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.
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.
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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $33.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Any data and materials not in the public domain that were generated from these reported studies will be made available upon request.
Hales CM, Fryar CD, Carroll MD, Freedman DS, Ogden CL. Trends in obesity and severe obesity prevalence in us youth and adults by sex and age, 2007–2008 to 2015–2016. JAMA. 2018;319:1723–5.
De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011;32:373–9.
Naukkarinen J, Rissanen A, Kaprio J, Pietilainen KH. Causes and consequences of obesity: the contribution of recent twin studies. Int J Obes. 2012;36:1017–24.
Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815–25.
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898–918.
van den Brandt PA, Spiegelman D, Yaun S-S, Adami H-O, Beeson L, Folsom AR, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 2000;152:514–27.
Cawley J, Meyerhoefer C. The medical care costs of obesity: an instrumental variables approach. J Health Econ. 2012;31:219–30.
Rask-Andersen M, Karlsson T, Ek WE, Johansson Å. Gene-environment interaction study for BMI reveals interactions between genetic factors and physical activity, alcohol consumption and socioeconomic status. PLoS Genet. 2017;13:e1006977.
Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42:937–48.
Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518:197–206.
Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science. 1998;280:1371–4.
Moyer BJ, Rojas IY, Kerley-Hamilton JS, Nemani KV, Trask HW, Ringelberg CS, et al. Obesity and fatty liver are prevented by inhibition of the aryl hydrocarbon receptor in both female and male mice. Nutr Res. 2017;44:38–50.
Moyer BJ, Rojas IY, Kerley-Hamilton JS, Hazlett HF, Nemani KV, Trask HW, et al. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFbeta, and IDO1. Toxicol Appl Pharmacol. 2016;300:13–24.
Kerley-Hamilton JS, Trask HW, Ridley CJ, Dufour E, Ringelberg CS, Nurinova N, et al. Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet. Environ Health Perspect. 2012;120:1252–9.
Lahvis GP, Lindell SL, Thomas RS, McCuskey RS, Murphy C, Glover E, et al. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc Natl Acad Sci USA. 2000;97:10442–7.
Nebert DW, Puga A, Vasiliou V. Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci. 1993;685:624–40.
Guo J, Sartor M, Karyala S, Medvedovic M, Kann S, Puga A, et al. Expression of genes in the TGF-beta signaling pathway is significantly deregulated in smooth muscle cells from aorta of aryl hydrocarbon receptor knockout mice. Toxicol Appl Pharmacol. 2004;194:79–89.
Puga A, Sartor MA, Huang M, Kerzee JK, Wei Y, Tomlinson CR, et al. Gene expression profiles of mouse aorta and cultured vascular muscle cells are widely different yet show common responses to dioxin exposure. Cardiovasc Toxicol. 2004;4:385–404.
Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185:3190–8.
Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65.
Quintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive immunity. Pharmacol Rev. 2013;65:1148–61.
Kim SH, Henry EC, Kim DK, Kim YH, Shin KJ, Han MS, et al. Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor. Mol Pharmacol. 2006;69:1871–8.
Zhao B, DeGroot DE, Hayashi A, He G, Denison MS. CH223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. Toxicol Sci. 2010;117:393–403.
Smith KJ, Murray IA, Tanos R, Tellew J, Boitano AE, Bisson WH, et al. Identification of a high-affinity ligand that exhibits complete aryl hydrocarbon receptor antagonism. J Pharmacol Exp Ther. 2011;338:318–27.
Nguyen NT, Hanieh H, Nakahama T, Kishimoto T. The roles of aryl hydrocarbon receptor in immune responses. Int Immunol. 2013;25:335–43.
Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc Natl Acad Sci USA. 2010;107:19961–6.
Veldhoen M, Hirota K, Christensen J, O'Garra A, Stockinger B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med. 2009;206:43–9.
Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. J Am Med Assoc. 2014;311:74–86.
Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Ando T, Ito H, et al. Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. Cancer Sci. 2015;106:1008–15.
Wang X, Wang Q, Morris ME. Pharmacokinetic interaction between the flavonoid luteolin and gamma-hydroxybutyrate in rats: potential involvement of monocarboxylate transporters. AAPS J. 2008;10:47–55.
Jeffery E, Berry R, Church CD, Yu S, Shook BA, Horsley V, et al. Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte. 2014;3:206–11.
Jeffery E, Church CD, Holtrup B, Colman L, Rodeheffer MS. Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol. 2015;17:376.
Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45:593–605.
Berry R, Rodeheffer MS. Characterization of the adipocyte cellular lineage in vivo. Nat Cell Biol. 2013;15:302.
Irizarry RA, Bolstad BM, Collin F, Cope LM, Hobbs B, Speed TP. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 2003;31:e15.
Wright GW, Simon RM. A random variance model for detection of differential gene expression in small microarray experiments. Bioinformatics. 2003;19:2448–55.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.
Wang C, Xu C-X, Krager SL, Bottum KM, Liao D-F, Tischkau SA. Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR-α pathway activity in mice. Environ Health Perspect. 2011;119:1739–44.
Xu CX, Wang C, Zhang ZM, Jaeger CD, Krager SL, Bottum KM, et al. Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure. Int J Obes. 2015;39:1300–9.
Larsen MC, Bushkofsky JR, Gorman T, Adhami V, Mukhtar H, Wang S, et al. Cytochrome P450 1B1: an unexpected modulator of liver fatty acid homeostasis. Arch Biochem Biophys. 2015;571:21–39.
Li F, Jiang C, Larsen MC, Bushkofsky J, Krausz KW, Wang T, et al. Lipidomics reveals a link between CYP1B1 and SCD1 in promoting obesity. J Proteome Res. 2014;13:2679–87.
Liu X, Huang T, Li L, Tang Y, Tian Y, Wang S, et al. CYP1B1 deficiency ameliorates obesity and glucose intolerance induced by high fat diet in adult C57BL/6J mice. Am J Transl Res. 2015;7:761–71.
Girer NG, Carter D, Bhattarai N, Mustafa M, Denner L, Porter C, et al. Inducible loss of the aryl hydrocarbon receptor activates perigonadal white fat respiration and brown fat thermogenesis via fibroblast growth factor 21. Int J Mol Sci. 2019; 20:e950.
Jungermann K, Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr. 1996;16:179–203.
Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev. 1989;69:708–64.
Braeuning A, Ittrich C, Köhle C, Hailfinger S, Bonin M, Buchmann A, et al. Differential gene expression in periportal and perivenous mouse hepatocytes. FEBS J. 2006;273:5051–61.
Walker NJ, Crofts FG, Li Y, Lax SF, Hayes CL, Strickland PT, et al. Induction and localization of cytochrome P450 1B1 (CYP1B1) protein in the livers of TCDD-treated rats: detection using polyclonal antibodies raised to histidine-tagged fusion proteins produced and purified from bacteria. Carcinogenesis. 1998;19:395–402.
Ferre P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004;53(Suppl 1):S43–50.
Flowers MT, Ntambi JM. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr Opin Lipidol. 2008;19:248–56.
Liu X, Miyazaki M, Flowers MT, Sampath H, Zhao M, Chu K, et al. Loss of Stearoyl-CoA desaturase-1 attenuates adipocyte inflammation: effects of adipocyte-derived oleate. Arterioscler Thromb Vasc Biol. 2010;30:31–38.
Sessler AM, Kaur N, Palta JP, Ntambi JM. Regulation of stearoyl-CoA desaturase 1 mRNA stability by polyunsaturated fatty acids in 3T3-L1 adipocytes. J Biol Chem. 1996;271:29854–8.
Choudhary D, Jansson I, Stoilov I, Sarfarazi M, Schenkman JB. Metabolism of retinoids and arachidonic acid by human and mouse cytochrome P4501B1. Drug Metab Dispos. 2004;32:840–7.
Murakami M, Kudo I. Phospholipase A2. J Biochem. 2002;131:285–92.
Chuang CY, Chang H, Lin P, Sun SJ, Chen PH, Lin YY, et al. Up-regulation of osteopontin expression by aryl hydrocarbon receptor via both ligand-dependent and ligand-independent pathways in lung cancer. Gene. 2012;492:262–9.
Palenski TL, Sorenson CM, Jefcoate CR, Sheibani N. Lack of Cyp1b1 promotes the proliferative and migratory phenotype of perivascular supporting cells. Lab Investig. 2013;93:646–62.
Lancha A, Rodriguez A, Catalan V, Becerril S, Sainz N, Ramirez B, et al. Osteopontin deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice. PLoS One. 2014;9:e98398.
Shehin SE, Stephenson RO, Greenlee WF. Transcriptional regulation of the human CYP1B1 gene: evidence for involvement of an aryl hydrocarbon receptor response element in constitutive expression. J Biol Chem. 2000;275:6770–6.
Ellero S, Chakhtoura G, Barreau C, Langouet S, Benelli C, Penicaud L, et al. Xenobiotic-metabolizing cytochromes p450 in human white adipose tissue: expression and induction. Drug Metab Dispos. 2010;38:679–86.
Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Izaguirre M, Hernandez-Lizoain JL, et al. Increased obesity-associated circulating levels of the extracellular matrix proteins osteopontin, chitinase-3 like-1 and tenascin c are associated with colon cancer. PLoS ONE. 2016;11:e0162189.
Santostefano M, Merchant M, Arellano L, Morrison V, Denison MS, Safe S. alpha-Naphthoflavone-induced CYP1A1 gene expression and cytosolic aryl hydrocarbon receptor transformation. Mol Pharmacol. 1993;43:200–6.
Guerre-Millo M, Rouault C, Poulain P, André J, Poitout V, Peters JM, et al. PPAR-α–null mice are protected from high-fat diet–induced insulin resistance. Diabetes. 2001;50:2809–14.
Sampath H, Flowers MT, Liu X, Paton CM, Sullivan R, Chu K, et al. Skin-specific deletion of stearoyl-CoA desaturase-1 alters skin lipid composition and protects mice from high fat diet-induced obesity. J Biol Chem. 2009;284:19961–73.
Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, et al. Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci USA. 2002;99:11482–6.
Zhang L, Savas U, Alexander DL, Jefcoate CR. Characterization of the mouse Cyp1B1 gene. Identification of an enhancer region that directs aryl hydrocarbon receptor-mediated constitutive and induced expression. J Biol Chem. 1998;273:5174–83.
Angrish MM, Jones AD, Harkema JR, Zacharewski TR. Aryl hydrocarbon receptor-mediated induction of stearoyl-CoA desaturase 1 alters hepatic fatty acid composition in TCDD-elicited steatosis. Toxicol Sci. 2011;124:299–310.
Bushkofsky JR, Maguire M, Larsen MC, Fong YH, Jefcoate CR. Cyp1b1 affects external control of mouse hepatocytes, fatty acid homeostasis and signaling involving HNF4alpha and PPARalpha. Arch Biochem Biophys. 2016;597:30–47.
Miller CW, Ntambi JM. Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression. Proc Natl Acad Sci USA. 1996;93:9443–8.
Nakamachi T, Nomiyama T, Gizard F, Heywood EB, Jones KL, Zhao Y, et al. PPARalpha agonists suppress osteopontin expression in macrophages and decrease plasma levels in patients with type 2 diabetes. Diabetes. 2007;56:1662–70.
Bennett M, Gilroy DW. Lipid mediators in inflammation. Microbiol Spectr. 2016;4, https://doi.org/10.1128/microbiolspec.MCHD-0035-2016.
Kinehara M, Fukuda I, Yoshida K, Ashida H. Aryl hydrocarbon receptor-mediated induction of the cytosolic phospholipase A(2)alpha gene by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mouse hepatoma Hepa-1c1c7 cells. J Biosci Bioeng. 2009;108:277–81.
Miyazaki M, Flowers MT, Sampath H, Chu K, Otzelberger C, Liu X, et al. Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab. 2007;6:484–96.
Dobrzyn P, Dobrzyn A, Miyazaki M, Cohen P, Asilmaz E, Hardie DG, et al. Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci USA. 2004;101:6409–14.
Tanos R, Murray IA, Smith PB, Patterson A, Perdew GH. Role of the Ah receptor in homeostatic control of fatty acid synthesis in the liver. Toxicol Sci. 2012;129:372–9.
Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–33.
Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA. 1997;94:4312–7.
Subhash PK, David SG, David RJ, Letts LG. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. 2007;7:311–40.
Kahles F, Findeisen HM, Bruemmer D. Osteopontin: a novel regulator at the cross roads of inflammation, obesity and diabetes. Mol Metab. 2014;3:384–93.
Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem. 2018;59:17–24.
Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB, et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Investig. 2007;117:2877–88.
Lund SA, Giachelli CM, Scatena M. The role of osteopontin in inflammatory processes. J Cell Commun Signal. 2009;3:311–22.
Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology. 2008;134:1369–75.
Henderson Colin J, McLaughlin Lesley A, Osuna-Cabello M, Taylor M, Gilbert I, McLaren Aileen W, et al. Application of a novel regulatable Cre recombinase system to define the role of liver and gut metabolism in drug oral bioavailability. Biochem J. 2015;465:479–88.
Shimizu Y, Nakatsuru Y, Ichinose M, Takahashi Y, Kume H, Mimura J, et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci USA. 2000;97:779–82.
Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J, Siliart B, et al. Liver lipid metabolism. J Anim Physiol Anim Nutr. 2008;92:272–83.
Tanos R, Patel RD, Murray IA, Smith PB, Patterson AD, Perdew GH. Aryl hydrocarbon receptor regulates the cholesterol biosynthetic pathway in a dioxin response element-independent manner. Hepatology. 2012;55:1994–2004.
Bazotte RB, Silva LG, Schiavon FP. Insulin resistance in the liver: deficiency or excess of insulin? Cell Cycle. 2014;13:2494–500.
Michalopoulos GK. Hepatostat: liver regeneration and normal liver tissue maintenance. Hepatology. 2017;65:1384–92.
Grandone A, Di Sessa A, Umano GR, Toraldo R, Miraglia del Giudice E. New treatment modalities for obesity. Best Pract Res Clin Endocrinol Metab. 2018;32:535–49.
Hubbard TD, Liu Q, Murray IA, Dong F, Miller C, Smith PB, et al. Microbiota metabolism promotes synthesis of the human Ah receptor agonist 2,8-dihydroxyquinoline. J Proteome Res. 2019;18:1715–24.
We thank the editors and reviewers for their thoughtful comments. The authors acknowledge the following core facilities: Genomics & Molecular Biology Shared Resource, Clinical Pharmacology Shared Resource, Irradiation, Pre-clinical Imaging & Microscopy Shared Resource, and Pathology Shared Resource at the Norris Cotton Cancer Center at Dartmouth with NCI Cancer Center Support Grant 5P30CA023108-40.
This work was supported by funding from NCI 5P30CA023108-40, NIH-NCRR award 5P20RR024475-02, NIH-NIGMS award 8P20GM103534-02, and a NCCC Prouty Pilot Award.
The studies with mice (Mus musculus) were conducted using an animal protocol approved by the Dartmouth Hitchcock Medical Center Institutional Animal Care and Use Committee, IACUC PROTOCOL NUMBER toml.cr.1#2(m5ar5), ASSURANCE NUMBER A3259-01.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Rojas, I.Y., Moyer, B.J., Ringelberg, C.S. et al. Reversal of obesity and liver steatosis in mice via inhibition of aryl hydrocarbon receptor and altered gene expression of CYP1B1, PPARα, SCD1, and osteopontin. Int J Obes 44, 948–963 (2020). https://doi.org/10.1038/s41366-019-0512-z
Kynurenine‐Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia
Induction of aryl hydrocarbon receptor in granulosa cells by endoplasmic reticulum stress contributes to pathology of polycystic ovary syndrome
Molecular Human Reproduction (2021)
Deciphering Biochemical and Molecular Signatures Associated with Obesity in Context of Metabolic Health
Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner
American Journal of Physiology-Endocrinology and Metabolism (2020)
The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands
International Journal of Molecular Sciences (2020)