title: Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.
abstract: Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Moyer
authors.affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Itzel Y
authors.initials: IY
authors.lastname: Rojas
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Kerley-Hamilton
authors.affiliation: Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Department of Immunology & Microbiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Haley F
authors.initials: HF
authors.lastname: Hazlett
authors.affiliation: Department of Radiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Krishnamurthy V
authors.initials: KV
authors.lastname: Nemani
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Heidi W
authors.initials: HW
authors.lastname: Trask
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: West
authors.affiliation: Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Lupien
authors.affiliation: Department of Immunology & Microbiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Collins
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Carol S
authors.initials: CS
authors.lastname: Ringelberg
authors.affiliation: Department of Radiology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: Barjor
authors.initials: B
authors.lastname: Gimi
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States.
authors.forename: William B
authors.initials: WB
authors.lastname: Kinlaw
authors.affiliation: Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Department of Medicine, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States; Department of Pharmacology & Toxicology, Geisel School of Medicine at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756, United States. Electronic address: Craig.R.Tomlinson@Dartmouth.edu.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Tomlinson
mesh_terms: D050154:Adiposity; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D066273:Diet, Western; D005234:Fatty Liver / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000187:drug effects; D007737:Kynurenine / Q000096:biosynthesis*; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000517:prevention & control*; D011720:Pyrazoles / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D001571:Benzoflavones; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008055:Lipids; D008077:Lipoproteins, LDL; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; C099252:oxidized low density lipoprotein; D007737:Kynurenine; C011512:alpha-naphthoflavone
keywords: Aryl hydrocarbon receptor; Liver steatosis; Obesity; TLR2/TGFβ/PI3K/NF-κB/IDO1/AHR axis; α-Naphthoflavone and CH-223191