Pdgfrα-Cre mediated knockout of the aryl hydrocarbon receptor protects mice from high-fat diet induced obesity and hepatic steatosis

Abstract

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used plateletderived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahr fl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahr fl/fl mice (control mice). The Pdgfrα-Cre Ahr fl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahr fl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of

Activation of the aryl hydrocarbon receptor by clozapine induces preadipocyte differentiation and contributes to endothelial dysfunction

“…Here we present evidence that this preadipocyte differentiation was triggered by AhR signaling, because clozapine-induced differentiation was strongly inhibited either by the AhR inhibitor α-NF or the green tea extract EGCG, which has AhRantagonizing activities as well (Palermo et al, 2003(Palermo et al, , 2005. In line with our results, mice with an adipocyte-specific AhR gene deletion showed no weight gain under high fat diet (Gourronc et al, 2020). Increased glucose import together with decreased consumption by mitochondrial respiration leads to triglyceride accumulation in the preadipocytes (Vankoningsloo et al, 2005).…”

Adipose Tissue and Endocrine-Disrupting Chemicals: Does Sex Matter?

“…Consistently, mice deficient for AhR are resistant to diet-induced body weight gain, steatosis, and inflammation through increased energy expenditure [ 99 ]. The same phenotype of resistance to diet-induced obesity was described in mice with specific deletion of AhR in pre-adipocytes through the expression of Pdgfrα-Cre [ 100 ]. In contrast, AhR deficiency in mature adipocytes through expression of adiponectin-Cre [ 101 ] resulted in obesity, enhanced fat mass, and larger visceral adipocytes, a phenotype which was exacerbated in response to a high-fat diet.…”

Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease

“…The loss of AhR resulted in increased hepatic FGF21, offering hepatoprotection and increased energy expenditure [ 84 ]. Similar to the anti-steatotic properties exhibited by the whole body and inducible hepatocyte-specific AhR conditional knockout mice, knockout of the AhR in preadipocytes protected mice from high-fat diet induced obesity and liver steatosis suggesting a role for AhR in adipose tissue and possible cross-talk with liver [ 85 ].…”