Control of whole-body glucose metabolism by central lactate in the presence of antipsychotics

The brain-liver axis is important in maintaining whole-body glucose homeostasis. Antipsychotics are used to treat schizophrenia, but one of their side-effects is disruption of metabolism. We previously reported that the antipsychotics olanzapine and haloperidol block the ability of central glucose to stimulate whole-body glucose metabolism and suppress glucose production by the liver (EGP, endogenous glucose production). Both effects by central glucose require the conversion of glucose to lactate centrally. In the current study, we therefore examined whether antipsychotics affect the ability of central lactate to stimulate whole-body glucose metabolism and suppress EGP. Using our previous model of central (third ventricle to target the hypothalamus) infusion, acute subcutaneous administration of antipsychotics, and the pancreatic euglycemic clamp in rats, we found that olanzapine completely inhibited the ability of central lactate to stimulate whole-body glucose metabolism and partially blocked central lactate-induced suppression of EGP. Since activation of the hypothalamus-liver axis of glycemic control requires central glucose and lactate to be metabolized, relevant pathways were also investigated. The adverse effects of olanzapine on central lactate sensing were not associated with decreased levels of citrate, a tricarboxylic acid cycle intermediate, in the hypothalamus or robust alterations in hypothalamic mitochondrial complex I activity assessed with the positron emission tomography tracer [ 18 F]BCPP-EF. In summary, olanzapine impairs the ability of central lactate to control whole-body glucose metabolism and partially inhibits suppression of EGP by central lactate.