Fenofibrate Protects Against Antipsychotic-Induced Hyperglycemia Through Weight Loss and FGF21 Dependent Mechanisms

Antipsychotic (AP) medications, such as olanzapine, cause acute weight gain independent of hyperglycemia through a glucagon-dependent mechanism. Previous work has shown that exercise, a ketogenic diet, and fasting can protect against acute AP-induced hyperglycemia and attenuate increases in glucagon. As these interventions all increase circulating concentrations of fibroblast growth factor 21 (FGF21), we hypothesized that increasing endogenous FGF21 through treatment with fenofibrate would protect against AP-induced hyperglycemia. Male C57BL/6J mice were fed a low-fat diet with or without fenofibrate (0.2% w/w) for 1 week prior to an acute olanzapine (OLZ) challenge. Fenofibrate reduced food intake and caused weight loss while protecting against OLZ-induced increases in serum glucagon and blood glucose. Pair feeding mice with the same amount of food as fenofibrate-treated animals conferred a similar degree of protection against OLZ-induced hyperglycemia. Furthermore, an acute oral gavage with fenofibrate, despite increasing circulating FGF21 concentrations to a similar level as fenofibrate feeding, failed to protect against OLZ-induced glucose excursions. The effects of fenofibrate on weight loss and protection against OLZ-induced hyperglycemia were attenuated in FGF21^-/- mice. Fenofibrate attenuated both OLZ-induced hyperlipidemia and increases in whole-body fatty acid oxidation, with the latter effects being dependent upon FGF21. Together, our findings demonstrate that fenofibrate protects against acute olanzapine-induced hyperglycemia and hyperlipidemia in a weight loss and FGF21-dependent manner.