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1.
Obesity (Silver Spring) ; 29(2): 337-349, 2021 02.
Article in English | MEDLINE | ID: mdl-33491319

ABSTRACT

OBJECTIVE: The aryl hydrocarbon receptor (AHR) plays a key role in obesity. In vitro studies revealed that the tryptophan metabolite kynurenine (Kyn) activates AHR signaling in cultured hepatocytes. The objective of this study was to determine whether Kyn activated the AHR in mice to induce obesity. METHODS: Mice were fed a low-fat diet and the same diet supplemented with Kyn. Body mass, liver status, and the expression of identified relevant genes were determined. RESULTS: Kyn caused mice to gain significant body mass, develop fatty liver and hyperglycemia, and increase expression levels of cytochrome P450 1B1 and stearoyl-CoA desaturase 1. The hyperglycemia was accompanied with decreased insulin levels, which may have been due to the repression of genes involved in insulin secretion. Kyn plasma concentrations and BMI were measured in female patients, and a significant association was observed between Kyn and age in patients with obesity but not in patients who were lean. CONCLUSIONS: Results show that (1) Kyn or a metabolite thereof is a ligand responsible for inducing AHR-based obesity, fatty liver, and hyperglycemia in mice; (2) plasma Kyn levels increase with age in women with obesity but not in lean women; and (3) an activated AHR is necessary but not sufficient to attain obesity, a status that also requires fat in the diet.


Subject(s)
Fatty Liver/metabolism , Hyperglycemia/chemically induced , Kynurenine/pharmacology , Receptors, Aryl Hydrocarbon/metabolism , Weight Gain/drug effects , Animals , Liver/drug effects , Mice , Signal Transduction/drug effects
2.
Int J Obes (Lond) ; 44(4): 948-963, 2020 04.
Article in English | MEDLINE | ID: mdl-31911663

ABSTRACT

BACKGROUND/OBJECTIVES: Obesity is a global epidemic and the underlying basis for numerous comorbidities. We report that the aryl hydrocarbon receptor (AHR) plays a key role in the metabolism of obesity. The AHR is a promiscuous, ligand-activated nuclear receptor primarily known for regulating genes involved in xenobiotic metabolism and T cell polarization. The aims of the work reported here were to understand the underlying mechanism of AHR-based obesity and to determine whether inhibition of AHR activity would reverse obesity. METHODS: Mice were fed control (low fat) and Western (high fat) diets with and without the AHR antagonist alpha-naphthoflavone (aNF). Gene expression of identified AHR-regulated genes from liver and adipose tissue was characterized. To determine the role of the AHR in obesity reversal, selected mice in control and Western diet regimens were switched at midpoint to the respective control and Western diets containing aNF, and the identified AHR-regulated genes characterized. RESULTS: AHR inhibition prevented obesity in mice on a 40-week diet regimen. The likely AHR-regulated and cross-regulated downstream effectors of AHR-based obesity were shown to be CYP1B1, PPARα-target genes, SCD1, and SPP1 (osteopontin). Western diet caused an increase of mRNA and protein expression of the Cyp1b1, Scd1, and Spp1, and PPARα-target genes in the liver, and inhibition of the AHR maintained expression of these genes near control levels. The body weight of obese mice on Western diet switched to Western diet containing aNF decreased to that of mice on control diet concurrently with a reduction in the expression of liver CYP1B1, PPARα-target genes, SCD1, and SPP1. AHR inhibition prevented hypertrophy and hyperplasia in visceral adipose tissue and limited expression levels of CYP1B1 and SPP1 to that of mice on control diet. CONCLUSIONS: AHR inhibition prevents and reverses obesity by likely reducing liver expression of the Cyp1b1, Scd1, Spp1, and PPARα-target genes; and the AHR is a potentially potent therapeutic target for the treatment and prevention of obesity and linked diseases.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Cytochrome P-450 CYP1B1 , Fatty Liver/metabolism , Obesity/metabolism , PPAR alpha , Receptors, Aryl Hydrocarbon , Adipose Tissue/chemistry , Adipose Tissue/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cytochrome P-450 CYP1B1/genetics , Cytochrome P-450 CYP1B1/metabolism , Male , Mice , Mice, Inbred C57BL , Osteopontin/genetics , Osteopontin/metabolism , PPAR alpha/genetics , PPAR alpha/metabolism , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Stearoyl-CoA Desaturase/genetics , Stearoyl-CoA Desaturase/metabolism
3.
Nutr Res ; 44: 38-50, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28821316

ABSTRACT

Inhibition of the aryl hydrocarbon receptor (AHR) prevents Western diet-induced obesity and fatty liver in C57Bl/6J (B6) male mice. The AHR is a ligand-activated nuclear receptor that regulates genes involved in xenobiotic metabolism and T-cell differentiation. Here, we tested the hypothesis that AHR antagonism would also prevent obesity and fatty liver in female mice and that B6 mice (higher-affinity AHR) and congenic B6.D2 mice (lower-affinity AHR) would differentially respond to AHR inhibition. Female and male adult B6 and B6.D2 mice were fed control and Western diets with and without α-naphthoflavone (NF), an AHR inhibitor. A nonlinear mixed-model analysis was developed to project asymptote body mass. We found that obesity, adiposity, and liver steatosis were reduced to near control levels in all female and male B6 and B6.D2 experimental groups fed Western diet with NF. However, differences were noted in that female B6.D2 vs B6 mice on Western diet became more obese; and in general, female mice compared with male mice had a greater fat mass to body mass ratio, were less responsive to NF, and had reduced liver steatosis and hepatomegaly. We report that male mice fed Western diet containing NF or CH-223191, another AHR inhibitor, caused reduced mRNA levels of several liver genes involved in metabolism, including Cyp1b1 and Scd1, offering evidence for a possible mechanism by which the AHR regulates obesity. In conclusion, although there are some sex- and Ahr allelic-dependent differences, AHR inhibition prevents obesity and liver steatosis in both males and females regardless of the ligand-binding capacity of the AHR. We also present evidence consistent with the notion that an AHR-CYP1B1-SCD1 axis is involved in obesity, providing potentially convenient and effective targets for treatment.


Subject(s)
Benzoflavones/pharmacology , Fatty Liver/prevention & control , Obesity/prevention & control , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Adiposity/drug effects , Animals , Azo Compounds/pharmacology , Cytochrome P-450 CYP1B1/genetics , Cytochrome P-450 CYP1B1/metabolism , Diet, Western , Female , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Pyrazoles/pharmacology , Stearoyl-CoA Desaturase/genetics , Stearoyl-CoA Desaturase/metabolism
4.
Toxicol Appl Pharmacol ; 323: 74-80, 2017 05 15.
Article in English | MEDLINE | ID: mdl-28336214

ABSTRACT

Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/agonists , Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Receptors, Aryl Hydrocarbon/agonists , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Cytochrome P-450 CYP1A1/biosynthesis , Cytochrome P-450 CYP1A1/genetics , Enzyme Induction , Enzyme Inhibitors/toxicity , Genes, Reporter , Hep G2 Cells , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Ligands , Mice , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Risk Assessment , Transcription, Genetic , Transfection
5.
Toxicol Appl Pharmacol ; 300: 13-24, 2016 06 01.
Article in English | MEDLINE | ID: mdl-27020609

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 ß1 (TGFß1) 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 TGFß1 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.


Subject(s)
Azo Compounds/pharmacology , Diet, Western , Kynurenine/biosynthesis , Obesity/prevention & control , Pyrazoles/pharmacology , Receptors, Aryl Hydrocarbon/antagonists & inhibitors , Adiposity , Animals , Benzoflavones/pharmacology , Fatty Liver/prevention & control , Hepatocytes/drug effects , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Intra-Abdominal Fat/drug effects , Lipids/blood , Lipoproteins, LDL , Male , Mice , Mice, Inbred C57BL , Signal Transduction , Toll-Like Receptor 2/metabolism , Transforming Growth Factor beta/metabolism
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