TY - JOUR AU - Lord, Caleb C. AU - Wyler, Steven C. AU - Wan, Rong AU - Castorena, Carlos M. AU - Ahmed, Newaz AU - Mathew, Dias AU - Lee, Syann AU - Liu, Chen AU - Elmquist, Joel K. T1 - The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C PY - 2017/09/01/ AB - Atypical antipsychotics such as olanzapine often induce excessive weight gain and type 2 diabetes. However, the mechanisms underlying these drug-induced metabolic perturbations remain poorly understood. Here, we used an experimental model that reproduces olanzapine-induced hyperphagia and obesity in female C57BL/6 mice. We found that olanzapine treatment acutely increased food intake, impaired glucose tolerance, and altered physical activity and energy expenditure in mice. Furthermore, olanzapine-induced hyperphagia and weight gain were blunted in mice lacking the serotonin 2C receptor (HTR2C). Finally, we showed that treatment with the HTR2C-specific agonist lorcaserin suppressed olanzapine-induced hyperphagia and weight gain. Lorcaserin treatment also improved glucose tolerance in olanzapine-fed mice. Collectively, our studies suggest that olanzapine exerts some of its untoward metabolic effects via antagonism of HTR2C. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI93362 VL - 127 IS - 9 UR - https://doi.org/10.1172/JCI93362 SP - 3402 EP - 3406 PB - The American Society for Clinical Investigation ER -