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.