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

Abstract

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.

Figure 1. Olanzapine treatment profoundly alters energy homeostasis in female C57BL/6 mice.

(A) Body weight. (B) Body composition. (C) GTT. (D) Plasma insulin levels. (E–G) Metabolic cage analysis (n = 6) of food intake (E), physical activity (F), and heat production (G). (H) Weight gain in ad libitum– and pair-fed mice. Results are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 versus other genotypes assessed using either Student’s t test or 2-way ANOVA with Sidak’s multiple comparisons test. OLZ, olanzapine treated; Con, control.

Figure 2. Olanzapine’s effect on food intake and body weight is mediated by HTR2C.

(A) Body weight. (B) Body composition. (C) GTT. (D) Plasma insulin levels. (E–G) Metabolic cage analysis (n = 6) of food intake (E), physical activity (F), and heat production (G). Results are shown as the mean ± SEM. *P < 0.05 versus other genotypes assessed using either Student’s t test or 2-way ANOVA with Sidak’s multiple comparisons test.

Figure 3. Lorcaserin treatment suppresses olanzapine-induced hyperphagia and weight gain.

(A) Schematic of the experiment design. Female C57BL/6 mice (n = 16) were initially fed the olanzapine diet for 6 weeks so that they gained significantly more weight than those fed the control diet (n = 8). They were then separated into 2 groups with equal numbers and treated with either vehicle (VEH) or lorcaserin (LOR) for 7 days. Following drug treatment, mice were fed the olanzapine diet for 2 more weeks. (B) Body weight. (C) Daily food intake. (D) Weight gain during vehicle or lorcaserin treatment. (E) Body weight before and after drug treatment. (F and G) GTTs. Results are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 versus other genotypes assessed using either Student’s t test or 2-way ANOVA with Sidak’s multiple comparisons test.