Original Article | Published:

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 13001309 (2015) | Download Citation

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. 1.

    , , , . Prevalence of childhood and adult obesity in the United States, 2011-2012. JAMA 2014; 311: 806–814.

  2. 2.

    , . Causes of obesity. Abdom Imaging 2012; 37: 730–732.

  3. 3.

    , . The mechanisms of action of PPARs. Annu Rev Med 2002; 53: 409–435.

  4. 4.

    , , , , , et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 2003; 113: 159–170.

  5. 5.

    , , , , , et al. PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013; 62: 1876–1887.

  6. 6.

    , , , , , . Role of pregnane X receptor in obesity and glucose homeostasis in male mice. J Biol Chem 2014; 289: 3244–3261.

  7. 7.

    , , , . Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand. Epidemiology 1997; 8: 252–258.

  8. 8.

    , , . 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.

  9. 9.

    , , , , , 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.

  10. 10.

    , , , , , 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.

  11. 11.

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

  12. 12.

    , , , , . 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.

  13. 13.

    , , , , , 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.

  14. 14.

    , , , , . Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis. Environ Health Perspect 2008; 116: 761–768.

  15. 15.

    , , , , , et al. Obesity is mediated by differential aryl hydrocarbon receptor signaling in mice fed a Western diet. Environ Health Perspect 2012; 120: 1252–1259.

  16. 16.

    , , , , . 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.

  17. 17.

    , , , , , et al. Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 2002; 99: 419–424.

  18. 18.

    , . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246.

  19. 19.

    , . Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415–445.

  20. 20.

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

  21. 21.

    , , , , , et al. Persistent organic pollutant exposure leads to insulin resistance syndrome. Environ Health Perspect 2010; 118: 465–471.

  22. 22.

    , , , , , et al. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 2010; 139: 653–663.

  23. 23.

    , , , , , . Aryl hydrocarbon receptor deficiency enhances insulin sensitivity and reduces PPAR-alpha pathway activity in mice. Environ Health Perspect 2011; 119: 1739–1744.

  24. 24.

    , , , , , et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 2009; 15: 914–920.

  25. 25.

    , , , , , et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009; 15: 921–929.

  26. 26.

    , , , , , et al. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 2009; 15: 940–945.

  27. 27.

    , , , , , et al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 2012; 18: 1407–1412.

  28. 28.

    , , , , , et al. B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 2011; 17: 610–617.

  29. 29.

    , , , , , et al. Aryl hydrocarbon receptor controls murine mast cell homeostasis. Blood 2013; 121: 3195–3204.

  30. 30.

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

  31. 31.

    , , , , , et al. Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia. J Biol Chem 2001; 276: 5629–5635.

  32. 32.

    , , , , , et al. ‘New’ hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 2005; 1: 309–322.

  33. 33.

    , , . Transcriptional control of brown fat development. Cell Metab 2010; 11: 257–262.

  34. 34.

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

  35. 35.

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

  36. 36.

    , , . The aryl hydrocarbon receptor meets immunology: friend or foe? A little of both. Front Immunol 2014; 5: 458.

  37. 37.

    , , . Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 2014; 14: 801–814.

  38. 38.

    , , , . Interplay between Dioxin-mediated signaling and circadian clock: a possible determinant in metabolic homeostasis. Int J Mol Sci 2014; 15: 11700–11712.

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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.

Author information

Author notes

    • C-X Xu
    •  & C Wang

    These authors contributed equally to this work.

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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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to S A Tischkau.

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DOI

https://doi.org/10.1038/ijo.2015.63

Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)

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