPK β1 KO mice were more glucose intolerant than the WT control mice. On the other hand, the AMPK β1 KO male mice on both diets demonstrated lower circulating serum glycerol and NEFA levels but increased liver TAG accumulation. In conclusion, our findings provide evidence that the absence of AMPK β1 does not potentiate the effects of OLZ on weight gain, but worsens liver lipid accumulation and glucose tolerance.Support or Funding InformationThis study was supported by Canadian Institutes of Health Research