Effect of Pregnancy on Paroxetine-Induced Adiposity and Glucose Intolerance in Mice

Abstract

Long-term use of selective serotonin reuptake inhibitors (SSRIs) targeting the serotonin transporter (SERT) has been suggested to be associated with an increased risk for obesity and type 2 diabetes. Previously, using a murine knockout model of SERT, we showed that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance in nonpregnant mice. The present study investigated the effects of chronic paroxetine treatment on adiposity and glucose tolerance in mice before and during pregnancy. Chronic paroxetine treatment in nonpregnant mice resulted in visceral adiposity and glucose intolerance accompanied by reduced circulating 17β-estradiol levels and ovarian expression of the aromatase (CYP19a1). Remarkably, pregnancy significantly reduced adiposity and improved glucose tolerance in paroxetine-treated mice by rebooting ovarian CYP19a1 expression and 17β-estradiol production. These effects appear to be reversible as ovarian CYP19a1 expression and circulating 17β-estradiol returned to prepregnancy levels soon after parturition. As in pregnant mice, 17β-estradiol replacement treatment in nonpregnant mice reduced paroxetine-induced adiposity. Our findings further suggested that modulation of estrogen synthesis underlies the observed metabolic adverse effects of SSRIs. Although our data revealed a transient reversal effect of pregnancy on SSRI-induced metabolic abnormalities, these observations are experimental and limited to mice. The use of SSRIs during human pregnancy should be cautioned because of potential adverse effects to the fetuses.

Graphical abstract

Fig. 1.

Effects of paroxetine on body weight and food intake in nonpregnant and pregnant mice. (A) Body weights of wild-type (WT) female mice treated with or without paroxetine (10 mg/kg per day) for 12 weeks (n = 5 per group). (B) Body weights of WT female mice treated with or without paroxetine after 12 weeks at gestation day (GD) 0, 8, 13, 18, and postpartum day (PD) 1 (n = 5 per group). *P < 0.05. Values are the mean ± S.E.M.

Fig. 2.

Effect of pregnancy on paroxetine-induced adiposity. Gonadal (A), inguinal (B), retroperitoneal (C) WAT and (F) BAT weights from control WT nonpregnant mice and WT mice at nonpregnant stage (NP), GD 14, and PD 1 after 12-week treatment with paroxetine (10 mg/kg per day) (n = 5 per group). (D and G) Representative images of H&E-stained gWAT and BAT sections (scale bar, 100 µm). (E, H, and I) Average adipocyte size of gWAT per 10× field and average lipid droplet area and number of BAT per 20× field were quantified using NIH ImageJ. *P < 0.05. Values are reported as mean ± S.E.M.

Fig. 3.

mRNAs expression of genes involved in lipogenesis in gWAT and thermogenesis in BAT of paroxetine-treated mice. gWAT mRNA levels of LPL (A), FAS (B), ACC1 (C), and BAT mRNA levels of UCP1 (D) from WT mice at NP, GD 14, and PD 1 after 12-week treatment with paroxetine (10 mg/kg per day) were quantified by reverse transcription-quantitative polymerase chain reaction, normalized to GAPDH, and expressed relative to the nonpregnant paroxetine-treated group. *P < 0.05. Values are the mean ± S.E.M.

Fig. 4.

Effect of paroxetine on glucose tolerance in non-pregnant and pregnant mice. (A and B) Glucose tolerance test (GTT) (16 hours of fasting) was performed on virgin and pregnant (GD14) WT mice after 12-week treatment with or without paroxetine (10 mg/kg per day) (n = 5–10 per group). The repeated area under the curve (AUC) measures ANOVA; P value is provided. The corresponding GTT AUC (C) was calculated. *P < 0.05. Values are the mean ± S.E.M.

Fig. 5.

Effect of paroxetine treatment on circulating 17β-E levels and ovarian CYP19a1 expression. (A) Plasma 17β-estradiol (17β-E) levels (n = 5 per group), (B) ovarian Cyp19a1 mRNA (n = 5 per group), and (C) protein levels (n = 3 per group) were measured in nonpregnant, pregnant (GD14), and PD 1 WT mice after 12-week treatment with or without paroxetine (10 mg/kg per day). *P < 0.05. Values are the mean ± S.E.M.

Fig. 6.

Estrogen replacement reverses paroxetine-induced adiposity. WT mice were treated with paroxetine (10 mg/kg per day) in drinking water for 12 weeks. After 12 weeks, paroxetine treated- or -untreated mice were further treated with 17β-E (2 µg/day) or placebo control via subcutaneous implantation for 3 weeks. (A) Body weight changes for 15 weeks (n = 5 per group). (B–D and H) White and brown fat tissue weight at time of sacrifice (n = 5 per group). (E) Representative images of H&E-stained gWAT sections (scale bar, 100 µm). (F) Average adipocyte size per 10× field quantified using NIH ImageJ as described in Materials and Methods. Gene expression analysis in gWAT (G) and BAT (I) by quantitative reverse-transcribed polymerase chain reaction (n = 5 per group). *P < 0.05. Values are the mean ± S.E.