Effects of Aryl Hydrocarbon Receptor Deficiency on PCB-77-Induced Impairment of Glucose Homeostasis during Weight Loss in Male and Female Obese Mice

Abstract

Background: Lipophilic polychlorinated biphenyls (PCBs) accumulate with obesity, but during weight loss, liberated PCBs act as ligands of the aryl hydrocarbon receptor (AhR) to negatively influence health. Previous studies demonstrated that PCB-77 administration to obese male mice impaired glucose tolerance during weight loss. Recent studies indicate higher toxic equivalencies of dioxin-like PCBs in exposed females than males.

Objectives: We compared effects of PCB-77 on weight gain or loss and glucose homeostasis in male vs. female mice. We defined effects of AhR deficiency during weight gain or loss in male and female mice exposed to PCB-77.

Methods: Study design was vehicle (VEH) or PCB-77 administration while fed a high-fat (HF) diet for 12 wk, followed by weight loss for 4 wk. The following groups were examined: male and female C57BL/6 mice administered VEH or PCB-77, female [Formula: see text] and [Formula: see text] mice administered VEH or PCB-77, and male [Formula: see text] and [Formula: see text] mice administered PCB-77. Glucose tolerance was quantified during weight gain (week 11) and loss (week 15); liver and adipose AhR and IRS2 (insulin receptor substrate 2) mRNA abundance, and PCB-77 concentrations were quantified at week 16.

Results: PCB-77 attenuated development of obesity in females but not males. During weight loss, PCB-77 impaired glucose tolerance of males. AhR-deficient females (VEH) were resistant to diet-induced obesity. Compared with VEH-treated mice, HF-fed [Formula: see text] females treated with PCB-77 has less weight gain, and [Formula: see text] females had greater weight gain. During weight loss, [Formula: see text] females but not [Formula: see text] males treated with PCB-77 exhibited impaired glucose tolerance. In [Formula: see text] females administered PCB-77, IRS2 mRNA abundance was lower in adipose tissue compared with VEH-treated mice.

Conclusion: Male and female mice responded differently to PCB-77 and AhR deficiency in body weight (BW) regulation and glucose homeostasis. AhR deficiency reversed PCB-77-induced glucose impairment of obese males losing weight but augmented glucose intolerance of females. These results demonstrate sex differences in PCB-77-induced regulation of glucose homeostasis of mice. https://doi.org/10.1289/EHP4133.

Figure 1.

Effect of polychlorinated biphenyl (PCB)-77 on the development of obesity, body composition, and glucose homeostasis in male and female mice fed a high-fat (HF) diet. Male and female mice were administered vehicle (VEH) or PCB-77 on weeks 1, 2, 9, and 10 during a HF diet for 12 wk. (A) Body weight (BW) of HF-fed male and female mice (arrows indicate PCB dosing). (B) Lean and fat mass as a percentage of BW measured on week 9. (C) Blood glucose concentrations over time following a glucose bolus [intraperitoneal (i.p.)] measured on week 11. (D) Area under the curve (AUC) for data in (C). Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=6–10\text{\hspace{0.17em} mice}/\text{sex}/\text{treatment}$. *$p<0.05$ compared with VEH within sex; ^#$p<0.05$ compared with male within treatment. A repeated measures two-way analysis of variance (ANOVA) tested sex and PCB-77 treatment on the development of BW (A), and glucose homeostasis (C). A two-way ANOVA tested sex and PCB-77 treatment on lean and fat mass (B), and AUC for glucose tolerance tests (D).

Figure 2.

Effect of a low-fat (LF) diet on body weight (BW), body composition, and glucose homeostasis of polychlorinated biphenyl (PCB)-77-treated male and female mice. Male and female mice were administered vehicle (VEH) or PCB-77 and fed a high-fat (HF) diet for 12 wk, and then switched to a LF diet for 4 wk. (A) Weekly BWs of LF-fed male and female mice. (B) Lean and fat mass as a percentage of BW measured on week 16. (C) Blood glucose concentrations over time following a glucose bolus [intraperitoneal (i.p.)] on week 15. (D) Area under the curve (AUC) for data in (C). Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=6–10\text{\hspace{0.17em} mice}/\text{sex}/\text{treatment}$. *$p<0.05$ compared with VEH within sex; ^#$p<0.05$ compared with male within treatment. A repeated measures two-way analysis of variance (ANOVA) tested sex and PCB-77 treatment on the development of BW (A), and glucose homeostasis (C). A two-way ANOVA tested sex and PCB-77 treatment on lean and fat mass (B), and AUC for glucose tolerance tests (D).

Figure 3.

Effect of aryl hydrocarbon receptor (AhR) deficiency on the development of obesity, body fat distribution, and glucose homeostasis in female mice administered vehicle (VEH) or polychlorinated biphenyl (PCB)-77, and in male mice administered PCB while being fed a high-fat (HF) diet. Female $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice were administered VEH or PCB-77 and fed a HF diet for 12 wk. Male $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice were administered PCB-77 and fed a HF diet for 12 wk. PCB dosing occurred on weeks 1, 2, 9, 10 during a HF diet for 12 wk. (A) Body weight (BW) of HF-fed female $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice administered VEH or PCB-77, and male $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice administered PCB-77 (arrows indicate PCB dosing). (B) Lean and fat mass as a percentage of BW measured on week 9. (C) Blood glucose concentrations over time following a glucose bolus [intraperitoneal (i.p.)] measured on week 11. (D) Area under the curve (AUC) for data in (C). Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=7–10\text{\hspace{0.17em} mice}/\text{sex}/\text{genotype}$. *$p<0.05$ compared with $Ah{R}^{+/+}$ within sex; ^#$p<0.05$ compared with VEH within genotype; **$p<0.05$ compared with female within treatment. A repeated measures two-way analysis of variance (ANOVA) tested AhR deficiency and PCB-77 treatment on the development of BW (A), and glucose homeostasis (C). A two-way ANOVA tested AhR deficiency and PCB-77 treatment on lean and fat mass (B), and AUC for glucose tolerance tests (D).

Figure 4.

Effect of aryl hydrocarbon receptor (AhR) deficiency during weight loss on body weight (BW), body fat distribution, and glucose homeostasis in female mice administered vehicle (VEH) or polychlorinated biphenyl (PCB)-77, and in male mice administered PCB while being fed a high-fat (HF) diet. Female $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice were administered VEH or PCB-77 and fed a HF diet for 12 wk, and then switched to a low-fat LF diet for 4 wk. Male $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice were administered PCB-77 and fed a HF diet for 12 wk, and then switched to a LF diet for 4 wk. (A) Weekly BWs of LF-fed female $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice administered VEH or PCB-77, and male $Ah{R}^{+/+}$ and ${\phantom{}}^{-/-}$ mice administered PCB-77. (B) Lean and fat mass as a percentage of BW measured on week 16. (C) Blood glucose concentrations over time following a glucose bolus [intraperitoneal (i.p.)] on week 15. (D) Area under the curve (AUC) for data in (C). Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=7–10\text{\hspace{0.17em} mice}/\text{sex}/\text{genotype}$. *$p<0.05$ compared with $Ah{R}^{+/+}$ within sex; ^#$p<0.05$ compared with VEH within genotype; **$p<0.05$ compared with female within treatment. A repeated measures two-way analysis of variance (ANOVA) tested Ahr deficiency and PCB-77 treatment on the development of body weight (BW) (A), and glucose homeostasis (C). A two-way ANOVA tested AhR deficiency and PCB-77 treatment on lean and fat mass (B), and AUC for glucose tolerance tests (D).

Figure 5.

CYP1A1 (cytochrome P450 1A1), PEPCK (phosphoenolpyruvate carboxykinase), and $TNF\mathrm{\alpha }$ (tumor necrosis $\text{factor -}\mathrm{\alpha }$) mRNA abundance in (A) liver, and (B) adipose of polychlorinated biphenyl (PCB)-77-treated male and female mice at week 16 (end of weight loss phase). Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=3–5\text{\hspace{0.17em} mice}/\text{genotype}$ and are normalized to PCB-treated male of aryl hydrocarbon receptor ${\left(AhR\right)}^{+/+}$ mice. *$p<0.05$ compared with $Ah{R}^{+/+}$ within sex; ^#$p<0.05$ compared with male within genotype. A two-way analysis of variance (ANOVA) tested sex and AhR deficiency on gene expression in male and female mice (A,B).

Figure 6.

Liver and adipose tissue of aryl hydrocarbon receptor (AhR) and IRS2 (insulin receptor substrate 2) mRNA abundance in polychlorinated biphenyl (PCB)-77-treated AhR-proficient and AhR-deficient males and females at week 16 (end of weight loss phase). (A) AhR and IRS2 mRNA abundance in livers from male and female mice of each genotype. (B) AhR and IRS2 mRNA abundance in adipose tissue from male and female mice of each genotype. Data are $\text{mean}\pm \text{standard error of the mean \hspace{0.17em}}\left(\text{SEM}\right)$ from $n=3–5\text{\hspace{0.17em} mice}/\text{genotype}$. *$p<0.05$ compared with $Ah{R}^{+/+}$ within sex; ^#$p<0.05$ compared with male within genotype. A two-way analysis of variance (ANOVA) tested sex and AhR deficiency on gene expression in liver and adipose tissue from male and female mice.