Deficiency of Adipose Aryl Hydrocarbon Receptor Protects against Diet-Induced Metabolic Dysfunction through Sexually Dimorphic Mechanisms

Abstract

The molecular mechanisms underlying diet-induced obesity are complex and remain unclear. The activation of the aryl hydrocarbon receptor (AhR), a xenobiotic sensor, by obesogens may contribute to diet-induced obesity through influences on lipid metabolism and insulin resistance acting at various sites, including adipose tissue. Thus, our hypothesis was that conditional AhR depletion, specifically from mature adipose tissue (CadKO), would improve high-fat diet (HFD)-induced metabolic dysfunction. CadKO protects mice from HFD-induced weight gain. CadKO females eat fewer calories, leading to increased energy expenditure (EE) and improved glucose tolerance on HFD. Our exploration of adipose tissue biology suggests that the depletion of AhR from adipocytes provides female mice with an increased capacity for adipogenesis and lipolysis, allowing for the maintenance of a healthy adipocyte phenotype. The HFD-induced leptin rise was reduced in CadKO females, but the hypothalamic leptin receptor (LepR) was increased in the energy regulatory regions of the hypothalamus, suggesting an increased sensitivity to leptin. The estrogen receptor α (ERα) was higher in CadKO female adipose tissue and the hypothalamus. CadKO males displayed a delayed progression of obesity and insulin resistance. In males, CadKO ameliorated proinflammatory adipocytokine secretion (such as TNFα, IL1β, IL6) and displayed reduced inflammatory macrophage infiltration into adipose depots. Overall, CadKO improves weight control and systemic glucose homeostasis under HFD challenge but to a more profound extent in females. CadKO facilitates a lean phenotype in females and mediates healthy adipose–hypothalamic crosstalk. In males, adipose-specific AhR depletion delays the development of obesity and insulin resistance through the maintenance of healthy crosstalk between adipocytes and immune cells.

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

“…We found that Cyp KO females were generally leaner than Cyp WT mice and, when fed HFD, Cyp KO females developed milder glucose intolerance than Cyp WT females. Similar results were found in global Ahr knockout (Ahr KO ) female mice, where Ahr KO females were protected from HFDinduced weight gain, exhibited higher energy expenditure, and had better glucose tolerance compared to Ahr wildtype (Ahr WT ) females [27]. While plasma insulin levels were not assessed during the GTTs in the Ahr KO study [27], our results show that chowfed Cyp KO females had lower plasma insulin levels than chow-fed Cyp WT females.…”

“…Similar results were found in global Ahr knockout (Ahr KO ) female mice, where Ahr KO females were protected from HFDinduced weight gain, exhibited higher energy expenditure, and had better glucose tolerance compared to Ahr wildtype (Ahr WT ) females [27]. While plasma insulin levels were not assessed during the GTTs in the Ahr KO study [27], our results show that chowfed Cyp KO females had lower plasma insulin levels than chow-fed Cyp WT females. Furthermore, isolated Cyp KO female islets also had reduced GSIS ex vivo compared to Cyp WT female islets, pointing to a role for Cyp1a1/1a2 in regulating insulin secretion and/or insulin clearance.…”

“…However, Cyp WT males exhibited HFD-induced hyperinsulinemia earlier than Cyp KO males and became insulin resistant after only 2 weeks of HFD feeding. A similar pattern was observed in a global Ahr KO model, where HFD-fed Ahr KO males developed less severe insulin resistance than HFD-fed Ahr WT males [27,28]. Interestingly, Ahr KO males were also partially protected from HFD-induced weight gain and glucose intolerance [27,28].…”

“…Given the central role of the liver in xenobiotic clearance, we hypothesized that deleting xenobiotic metabolism enzymes, Cyp1a1/1a2, will have the greatest impact on the liver. We also expected the effect to be pronounced in fat, since previous reports have shown that AhR activity is involved in HFD-induced obesity [25][26][27][28][29][30][31]. The role of the AhR pathway is least understood in islets, but we hypothesized islets would be highly susceptible to damage associated with CYP1A1/1A2 activity, given their relatively weak antioxidant defense system [44,45].…”

“…Numerous studies have shown that downregulating or deleting AhR protects against highfat diet (HFD)-induced obesity and glucose dysregulation in mice [24][25][26][27][28][29][30][31]. These studies emphasize the importance of the AhR pathway in metabolic adaptation to HFD, but the role of downstream AhR target genes, Cyp1a1 and Cyp1a2, remains unclear.…”