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Animal Models

Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure

International Journal of Obesity volume 39, pages 1300–1309 (2015)Cite this article

Subjects

Abstract

Background/Objectives:

Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined.

Methods:

Male wild-type (WT), AhR null (AhR−/−) and AhR heterozygote (AhR+/−) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed.

Results:

AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared with WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR−/− and AhR+/− mice compared with WT.

Conclusions:

This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.

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References

  1. Ogden CL, Carroll MD, Kit BK, Flegal KM . Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311: 806–814.

    Article  CAS  Google Scholar 

  2. Wright SM, Aronne LJ . Causes of obesity. Abdom Imaging 2012; 37: 730–732.

    Article  Google Scholar 

  3. Berger J, Moller DE . The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409–435.

    Article  CAS  Google Scholar 

  4. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113: 159–170.

    Article  CAS  Google Scholar 

  5. He J, Gao J, Xu M, Ren S, Stefanovic-Racic M, O'Doherty RM et al. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013; 62: 1876–1887.

    Article  CAS  Google Scholar 

  6. Spruiell K, Richardson RM, Cullen JM, Awumey EM, Gonzalez FJ, Gyamfi MA . Role of pregnane X receptor in obesity and glucose homeostasis in male mice. J Biol Chem 2014; 289: 3244–3261.

    Article  CAS  Google Scholar 

  7. Henriksen GL, Ketchum NS, Michalek JE, Swaby JA . Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology 1997; 8: 252–258.

    Article  CAS  Google Scholar 

  8. Fujiyoshi PT, Michalek JE, Matsumura F . Molecular epidemiologic evidence for diabetogenic effects of dioxin exposure in U.S. Air force veterans of the Vietnam war. Environ Health Perspect 2006; 114: 1677–1683.

    Article  CAS  Google Scholar 

  9. Warner M, Mocarelli P, Brambilla P, Wesselink A, Samuels S, Signorini S et al. Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: The Seveso Women's Health Study. Environ Health Perspect 2013; 121: 906–911.

    Article  Google Scholar 

  10. Taylor KW, Novak RF, Anderson HA, Birnbaum LS, Blystone C, Devito M et al. Evaluation of the association between persistent organic pollutants (POPs) and diabetes in epidemiological studies: a national toxicology program workshop review. Environ Health Perspect 2013; 121: 774–783.

    Article  Google Scholar 

  11. Lee HK . Mitochondrial dysfunction and insulin resistance: the contribution of dioxin-like substances. Diabetes Metab J 2011; 35: 207–215.

    Article  Google Scholar 

  12. Nishiumi S, Yoshida M, Azuma T, Yoshida K, Ashida H . 2,3,7,8-tetrachlorodibenzo-p-dioxin impairs an insulin signaling pathway through the induction of tumor necrosis factor-alpha in adipocytes. Toxicol Sci 2010; 115: 482–491.

    Article  CAS  Google Scholar 

  13. He J, Hu B, Shi X, Weidert ER, Lu P, Xu M et al. Activation of the aryl hydrocarbon receptor sensitizes mice to nonalcoholic steatohepatitis by deactivating mitochondrial sirtuin deacetylase Sirt3. Mol Cell Biol 2013; 33: 2047–2055.

    Article  CAS  Google Scholar 

  14. Arsenescu V, Arsenescu RI, King V, Swanson H, Cassis LA . Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis. Environ Health Perspect 2008; 116: 761–768.

    Article  CAS  Google Scholar 

  15. 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: 1252–1259.

    Article  CAS  Google Scholar 

  16. Schmidt JV, Su GH, Reddy JK, Simon MC, Bradfield CA . Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc Natl Acad Sci USA 1996; 93: 6731–6736.

    Article  CAS  Google Scholar 

  17. Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR et al. Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 2002; 99: 419–424.

    Article  CAS  Google Scholar 

  18. Olefsky JM, Glass CK . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246.

    Article  CAS  Google Scholar 

  19. Gregor MF, Hotamisligil GS . Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415–445.

    Article  CAS  Google Scholar 

  20. Tarantino G, Finelli C . What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? World J Gastroenterol 2013; 19: 3375–3384.

    Article  CAS  Google Scholar 

  21. Ruzzin J, Petersen R, Meugnier E, Madsen L, Lock EJ, Lillefosse H et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect 2010; 118: 465–471.

    Article  CAS  Google Scholar 

  22. Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ et al. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 2010; 139: 653–663.

    Article  CAS  Google Scholar 

  23. Wang C, Xu CX, Krager SL, Bottum KM, Liao DF, Tischkau SA . Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR-alpha pathway activity in mice. Environ Health Perspect 2011; 119: 1739–1744.

    Article  CAS  Google Scholar 

  24. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914–920.

    Article  CAS  Google Scholar 

  25. Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009; 15: 921–929.

    Article  CAS  Google Scholar 

  26. Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 2009; 15: 940–945.

    Article  CAS  Google Scholar 

  27. Talukdar S, Oh da Y, Bandyopadhyay G, Li D, Xu J, McNelis J et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012; 18: 1407–1412.

    Article  CAS  Google Scholar 

  28. Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 2011; 17: 610–617.

    Article  CAS  Google Scholar 

  29. Zhou Y, Tung HY, Tsai YM, Hsu SC, Chang HW, Kawasaki H et al. Aryl hydrocarbon receptor controls murine mast cell homeostasis. Blood 2013; 121: 3195–3204.

    Article  CAS  Google Scholar 

  30. Ferre P . The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 2004; 53: S43–S50.

    Article  CAS  Google Scholar 

  31. Lee Y, Wang MY, Kakuma T, Wang ZW, Babcock E, McCorkle K et al. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem 2001; 276: 5629–5635.

    Article  CAS  Google Scholar 

  32. Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, Coleman T et al. ‘New’ hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 2005; 1: 309–322.

    Article  CAS  Google Scholar 

  33. Kajimura S, Seale P, Spiegelman BM . Transcriptional control of brown fat development. Cell Metab 2010; 11: 257–262.

    Article  CAS  Google Scholar 

  34. Kajimura S, Saito M . A new era in brown adipose tissue biology: molecular control of brown fat development and energy homeostasis. Annu Rev Physiol 2014; 76: 225–249.

    Article  CAS  Google Scholar 

  35. McMillan BJ, Bradfield CA . The aryl hydrocarbon receptor is activated by modified low-density lipoprotein. Proc Natl Acad Sci USA 2007; 104: 1412–1417.

    Article  CAS  Google Scholar 

  36. Julliard W, Fechner JH, Mezrich JD . The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both. Front Immunol 2014; 5: 458.

    Article  Google Scholar 

  37. Murray IA, Patterson AD, Perdew GH . Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014; 14: 801–814.

    Article  CAS  Google Scholar 

  38. Wang C, Zhang ZM, Xu CX, Tischkau SA . Interplay between Dioxin-mediated signaling and circadian clock: a possible determinant in metabolic homeostasis. Int J Mol Sci 2014; 15: 11700–11712.

    Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge Dr Andrzej Bartke and Cristal Hill (Southern Illinois University School of Medicine Geriatrics Research Laboratory) for helping the indirect calorimetry testing and analysis. This work was supported by grant from NIEHS (ES017774) to SAT.

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Author notes

  1. C-X Xu and C Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL, USA

    C-X Xu, C Wang, Z-M Zhang, C D Jaeger & S A Tischkau

  2. Department of Anesthesiology, Institute of Translation Medicine, The First People's Hospital of Chenzhou, Chenzhou, China

    Z-M Zhang

  3. Department of Internal Medicine, Southern Illinois University School of Medicine, Springfield, IL, USA

    S L Krager & K M Bottum

  4. Department of Metabolism and Endocrinology, The First Affiliated Hospital of University of South China, Hengyang, China

    J Liu

  5. Division of Stem Cell Regulation and Application, College of Medicine, Hunan University of Traditional Chinese Medicine, Changsha, China

    D-F Liao

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  1. C-X Xu
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Correspondence to S A Tischkau.

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Xu, CX., Wang, C., Zhang, ZM. et al. Aryl hydrocarbon receptor deficiency protects mice from diet-induced adiposity and metabolic disorders through increased energy expenditure. Int J Obes 39, 1300–1309 (2015). https://doi.org/10.1038/ijo.2015.63

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