The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands

Abstract

The aryl hydrocarbon receptor (AHR) has been studied for over 40 years, yet our understanding of this ligand-activated transcription factor remains incomplete. Each year, novel findings continually force us to rethink the role of the AHR in mammalian biology. The AHR has historically been studied within the context of potent activation via AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with a focus on how the AHR mediates TCDD toxicity. Research has subsequently revealed that the AHR is actively involved in distinct physiological processes ranging from the development of the liver and reproductive organs, to immune system function and wound healing. More recently, the AHR was implicated in the regulation of energy metabolism and is currently being investigated as a potential therapeutic target for obesity. In this review, we re-trace the steps through which the early toxicological studies of TCDD led to the conceptual framework for the AHR as a potential therapeutic target in metabolic disease. We additionally discuss the key discoveries that have been made concerning the role of the AHR in energy metabolism, as well as the current and future directions of the field.

New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases

“…The aromatic hydrocarbon receptor (AhR) is distributed in almost all tissues in various mammals and is expressed abundantly in the placenta, liver, and lungs, where it plays multiple roles in regulating the immune response, carcinogenesis, metabolic diseases, and neurophysiology ( Xue et al, 2018 ; Girer et al, 2020 ; Vogel et al, 2020 ). In the gut, AhR is expressed in epithelial cells and immune cells ( Nguyen et al, 2013 ; Ikuta et al, 2016 ).…”

DNA methylation profile of liver of mice conceived by in vitro fertilization

“…The AhR is a highly conserved transcription factor that integrates environmental cues and metabolic processes, particularly the regulation of energy metabolism. 63,64 Mice expressing a constitutively active form of AhR spontaneously develop hepatic steatosis, possibly secondary to increased fatty acid import, suppression of fatty acid oxidation, and increased oxidative stress. 65 Global Ahr loss enhances insulin sensitivity and glucose tolerance and reduces the activity of the PPARα pathway that regulates fatty acid oxidation and glucose metabolism.…”

Bioinformatics analysis of differentially expressed genes in non alcoholic fatty liver disease using next generation sequencing data

“…Hsa-mir-199a-5p [698], GATA2 [706], FOXP2 [707] and AHR (aryl hydrocarbon receptor) [708] have been demonstrated to function in hypertension, but these genes might be novel targets for NAFLD. Previous studies have demonstrated that hsa-mir-22-5p [709], hsa-mir-150-5p [710], RUNX1 [711], TP53 [712], AHR (aryl hydrocarbon receptor) [713] and TRIM28 [714] are an independent prognostic factor in obesity and might be associated with obesity pathogenesis, but these genes might be novel targets for NAFLD. Wang et al [715], Lu et al [716], Shi et al [717], Yu et al [718], Zhang et al [719] and Ren et al [720] reported that altered expression of hsa-mir-3613-3p, hsa-mir-103a-3p, hsa-mir-150-5p, GATA2, RUNX1 and AHR (aryl hydrocarbon receptor) correlated in patients with kidney disease, but these genes might be novel targets for NAFLD.…”