The aryl hydrocarbon receptor in β-cells mediates the effects of TCDD on glucose homeostasis in mice
Molecular Metabolism(2023)
Abstract
Chronic exposure to persistent organic pollutants (POPs) is associated with increased incidence of type 2 diabetes, hyperglycemia, and poor insulin secretion in humans. Dioxins and dioxin-like compounds are a broad class of POPs that exert cellular toxicity through activation of the aryl hydrocarbon receptor (AhR). We previously showed that a single high-dose injection of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD, aka dioxin; 20 µg/kg) in vivo reduced fasting and glucose-stimulated plasma insulin levels for up to 6 weeks in male and female mice. TCDD-exposed male mice were also modestly hypoglycemic and had increased insulin sensitivity, whereas TCDD-exposed females were transiently glucose intolerant; whether these effects are driven by AhR activation in β-cells requires investigation. Here we exposed female and male β-cell specific AhR knockout (βAhrKO) mice and littermate Ins1-Cre genotype controls (βAhrWT) to a single high dose of 20 µg/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from β-cells increased insulin secretion ex vivo in female mouse islets and promoted modest weight gain in male mice under baseline conditions. Importantly, high-dose TCDD exposure impaired glucose homeostasis and β-cell function in βAhrWT mice, but these phenotypes were largely abolished in TCDD-exposed βAhrKO mice. Our study demonstrates that AhR signaling in β-cell is important for regulating baseline β-cell function in female mice and energy homeostasis in male mice. We also show that β-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both female and male mice, suggesting that the effects of TCDD on β-cell function/health are driving metabolic phenotypes in peripheral tissues.
### Competing Interest Statement
The authors have declared no competing interest.
* AhR
: Aryl hydrocarbon receptor
CO
: Corn oil
Cyp1a1
: Cytochrome P450 1A1
GTT
: Glucose tolerance test
GSIS
: Glucose-stimulated insulin secretion
Gsta1
: Glutathione S-transferase alpha 1
Il-1β
: Interleukin-1β
ITT
: Insulin tolerance test
Nqo1
: NAD(P)H: quinone oxidoreductase
POPs
: Persistent Organic Pollutants
Ppargc1a
: Peroxisome proliferative activated receptor 1α
TCDD
: 2,3,7,8-tetrachlorodibenzo-p-dioxin
T2D
: Type 2 diabetes
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