Metformin ameliorates olanzapine-induced obesity and glucose intolerance by regulating hypothalamic inflammation and microglial activation in female mice.

Olanzapine (OLZ), a widely used second-generation antipsychotic drug, is known to cause metabolic side effects, including diabetes and obesity. Interestingly, OLZ-induced metabolic side effects have been demonstrated to be more profound in females in human studies and animal models. Metformin (MET) is often used as a medication for the metabolic side effects of OLZ. However, the mechanisms underlying OLZ-induced metabolic disturbances and their treatment remain unclear. Recent evidence has suggested that hypothalamic inflammation is a key component of the pathophysiology of metabolic disorders. On this background, we conducted this study with the following three objectives: 1) to investigate whether OLZ can independently induce hypothalamic microgliosis; 2) to examine whether there are sex-dependent differences in OLZ-induced hypothalamic microgliosis; and 3) to examine whether MET affects hypothalamic microgliosis. We found that administration of OLZ for 5 days induced systemic glucose intolerance and hypothalamic microgliosis and inflammation. Of note, both hypothalamic microglial activation and systemic glucose intolerance were far more evident in female mice than in male mice. The administration of MET attenuated hypothalamic microglial activation and prevented OLZ-induced systemic glucose intolerance and hypothalamic leptin resistance. Minocycline, a tetracycline derivative that prevents microgliosis, showed similar results when centrally injected. Our findings reveal that OLZ induces metabolic disorders by causing hypothalamic inflammation and that this inflammation is alleviated by MET administration.