The aryl hydrocarbon receptor as a tissue-specific modulator of insulin sensitivity: Evidence from conditional deletion studies

The aryl hydrocarbon receptor (AhR) has emerged as a consequential regulator of fuel homeostasis and insulin action, yet its tissue-specific contributions remain incompletely resolved. Using evidence from conditional and inducible AhR deletion models, the purpose of this review is to evaluate the role of AhR in metabolically active tissues including adipose, liver, skeletal muscle, intestinal epithelium, kidney, pancreatic β-cells and the central nervous system. Tissue-specific phenotypes reveal that AhR may modulate insulin sensitivity in a context-dependent manner shaped by at least three critical variables: i) the timing of receptor deletion (developmental vs. post-developmental), ii) sex (with divergent mechanisms operating in males vs. females), and iii) dietary context (chow vs. metabolic challenge). In adipocytes, for instance, post-developmental AhR deletion protects females against diet-induced metabolic dysfunction by mechanisms potentially associated with estrogen receptor-dependent enhancement of hypothalamic leptin sensitivity, while males show only partial protection mediated in part through reduced adipose tissue inflammation. Hepatocyte-specific AhR deletion worsens steatosis but may improve systemic metabolism through FGF21-dependent mechanisms, suggesting opposing local vs. endocrine effects. Specific deletion in insulin-secreting β-cells suggests that AhR may contribute to dioxin-induced glucose dysregulation in a sex-contingent manner. Collectively, these tissue-specific phenotypes suggest that physiological AhR signaling contributes to metabolic homeostasis under basal conditions, whereas dietary lipid excess or xenobiotic exposure may reveal tissue-specific functions that either impair or preserve insulin sensitivity. These observations position AhR as a tissue-restricted modulator of insulin action whose physiological impact is shaped by cellular context, hormonal milieu and ligand environment.