Aryl hydrocarbon receptor-deficient mice are protected from high fat diet-induced changes in metabolic rhythms

Jan 20, 2017Chronobiology international

Mice lacking a specific receptor avoid metabolism changes caused by a high-fat diet

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Abstract

High fat diet (HFD) consumption for 15 weeks significantly disrupted serum glucose rhythms in wild-type mice.

HFD altered the circadian timing system, affecting transcriptional oscillations in metabolism.
Activation of the aryl hydrocarbon receptor (AhR) is linked to changes in circadian rhythmicity.
AhR-deficient mice showed protection against metabolic dysfunction, with improved insulin sensitivity and glucose tolerance.
AhR reduction preserved the rhythmicity of serum glucose and metabolic gene expression during HFD feeding.
These findings indicate that AhR signaling may play a critical role in metabolic regulation.

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High fat diet (HFD) consumption alters the synchronized circadian timing system resulting in harmful loss, gain or shift of transcriptional oscillations. The aryl hydrocarbon receptor (AhR) shares structural homology to clock genes, containing both PAS domains and basic helix-loop helix structural motifs, allowing for interaction with components of the primary circadian feedback loop. Activation of AhR alters circadian rhythmicity, primarily through inhibition of Clock/Bmal1-mediated regulation of Per1. AhR-deficient mice are protected from diet-induced metabolic dysfunction, exhibiting enhanced insulin sensitivity and glucose tolerance. This study examined whether AhR haploinsufficiency can also protect against diet-induced alterations in rhythm. After feeding AhR+/+ and AhR+/- mice an HFD (60% fat) for 15 weeks, samples were collected every 4 hours over a 24-hour period. HFD altered the rhythm of serum glucose and the metabolic transcriptome, including hepatic nuclear receptors Rev-erbα and PPARγ in wild-type c57bl6/j mice. AhR reduction provided protection against diet-induced transcriptional oscillation changes; serum glucose and metabolic gene rhythms were protected from the disruption caused by HFD feeding. These data highlight the critical role of AhR signaling in the regulation of metabolism and provide a potential therapeutic target for diseases characterized by rhythmic desynchrony.

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Aryl hydrocarbon receptor-deficient mice are protected from high fat diet-induced changes in metabolic rhythms

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