Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet

Abstract

Background: Obesity is a growing worldwide problem with genetic and environmental causes, and it is an underlying basis for many diseases. Studies have shown that the toxicant-activated aryl hydrocarbon receptor (AHR) may disrupt fat metabolism and contribute to obesity. The AHR is a nuclear receptor/transcription factor that is best known for responding to environmental toxicant exposures to induce a battery of xenobiotic-metabolizing genes.

Objectives: The intent of the work reported here was to test more directly the role of the AHR in obesity and fat metabolism in lieu of exogenous toxicants.

Methods: We used two congenic mouse models that differ at the Ahr gene and encode AHRs with a 10-fold difference in signaling activity. The two mouse strains were fed either a low-fat (regular) diet or a high-fat (Western) diet.

Results: The Western diet differentially affected body size, body fat:body mass ratios, liver size and liver metabolism, and liver mRNA and miRNA profiles. The regular diet had no significant differential effects.

Conclusions: The results suggest that the AHR plays a large and broad role in obesity and associated complications, and importantly, may provide a simple and effective therapeutic strategy to combat obesity, heart disease, and other obesity-associated illnesses.

Figure 1

Effect of diet on male B6 and B6.D2 mice. (A) B6 and B6.D2 mouse strains. (B) Body mass of mice fed the regular diet or Western diet for 28 weeks (n = 8 mice/group). Gonadal fat pad mass (C) and gonadal fat pad mass:body mass ratio (D) of mice fed the diets for 28 weeks (n = 8 mice/group). (E) Consumption and excretion amounts (n = 3 mice/group) at week 20. (F) Consumed kilocalories during a 48-hr period in week 20 (n = 3 mice/group). Values are mean ± SE.

Figure 2

Effect of diet on liver size and on and fat content in the livers of male B6 and B6.D2 mice. Body mass (A), liver mass (B), and body mass:liver mass ratio (C) of B6 and B6.D2 mice (n = 8 mice/group) fed regular diet or Western diet for 28 weeks. (D–G) Photomicrographs of H&E-stained liver sections (200× magnification; bar = 100 mm) from B6 mouse fed regular diet (D), B6.D2 mouse fed regular diet (E), B6 mouse fed Western diet (F), and B6.D2 mouse fed Western diet (G). (H) Total vacuole area in liver per 10 fields of vision for (n = 4/group). For A–C and H, values are mean ± SE.

Figure 3

Levels of liver damage markers and cholesterol in male B6 and B6.D2 mice fed regular diet or Western diet for 28 weeks. (A) ALT (reference range, 27.3–115.3). (B) AST (reference range, 45.0–386.1). (C) AST/ALT ratio. (D) ALP (reference range, 65.5–272.6). (E) Total protein (reference range, 4.6–6.9). (F) Total cholesterol (reference range, 74.0–167.0). Values are mean ± SE (n = 8 mice/group).

Figure 4

Shared and uniquely differentially expressed genes from B6 and B6.D2 mice fed regular or Western diets by micro­array analysis (n = 4 mice/group). Venn diagrams display the number of differentially expressed genes from the effect of diet on Ahr genotype (A) and the effect of Ahr genotype on diet (B).