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  • br Impact of global AHR deficiency on diet

    2024-04-02


    Impact of global AHR deficiency on diet-induced obesity Two subsequent studies in which AHR function was affected at the whole animal level corroborated the role of AHR in dietary obesity. Xu et al. [14] showed that on a high-fat diet, both AHR-deficient Ahr−/− and hemizygous Ahr+/− mice gained significantly less weight than wildtype mice from 8 weeks on. Compared with the mutant strains, the wildtype mice had more epididymal and hepatic fat. The hepatic expression of genes involved in fatty 4 oht translocation (Cd36), lipogenesis (Fas, Acc), β-oxidation (Cpt1a, Acox1, Ppara), gluconeogenesis (Pck1, G6pc) and glucose oxidation (Pdk4) was higher in wildtype animals. These also had higher concentrations of insulin and leptin but lower levels of adiponectin in the serum. The obese wildtype mice displayed glucose intolerance and insulin insensitivity, whereas both were improved in the mutant strains in line with their higher serum adiponectin levels. In mice fed the high-fat diet, there was further evidence of aggravated inflammatory reaction in both the liver and white adipose tissue in the wildtype animals vs. Ahr−/− and Ahr+/− mice. Again, feed intake was not affected, and neither was locomotor activity. However, energy expenditure was higher in high-fat-fed Ahr+/− mice than in wildtype mice on either control or high-fat diet (Ahr−/− mice were not analyzed). This was associated with enhanced expression of the genes for the primary uncoupling protein (Ucp1) and for the regulator of mitochondrial biogenesis (Pgc1a) in the brown adipose tissue as well as those for Ppard (a major regulator of muscle fuel utilization favoring lipid oxidation [15]), Pgc1a, Acox1, Cpt1b, Ucp2 and Ucp3 in skeletal muscle, which may account for the increased energy expenditure. It is noteworthy that compared with wildtype mice, the Ahr+/− mice expressed approximately 30% of the AHR mRNA in the liver, and that Cyp1a1 or other AHR battery genes were not influenced by high-fat diet in wildtype mice [14]. This indicates that even partial elimination of AHR expression can have a substantial influence on energy homeostasis and that high-fat diet does not seem to elicit a general AHR activation as measured by expression of genes regulated by it.
    Modulation of diet-induced obesity by AHR antagonists Moyer et al. [16] proved that also pharmacological inhibition of AHR function is capable of preventing obesity in mice fed on a high-fat diet. Initially, they tested two AHR antagonists, α-naphtoflavone (aNF) and CH-223191 (approximate doses 3 and 10 mg/kg/day, respectively; added into diet), and found that during a 5-week exposure, both effectively counteracted the increasing impacts of high-fat diet on body, fat and liver masses. For CH-223191, the outcome was somewhat surprising, because this compound has been reported to be a selective antagonist of dioxin-type AHR agonists [17]. The team next extended the duration of aNF exposure to 26 weeks. In this case, aNF prevented B6 mice from gaining extra weight on high-fat diet, ameliorated hepatic steatosis and reduced serum LDL-cholesterol levels. However, it also decelerated the growth of control mice on regular chow, increased their liver-to-body mass ratio, and caused degenerative changes in their hepatocytes, indicating liver toxicity of the compound. The researchers then showed that the gene for indoleamine 2,3-dioxygenase (Ido1), an important tryptophan-metabolizing enzyme, is required for the full development of high-fat diet-induced obesity in mice. Their additional in vitro studies revealed that kynurenine rather than kynurenic acid is the probable tryptophan metabolite to activate the AHR. Furthermore, TGFβ1 (an indirect Ido1 inducer [18] whose hepatic gene expression is enhanced by high-fat diet [19]) and oxidized LDL (a ligand for toll-like receptors 2 & 4 [20]) stimulated AHR activity, but more slowly than kynurenine or TCDD. Finally, antagonism of toll-like receptors 2/4 was shown to prevent oxidized LDL-induced AHR activation, while IDO1 inhibition could only diminish it [16]. The effects of a global reduction in AHR activity caused by genetic or pharmacological means are compiled in Figure 1.