Metformin ameliorates olanzapine-induced disturbances in POMC neuron number, axonal projection, and hypothalamic leptin resistance

Abstract

Antipsychotics have been widely accepted as a treatment of choice for psychiatric illnesses such as schizophrenia. While atypical antipsychotics such as aripiprazole are not associated with obesity and diabetes, olanzapine is still widely used based on the anticipation that it is more effective in treating severe schizophrenia than aripiprazole, despite its metabolic side effects. To address metabolic problems, metformin is widely prescribed. Hypothalamic proopiomelanocortin (POMC) neurons have been identified as the main regulator of metabolism and energy expenditure. Although the relation between POMC neurons and metabolic disorders is well established, little is known about the effects of olanzapine and metformin on hypothalamic POMC neurons. In the present study, we investigated the effect of olanzapine and metformin on the hypothalamic POMC neurons in female mice. Olanzapine administration for 5 days significantly decreased Pomc mRNA expression, POMC neuron numbers, POMC projections, and induced leptin resistance before the onset of obesity. It was also observed that coadministration of metformin with olanzapine not only increased POMC neuron numbers and projections but also improved the leptin response of POMC neurons in the olanzapine-treated female mice. These findings suggest that olanzapine-induced hypothalamic POMC neuron abnormality and leptin resistance, which can be ameliorated by metformin administration, are the possible causes of subsequent hyperphagia. [BMB Reports 2022; 55(6): 293-298].

Fig. 1

Short-term administration of olanzapine and metformin modulated hypothalamic neuropeptides without altering body weight and food intake in female mice. (A) Experimental scheme in female mice that were orally injected with vehicle, OLZ, and OLZ + MET (n = 4-5). (B) Body weights of mice that were treated with OLZ and OLZ + MET for 21 days (n = 4-5). (C) Average daily food intake before the onset of obesity (n = 4-5). (D) Effect of OLZ and OLZ + MET treatment on hypothalamic Pomc, Npy, and Agrp mRNA expression. Data are presented as mean ± SEM values. Arrow indicates the time point of analysis. Statistical analyses were performed using one-sided two-way ANOVA (B), and one-sided one-way ANOVA (C, D) followed by a post hoc LSD test. *P (CON vs OLZ) and ^†P (OLZ vs. OLZ + MET) < 0.05, and ***P < 0.001 between the indicated groups.

Fig. 2

MET restored OLZ-induced reduction in POMC neuronal distribution. The numbers and sizes of β-endorphin⁺ POMC neurons in ARH of female mice that were treated with OLZ and OLZ + MET (n = 3-4). Data are presented as mean ± SEM values. Statistical analyses were performed using one-sided one-way ANOVA followed by a post hoc LSD test. *P < 0.05 and **P < 0.01 between the indicated groups. ARH: arcuate nucleus of the hypothalamus. 3V: third ventricle. Scale bars: 100 μm.

Fig. 3

MET restored OLZ-induced reduction in POMC axonal projection. (A, B) Representative images of POMC axonal projection to PVH or DMH and the graph depicting the axonal fiber density of POMC neurons (n = 3-4). (C, D) The graph depicting the axonal fiber densities of POMC neurons relative to neuron numbers (n = 3-4). Data are pre-sented as mean ± SEM values. Statistical analyses were performed using one-sided one-way ANOVA followed by a post hoc LSD test. *P < 0.05, **P < 0.01, and ***P < 0.001 between the indicated groups. 3V: third ventricle. Scale bars: 100 μm.

Fig. 4

MET ameliorated OLZ-induced leptin resistance in POMC neurons. (A) Experimental scheme in female mice that was intracerebroventricularly injected with leptin after OLZ or OLZ + MET administration. (B) Illustration of leptin ICV injection. (C) Representative images of c-Fos and POMC neurons in ARH. The graph depicting percentage of c-Fos⁺ POMC neurons (n = 4-5). Data are presented as mean ± SEM values. Statistical analyses were performed using one-sided one-way ANOVA followed by a post hoc LSD test. **P < 0.01 and ***P < 0.001 between indicated groups. 3V: third ventricle. Scale bars: 100 μm.