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

Aims/hypothesis The 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. Methods At 29 to 31 weeks of age, male and female global Cyp1a1/1a2 knockout ( Cyp KO) and wildtype littermate control ( Cyp WT) mice were fed either a 45% HFD or standard rodent chow for 14 weeks. Metabolic assessments were conducted throughout the study. Results Cyp KO females were partially protected from HFD-induced glucose intolerance compared to Cyp WT females, but both genotypes exhibited similar levels of insulin resistance. Cyp KO females also had lower plasma insulin levels in vivo and suppressed insulin secretion in isolated islets ex vivo compared to Cyp WT females. Gene expression patterns in female islets were generally similar across genotype and diet groups. In contrast, Cyp WT males became hyperinsulinemic and insulin resistant within 2 weeks of HFD feeding, while Cyp KO males maintained normal plasma insulin levels and insulin sensitivity. HFD feeding upregulated Cyp1a1 in Cyp WT male islets and this was accompanied by elevation of other islet stress genes. Interestingly, HFD feeding did not induce these stress gene responses in Cyp KO 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. Conclusions Our 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. ### Competing Interest Statement The authors have declared no competing interest. * AhR : Aryl hydrocarbon receptor Cyp1a1 : Cytochrome P450 1A1 Cyp1a2 : Cytochrome P450 1A2 Cyp KO : Global Cyp1a1/1a2 double knockout mice on C57Bl/6J background Cyp WT : Cyp1a1/1a2 wildtype C57Bl/6J mice GSIS : Glucose-stimulated insulin secretion GTT : Glucose tolerance test HFD : High-fat diet ITT : Insulin tolerance test ROS : Reactive oxygen species