No abstract

Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR, with its broad ligand binding specificity, is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.

Phthalates are widely used as plasticizers in everyday products. Yet, studies on the effects of phthalates on female reproductive health are limited. In this study, pregnant C57/Bl6 mice were exposed via oral gavage to corn oil, 100, 500, or 1000mg/kg MEHP from gestational days 17–19. Reproductive lifespan was decreased by one month in the highest F1 exposure group (9.8±0.4 versus 11.1±0.6 months in control F1 females). F1 females exhibited delayed estrous onset at the two higher exposures and prolonged estrus was observed in all MEHP-exposed females. Serum FSH and estradiol were significantly elevated at the highest exposure and altered mRNA expression was found for the steroidogenic genes LHCGR, aromatase, and StAR. At one year of age, mammary gland hyperplasia was observed in high dose MEHP-exposed females. In summary, late gestational exposure to MEHP leads to multiple latent reproductive effects throughout murine life resulting in premature ovarian senescence and mammary hyperplasia.

Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone, an AHR inhibitor. A nonlinear mixed model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with α-naphthoflavone. However, differences were noted in that female B6.D2 versus B6 mice on Western diet became more obese; and in general, female mice to that of male mice had a greater fat mass to body mass ratio, were less responsive to α-naphthoflavone, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing α-naphthoflavone or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity providing potentially convenient and effective targets for treatment.