Effect of Clozapine on the Enteric System: Implications for Antipsychotic‐induced Weight Gain

Abstract

It is well established that the use of atypical antipsychotics results in weight gain and metabolic diseases such as obesity, type‐2 diabetes and metabolic syndrome. However, the underlying mechanisms for weight gain are not clear. Recent studies have shown that various dopamine receptor subtypes are expressed in the enteric system; however, the physiological role as well the effect of antipsychotics on the enteric dopamine receptors is not well understood. We hypothesized that the dopamine receptors might be involved in the modulation of nutrient transport in the intestine and alteration of this modulation by chronic antipsychotic treatment might contribute towards weight gain. In particular, excessive and chronic intake of fructose is known to adversely affect long‐term health and lead to obesity, type‐2 diabetes and metabolic syndrome. The intestinal fructose transporter GLUT5 is considered as a biomarker of excessive fructose consumption. In this project, we test the hypothesis that antipsychotics acting at D2‐like dopamine receptors modulate the expression or function of intestinal GLUT5 transporters, resulting in weight gain. To test this hypothesis, we compared the ability of clozapine (CLZ) to induce weight gain in wild type C57BL/6 mice and GLUT5‐null mice. Preliminary results showed that CLZ dose‐dependently induced weight gain in the wild type C57BL/6 mice but not in the GLUT5‐null mice. In addition, there was a dose‐dependent increase in fructose uptake in the C57BL/6 wild type mice treated with CLZ. The expression of GLUT5 mRNA was not altered by CLZ treatment suggesting that the increase in fructose uptake induced by CLZ might be mediated by an increase in GLUT5 activity. The results suggest that modulation of intestinal nutrient transport by antipsychotics might contribute to weight gain.