Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice.

Abstract

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 (NF), 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 NF. However, differences were noted in that female B6.D2 vs B6 mice on Western diet became more obese; and in general, female mice compared with male mice had a greater fat mass to body mass ratio, were less responsive to NF, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing NF 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.

• Authors: Benjamin J Moyer, Itzel Y Rojas, Joanna S Kerley-Hamilton, Krishnamurthy V Nemani, Heidi W Trask, Carol S Ringelberg, Barjor Gimi, Eugene Demidenko, Craig R Tomlinson
• Journal: Nutrition research (New York, N.Y.) (Nutr Res) Vol. 44 Pg. 38-50 (Aug 2017) ISSN: 1879-0739 [Electronic] United States
• PMID: 28821316 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
• Azo Compounds
• Benzoflavones
• Pyrazoles
• Receptors, Aryl Hydrocarbon
• alpha-naphthoflavone
• Cyp1b1 protein, mouse
• Cytochrome P-450 CYP1B1
• Scd1 protein, mouse
• Stearoyl-CoA Desaturase

Topics

• Adiposity (drug effects)
• Animals
• Azo Compounds (pharmacology)
• Benzoflavones (pharmacology)
• Cytochrome P-450 CYP1B1 (genetics, metabolism)
• Diet, Western
• Fatty Liver (prevention & control)
• Female
• Liver (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Obesity (prevention & control)
• Pyrazoles (pharmacology)
• Receptors, Aryl Hydrocarbon (antagonists & inhibitors)
• Stearoyl-CoA Desaturase (genetics, metabolism)