Coplanar polychlorinated biphenyls impair glucose homeostasis in lean C57BL/6 mice and mitigate beneficial effects of weight loss on glucose homeostasis in obese mice

Abstract

Background: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes.

Objectives: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor α (TNF-α) and on glucose and insulin homeostasis in lean and obese mice.

Methods: We quantified glucose and insulin tolerance, as well as TNF-α levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-α expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis.

Results: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77-treated mice, TNF-α expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss.

Conclusions: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose-specific elevations in TNF-α expression by PCBs may contribute to impaired glucose homeostasis.

Figure 1

PCB-77 and PCB-126 impaired glucose tolerance in LF-fed mice. Blood glucose concentrations were examined in mice administered vehicle, PCB‑77 (2.5, 50, or 248 mg/kg; A), or PCB‑126 (0.3, 1.6, or 3.3 mg/kg; B) twice during 2 weeks, and then given a bolus of glucose 48 hr after the second dose. (C,D) Quantification of total AUC for data in A and B, respectively. Data are mean ± SE and represent five mice per treatment group. *p< 0.05 compared with vehicle within a time point. **p < 0.05 compared with vehicle.

Figure 2

PCB-77–treated LF-fed mice had elevated TNF-α expression in adipose tissue (C), but not in liver (A) or soleus muscle (B). Expression levels of TNF-α were quantified in week 4, 2 weeks after the second dose of vehicle or PCB-77 (50 mg/kg). Data are mean ± SE and represent three mice per treatment group. **p < 0.05 compared with vehicle.

Figure 3

PCB-77 had no effect on glucose (A) or insulin (B) tolerance in HF-fed mice during weight gain, but impaired glucose homeostasis during weight loss. Quantification of total AUC for glucose (A) and insulin (B) tolerance in mice administered vehicle or PCB-77 (50 mg/kg, two doses during weeks 1 and 2 and two more doses during weeks 9 and 10) during weight gain (weeks 4 and 12 of HF feeding) or weight loss (week 16, after mice were switched to the LF diet). Data are mean ± SE and represent five mice per treatment group. *p< 0.05 compared with vehicle within a time point. ^#p < 0.05 compared with week 12 within a treatment group.