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CYP1A1/1A2 enzymes mediate glucose homeostasis and insulin secretion in mice in a sex-specific manner | American Journal of Physiology-Endocrinology and Metabolism | American Physiological Society 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 (CypKO) and wild-type (CypWT) mice a 45% HFD or standard chow for 14 wk. CypKO females were partially protected from HFD-induced glucose intolerance, and chow-fed CypKO females had lower plasma insulin and suppressed insulin secretion in isolated islets compared with CypWT females. Meanwhile, CypKO males exhibited HFD-induced hyperinsulinemia later than CypWT males. HFD feeding elevated Cyp1a1 and other stress genes in CypWT male islets but not in CypKO 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. https://doi.org/10.1152/ajpendo.00284.2024