Obesity Is Mediated by Differential Aryl Hydrocarbon Receptor Signaling in Mice Fed a Western Diet
Kerley-Hamilton, Joanna S., Trask, Heidi W., Ridley, Christian J. A., DuFour, Eric, Ringelberg, Carol S., Nurinova, Nilufer, Wong, Diandra, Moodie, Karen L., Shipman, Samantha L., Moore, Jason H., Korc, Murray, Shworak, Nicholas W., Tomlinson, Craig R., Environmental Health Perspectives
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.
KEY WORDS: aryl hydrocarbon receptor, gene-environment interaction, liver, mRNA, miRNA, obesity, Western diet. Environ Health Perspect 120:1252-1259 (2012). http://dx.doi.org/10.1289/ehp.1205003 [Online 18 May 2012]
It has been estimated that 25-70% of the underlying basis for obesity is gene based (Cardon et al. 1994; Stunkard et al. 1986); thus, environmental factors are a major contributor with 30-75% (Baillie-Hamilton 2002). One of the accepted environmental causes for the worldwide rise in obesity and associated problems is the increased consumption of the high-calorie, high-fat, low-fiber Western diet. A biological entity that tightly links genes and the environment is a nuclear receptor best known for its role in xenobiotic metabolism: the aryl hydrocarbon receptor (AHR). AHR is a ligandactivated nuclear receptor/transcription factor that regulates genes involved in toxicant metabolism and provides a major defense to environmental exposures. AHR signaling is also involved in a number of essential nonxenobiotic biological and developmental pathways (Fernandez-Salguero et al. 1995). Upon ligand binding, the AHR translocates to the nucleus, where it complexes with the AHR nuclear translocator (ARNT). The AHR/ARNT heterodimer regulates the transcription of genes in the cytochrome P450 Cyp1 family, some phase II detoxification genes, and thousands of other genes (Trask et al. 2009), including the gene expression of other nuclear receptors relevant to obesity [e.g., Ppara (peroxisome proliferator - activated receptor-[alpha])] (Wang et al. 2011). The AHR is also activated by dietary components such as fats and fat derivatives (McMillan and Bradfield 2007), and there is evidence linking the activated AHR to major diseases, including obesity (La Merrill et al. 2009).
Although several studies have examined the relationship between the AHR and fat metabolism using a model system comparing functional AHR signaling to one that is AHR deficient, none have examined the consequences resulting from different levels of AHR signaling activity. To identify a possible role for the AHR in obesity, we used two mouse models that differ at the Ahr gene (Figure 1A). The two strains were C57BL/6 (B6 strain), which naturally bears the high-affinity AHR encoded by the [Ahr.sup.b1] allele, and the congenic C57BL/6.D2 (B6.D2 strain), which bears the low-affinity AHR encoded by the [Ahr.sup.d] allele naturally found in the DBA/2 mouse strain. The two Ahr alleles encode AHRs that differ by approximately 10-fold in ligand binding affinity, as well as gene induction and gene expression levels, including that of the Cyp1a1 and Cyp1b1 xenobiotic genes (Thomas et al. …