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

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that controls the expression of several downstream targets including xenobiotic metabolism enzymes, cytochrome P450 1A1 and 1A2 (Cyp1a1/1a2). Besides xenobiotic metabolism, AhR also mediates responses to other stressors including high-fat diets (HFDs). Although global deletion or downregulation of AhR protects against metabolic dysfunction in HFD-fed mice, the role of Cyp1a1/1a2 in glucose homeostasis remains unclear. We demonstrated that Cyp1a1 expression is induced in mouse pancreatic islets not only by xenobiotic exposure but also by HFD feeding. Since CYP1A1/1A2 enzymes can produce reactive oxygen intermediates, we hypothesized that chronic CYP1A1/1A2 activation may contribute to HFD-induced metabolic dysfunction in mice, and thus, deleting these enzymes may be protective. We fed 29- to 31-wk-old male and female global Cyp1a1/1a2 knockout (Cyp^KO) and wild-type (Cyp^WT) mice a 45% HFD or standard chow for 14 wk. Cyp^KO females were partially protected from HFD-induced glucose intolerance, and chow-fed Cyp^KO females had lower plasma insulin and suppressed insulin secretion in isolated islets compared with Cyp^WT females. Meanwhile, Cyp^KO males exhibited HFD-induced hyperinsulinemia later than Cyp^WT males. HFD feeding elevated Cyp1a1 and other stress genes in Cyp^WT male islets but not in Cyp^KO islets, indicating that CYP1A1 mediates islet stress responses. Liver pathology, adiposity, and adipose inflammation were primarily affected by diet, not genotype, in both sexes. Our study highlights a novel sex-dependent role for Cyp1a1/1a2 in shaping the systemic metabolic response to HFD feeding, suggesting that CYP1A1/1A2 enzymes are involved in glucose homeostasis, insulin secretion, and islet stress responses.NEW & NOTEWORTHY Cytochrome P450 (CYP)1A1/1A2 enzymes have sex-specific roles in glucose homeostasis in mice. In females, global Cyp1a1/1a2 deletion partially protects from glucose intolerance in high-fat diet (HFD)-fed mice and lowers plasma insulin in chow-fed mice. In males, Cyp1a1/1a2 deletion delays HFD-induced hyperinsulinemia in vivo and inhibits HFD-induced islet stress responses. Genotype-driven differences were only seen in islets, suggesting a novel role for islet CYP1A1/1A2 enzymes in responding to metabolic stress.