Effects of aryl hydrocarbon receptor deficiency on PCB-77-induced impairment of glucose homeostasis during weight loss in male and female obese mice

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 AhR^{+ /+} and^{−< −} mice administered VEH or PCB-77, and male AhR^{+ /+} and^{−< −} 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 AhR^{+ /+} females treated with PCB-77 has less weight gain, and AhR^{−/ −} females had greater weight gain. During weight loss, AhR^{−/ −} females but not AhR^{−/ −} males treated with PCB-77 exhibited impaired glucose tolerance. In AhR^{−/ −} 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.