Hepatic Aryl Hydrocarbon Receptor Regulation of Obesity: Mechanisms of Action

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PROJECT SUMMARY/ABSTRACT The Aryl Hydrocarbon Receptor (AhR) is a member of the eukaryotic Per-ARNT-Sim (PAS) domain protein family that regulates adaptive and toxic responses to a variety of chemical pollutants, including polycyclic aromatic hydrocarbons and polychlorinated dioxins, most notably 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We recently showed that female, but not male liver-specific AhR conditional knockout mice are protected from high fat diet-induced obesity and exhibited improved metabolic homeostasis. The sexually dimorphic phenotype was attributed to increased hepatic expression of fibroblast growth factor 21 (FGF21) in females. FGF21 is a circulating hepatokine that affects carbohydrate and lipid metabolism, and induces thermogenesis in white and brown fat deposits by uncoupling mitochondrial respiration from the electron transport chain. These properties have motivated research into the development of FGF21-based therapeutics to combat metabolic disorders and obesity, but with little success to date. Hence, understanding how AhR activity controls Fgf21 expression may point to novel strategies or targets for the development of clinical interventions. Hepatic Fgf21 expression is also under the control of sex steroids and is subject to circadian rhythms. The latter observation is of note because both the AhR and its partner protein, the AhR Nuclear Translocator (ARNT), belong to the same PAS protein family as several of the circadian rhythm (clock) proteins, including brain and muscle ARNT-like 1 (BMAL1). Hepatic AhR expression exhibits a 24 h periodicity in phase with BMAL1 oscillations, suggestive of co-regulation of these proteins. Moreover, ARNT shares considerable sequence similarity to BMAL1, and an AhR-BMAL1 interaction has been reported, implying that interactions between circadian rhythmicity and AhR signaling are reciprocal and significant. The central premise of this application is, that hepatic Fgf21 expression represents a nexus where AhR signaling and the molecular events underlying sexual dimorphism and circadian rhythmicity, coalesce. We hypothesize that a comprehensive assessment of how these physiologically disparate signaling processes are integrated is required to fully understand AhR regulated Fgf21 expression, and its impact on diet-induced obesity. To test the hypothesis, we propose experimental strategies that preserve the physiological context and genomic milieu. Specific Aim 1 will examine Fgf21 promoter functionality from the standpoint of AhR, ARNT, and BMAL1 activity as a function of circadian rhythmicity. Specific Aim 2 will use single-cell transcriptomics to identify diurnal changes in liver gene expression due to AhR, ARNT, and BMAL1 activity. Specific Aim 3 will interrogate sexually dimorphic Fgf21 expression as a function of estrogenicity. The Specific Aims constitute distinct yet integrated endeavors to mechanistically understand how the AhR regulates Fgf21 expression in the liver, under experimental conditions that preserve the physiological processes responsible for the sexual dimorphism and circadian rhythmicity in the context of a native genomic milieu that retains normal chromatin architecture.