| First Author | Hoyeck MP | Year | 2024 |
| Journal | Mol Metab | Volume | 81 |
| Pages | 101893 | PubMed ID | 38309623 |
| Mgi Jnum | J:360424 | Mgi Id | MGI:7594847 |
| Doi | 10.1016/j.molmet.2024.101893 | Citation | Hoyeck MP, et al. (2024) The aryl hydrocarbon receptor in beta-cells mediates the effects of TCDD on glucose homeostasis in mice. Mol Metab 81:101893 |
| abstractText | OBJECTIVE: 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 mug/kg) in vivo reduced fasted 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 beta-cells requires investigation. METHODS: We exposed female and male beta-cell specific Ahr knockout (betaAhr(KO)) mice and littermate Ins1-Cre genotype controls (betaAhr(WT)) to a single high dose of 20 mug/kg TCDD and tracked the mice for 6 weeks. RESULTS: Under baseline conditions, deleting AhR from beta-cells caused hypoglycemia in female mice, increased insulin secretion ex vivo in female mouse islets, and promoted modest weight gain in male mice. Importantly, high-dose TCDD exposure impaired glucose homeostasis and beta-cell function in betaAhr(WT) mice, but these phenotypes were largely abolished in TCDD-exposed betaAhr(KO) mice. CONCLUSION: Our study demonstrates that AhR signaling in beta-cells is important for regulating baseline beta-cell function in female mice and energy homeostasis in male mice. We also show that beta-cell AhR signaling largely mediates the effects of TCDD on glucose homeostasis in both sexes, suggesting that the effects of TCDD on beta-cell function and health are driving metabolic phenotypes in peripheral tissues. |
