The atypical antipsychotic olanzapine causes weight gain by targeting serotonin receptor 2C

Caleb C. Lord, Steven C. Wyler, Rong Wan, Carlos M. Castorena, Newaz Ahmed, Dias Mathew, Syann Lee, Chen Liu, Joel K. Elmquist

Research output: Contribution to journalArticle

38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3402-3406
Number of pages5
JournalJournal of Clinical Investigation
Issue number9
StatePublished - Sep 1 2017


ASJC Scopus subject areas

  • Medicine(all)

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