Chronic Paroxetine Treatment in Mice Leads to Adiposity and Glucose Intolerance

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed class of antidepressants for the treatment of depression and anxiety disorders. Recent epidemiologic results have suggested an association between long term use of SSRIs and an increased risk for type 2 diabetes. However, depression itself has been associated with diabetes, and it therefore is unclear whether the association is solely due to SSRI use, depression, or an interaction of both circumstances. The goal of this study is to determine the effects of chronic paroxetine (a common SSRI) treatment on adiposity and glucose tolerance in wild‐type (WT) mice and mice with targeted disruption of serotonin reuptake transporter (SERT−/−). Three ‐to‐four week old male C57BL/6 mice (n=5–6 per group) were treated with paroxetine (10 mg/kg/day) or control vehicle for 12 weeks. This dose is known to achieve serum concentrations in mice comparable to the therapeutic levels in humans. Compared to vehicle control, paroxetine‐treated WT mice exhibited significantly increased weight gain (+20.4±0.7 vs +17.1±0.4 g, P<0.05 vs. WT‐control), adipose tissue expansion, and pro‐lipogenic gene expression. Glucose and insulin tolerance tests further revealed that paroxetine‐treated WT mice exhibited glucose intolerance [glucoseAUC0–120 min(2 g/kg IP following fasting):30.6±0.7 vs. 26.6±0.7g*min/dl, P<0.05 vs. WT‐control] and insulin resistance [glucose AUC0–120 min(following fasting and insulin0.75 units/kg IP): 24.9±1.2 vs. 20.1±1.2g*min/dl, P<0.05 vs. WT‐control]. In parallel, three to‐four week old male SERT−/− mice (n=5–6 per group) were also treated with paroxetine or control vehicle for 12 weeks. Compared to non‐treated SERT−/− mice, paroxetine‐treated SERT−/− mice showed minimal difference in weight gain and a significant attenuation of fat mass expansion. Collectively, these findings demonstrate that chronic paroxetine treatment at a clinically relevant dose leads to adiposity and glucose intolerance in mice, and this effect is largely SERT‐dependent.Support or Funding InformationThis study is supported by NIH grant R01 GM066233 and the Elmer M. Plein Endowment Research Fund.