Ching, M. E. A. | Search bioRxiv

bioRxiv2024

CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner

Aims/hypothesisThe aryl hydrocarbon receptor (AhR) pathway is involved in cellular responses to a broad range of external stressors, making it an excellent candidate for understanding the interaction between environmental factors and type 2 diabetes risk. Studies suggest deleting or downregulating AhR protects against metabolic dysfunction in high-fat diet (HFD) fed mice; however, the contribution of downstream AhR targets in driving this phenotype remains unexamined. Cytochrome P450 1A1 and 1A2 (CYP1A1/1A2) are canonical AhR targets that encode xenobiotic metabolism enzymes. Interestingly, we have demonstrated that HFD feeding increases Cyp1a1 expression in mouse islets, which suggests CYP1A enzymes are involved in the response to metabolic stress. Since CYP1A1/1A2 activity can produce reactive oxygen intermediates, we hypothesized that chronic activation of these enzymes in tissues critical for regulating glucose homeostasis (e.g., liver, adipose, islets) will contribute to metabolic dysfunction following HFD feeding. MethodsAt 29 to 31 weeks of age, male and female global Cyp1a1/1a2 knockout (CypKO) and wildtype littermate control (CypWT) mice were fed either a 45% HFD or standard rodent chow for 14 weeks. Metabolic assessments were conducted throughout the study. ResultsCypKO females were partially protected from HFD-induced glucose intolerance compared to CypWT females, but both genotypes exhibited similar levels of insulin resistance. CypKO females also had lower plasma insulin levels in vivo and suppressed insulin secretion in isolated islets ex vivo compared to CypWT females. Gene expression patterns in female islets were generally similar across genotype and diet groups. In contrast, CypWT males became hyperinsulinemic and insulin resistant within 2 weeks of HFD feeding, while CypKO males maintained normal plasma insulin levels and insulin sensitivity. HFD feeding upregulated Cyp1a1 in CypWT male islets and this was accompanied by elevation of other islet stress genes. Interestingly, HFD feeding did not induce these stress gene responses in CypKO male islets, suggesting the islet stress response is mediated by activation of CYP1A1. We expected the global deletion of Cyp1a1/1a2 to have pronounced effects in the liver, but surprisingly, changes in liver pathology were predominantly driven by diet and not genotype in both sexes. Similarly, overall adiposity and adipose tissue inflammation were not affected by genotype. ConclusionsOur study highlights a novel role of islet Cyp1a1/1a2 in shaping the systemic metabolic response to HFD feeding. Our data suggest that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and the islet stress response. Importantly, the effects of Cyp1a1/1a2 deletion are sex-dependent.

molecular biology↗

bioRxiv2023

The aryl hydrocarbon receptor in beta-cells mediates the effects of TCDD on glucose homeostasis in mice

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 {micro}g/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 {beta}-cells requires investigation. Here we exposed female and male {beta}-cell specific AhR knockout ({beta}AhrKO) mice and littermate Ins1-Cre genotype controls ({beta}AhrWT) to a single high dose of 20 {micro}g/kg TCDD and tracked the mice for 6 weeks. We found that deleting AhR from {beta}-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 {beta}-cell function in {beta}AhrWT mice, but these phenotypes were largely abolished in TCDD-exposed {beta}AhrKO mice. Our study demonstrates that AhR signaling in {beta}-cell 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 female and male mice, suggesting that the effects of TCDD on {beta}-cell function/health are driving metabolic phenotypes in peripheral tissues.

molecular biology↗