Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling

Nature Medicine volume 23, pages 829–838 (2017)Cite this article

Subjects

An Erratum to this article was published on 01 October 2017

This article has been updated

Abstract

Nonalcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the disease spectrum in humans, including bridging hepatic fibrosis. Here we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high-fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways that are associated with the disease in humans. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the IL-17 axis resulted in altered immune responsiveness and protection from thermoneutral-housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full disease characteristics at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Thermoneutral housing relieves stress and augments inflammation.
Figure 2: Thermoneutral housing exacerbates HFD-driven NAFLD pathogenesis.
Figure 3: Thermoneutral housing is associated with augmented intestinal permeability and dysbiosis of the microbiome.
Figure 4: Thermoneutral-housing-driven modulation of hematopoietic TLR4 signaling regulates NAFLD progression.
Figure 5: Thermoneutral housing is associated with pathogenic upregulation of the IL-17 axis.
Figure 6: Thermoneutral housing removes the barrier to modeling obesity and NAFLD in female mice.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Change history

  • 21 June 2017

    In the version of this article initially published online, a grant supporting the authors’ work was omitted from the Acknowledgments section. The grant “NIH T32AI118697 (associated with D.A.G.)” has now been added. The error has been corrected in the print, PDF and HTML versions of this article.

References

  1. Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rinella, M.E. Will the increased prevalence of nonalcoholic steatohepatitis (NASH) in the age of better hepatitis C virus therapy make NASH the deadlier disease? Hepatology 54, 1118–1120 (2011).

    Article  PubMed  Google Scholar 

  3. Tiniakos, D.G., Vos, M.B. & Brunt, E.M. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu. Rev. Pathol. 5, 145–171 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Rahman, K. et al. Loss of junctional adhesion molecule A promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 151, 733–746 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Mehal, W.Z. The Gordian Knot of dysbiosis, obesity and NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 637–644 (2013).

    Article  PubMed  Google Scholar 

  6. Zhu, L. et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57, 601–609 (2013).

    Article  CAS  PubMed  Google Scholar 

  7. Miele, L. et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology 49, 1877–1887 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Vespasiani-Gentilucci, U. et al. Hepatic Toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int. 35, 569–581 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Kiziltas, S. et al. TLR4 gene polymorphism in patients with nonalcoholic fatty liver disease in comparison to healthy controls. Metab. Syndr. Relat. Disord. 12, 165–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Mills, K.H. TLR-dependent T cell activation in autoimmunity. Nat. Rev. Immunol. 11, 807–822 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Harley, I.T. et al. IL-17 signaling accelerates the progression of nonalcoholic fatty liver disease in mice. Hepatology 59, 1830–1839 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Rau, M. et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J. Immunol. 196, 97–105 (2016).

    Article  CAS  PubMed  Google Scholar 

  13. Hebbard, L. & George, J. Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 8, 35–44 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Karp, C.L. Unstressing intemperate models: how cold stress undermines mouse modeling. J. Exp. Med. 209, 1069–1074 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gordon, C.J. Temperature Regulation in Laboratory Rodents (Cambridge University Press, 1993).

  16. Maloney, S.K., Fuller, A., Mitchell, D., Gordon, C. & Overton, J.M. Translating animal model research: does it matter that our rodents are cold? Physiology (Bethesda) 29, 413–420 (2014).

    CAS  Google Scholar 

  17. Stemmer, K. et al. Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice. Int. J. Obes. (Lond) 39, 791–797 (2015).

    Article  CAS  Google Scholar 

  18. Bowers, S.L., Bilbo, S.D., Dhabhar, F.S. & Nelson, R.J. Stressor-specific alterations in corticosterone and immune responses in mice. Brain Behav. Immun. 22, 105–113 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Giles, D.A. et al. Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice. Mol. Metab. 5, 1121–1130 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rudaya, A.Y., Steiner, A.A., Robbins, J.R., Dragic, A.S. & Romanovsky, A.A. Thermoregulatory responses to lipopolysaccharide in the mouse: dependence on the dose and ambient temperature. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R1244–R1252 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Moragues, V. & Pinkerton, H. Variation in morbidity and mortality of murine typhus infection in mice with changes in the environmental temperature. J. Exp. Med. 79, 41–43 (1944).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Foxman, E.F. et al. Temperature-dependent innate defense against the common cold virus limits viral replication at warm temperature in mouse airway cells. Proc. Natl. Acad. Sci. USA 112, 827–832 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Eng, J.W. et al. Housing temperature–induced stress drives therapeutic resistance in murine tumour models through β2-adrenergic receptor activation. Nat. Commun. 6, 6426 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Tian, X.Y. et al. Thermoneutral housing accelerates metabolic inflammation to potentiate atherosclerosis but not insulin resistance. Cell Metab. 23, 165–178 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Athyros, V.G. et al. Cardiovascular risk across the histological spectrum and the clinical manifestations of non-alcoholic fatty liver disease: an update. World J. Gastroenterol. 21, 6820–6834 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kox, M. et al. Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans. Proc. Natl. Acad. Sci. USA 111, 7379–7384 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hanssen, M.J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Overton, J.M. Phenotyping small animals as models for the human metabolic syndrome: thermoneutrality matters. Int. J. Obes. (Lond) 34 (Suppl. 2), S53–S58 (2010).

    Article  Google Scholar 

  29. Swoap, S.J. et al. Vagal tone dominates autonomic control of mouse heart rate at thermoneutrality. Am. J. Physiol. Heart Circ. Physiol. 294, H1581–H1588 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Emre, Y. & Nübel, T. Uncoupling protein UCP2: when mitochondrial activity meets immunity. FEBS Lett. 584, 1437–1442 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Bhattacharyya, S., Brown, D.E., Brewer, J.A., Vogt, S.K. & Muglia, L.J. Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109, 4313–4319 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Izeboud, C.A., Mocking, J.A., Monshouwer, M., van Miert, A.S. & Witkamp, R.F. Participation of β-adrenergic receptors on macrophages in modulation of LPS-induced cytokine release. J. Recept. Signal Transduct. Res. 19, 191–202 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Emre, Y. et al. Mitochondria contribute to LPS-induced MAPK activation via uncoupling protein UCP2 in macrophages. Biochem. J. 402, 271–278 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wahle, M. et al. β2-adrenergic receptors mediate the differential effects of catecholamines on cytokine production of PBMC. J. Interferon Cytokine Res. 25, 384–394 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brunt, E.M., Kleiner, D.E., Wilson, L.A., Belt, P. & Neuschwander-Tetri, B.A. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 53, 810–820 (2011).

    Article  CAS  PubMed  Google Scholar 

  37. Nagaya, T. et al. Down-regulation of SREBP-1c is associated with the development of burned-out NASH. J. Hepatol. 53, 724–731 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Rizki, G. et al. Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1. J. Lipid Res. 47, 2280–2290 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Teufel, A. et al. Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients. Gastroenterology 151, 513–525 (2016).

    Article  CAS  PubMed  Google Scholar 

  40. Brown, M.P. et al. Knowledge-based analysis of microarray gene expression data by using support vector machines. Proc. Natl. Acad. Sci. USA 97, 262–267 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Alexander, J., Chang, G.Q., Dourmashkin, J.T. & Leibowitz, S.F. Distinct phenotypes of obesity-prone AKR/J, DBA2J and C57BL/6J mice compared to control strains. Int. J. Obes. (Lond) 30, 50–59 (2006).

    Article  CAS  Google Scholar 

  42. Li, L., Chen, L. & Hu, L. Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage of non-alcoholic fatty liver disease in mice. J. Clin. Exp. Hepatol. 1, 123–124 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wieckowska, A. et al. Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. Am. J. Gastroenterol. 103, 1372–1379 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ramesh, R. et al. Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids. J. Exp. Med. 211, 89–104 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163, 381–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pan, J.J. & Fallon, M.B. Gender and racial differences in nonalcoholic fatty liver disease. World J. Hepatol. 6, 274–283 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kanuri, G. & Bergheim, I. In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int. J. Mol. Sci. 14, 11963–11980 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bäckhed, F., Manchester, J.K., Semenkovich, C.F. & Gordon, J.I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. USA 104, 979–984 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Puddu, A., Sanguineti, R., Montecucco, F. & Viviani, G.L. Evidence for the gut microbiota short-chain fatty acids as key pathophysiological molecules improving diabetes. Mediators Inflamm. 2014, 162021 (2014).

    PubMed  PubMed Central  Google Scholar 

  52. Inra, C.N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466–471 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Alisi, A. et al. Plasma high mobility group box 1 protein reflects fibrosis in pediatric nonalcoholic fatty liver disease. Expert Rev. Mol. Diagn. 14, 763–771 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. do Nascimento, J.H., Epifanio, M., Soder, R.B. & Baldisserotto, M. MRI-diagnosed nonalcoholic fatty liver disease is correlated to insulin resistance in adolescents. Acad. Radiol. 20, 1436–1442 (2013).

    Article  PubMed  Google Scholar 

  55. Sorrentino, P. et al. Predicting fibrosis worsening in obese patients with NASH through parenchymal fibronectin, HOMA-IR, and hypertension. Am. J. Gastroenterol. 105, 336–344 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Jin, W. & Dong, C. IL-17 cytokines in immunity and inflammation. Emerg. Microbes Infect. 2, e60 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Giles, D.A., Moreno-Fernandez, M.E. & Divanovic, S. IL-17 axis driven inflammation in non-alcoholic fatty liver disease progression. Curr. Drug Targets 16, 1315–1323 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. McKee, C. et al. Propranolol, a β-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis. Biochem. Biophys. Res. Commun. 437, 597–602 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. McAlees, J.W. et al. Distinct Tlr4-expressing cell compartments control neutrophilic and eosinophilic airway inflammation. Mucosal Immunol. 8, 863–873 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Komiyama, Y. et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Giles, D.A. et al. Regulation of inflammation by IL-17A and IL-17F modulates non-alcoholic fatty liver disease pathogenesis. PLoS One 11, e0149783 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, J., Bardes, E.E., Aronow, B.J. & Jegga, A.G. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 37, W305–W311 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Divanovic, S., Trompette, A., Ashworth, J.I., Rao, M.B. & Karp, C.L. Therapeutic enhancement of protective immunity during experimental leishmaniasis. PLoS Negl. Trop. Dis. 5, e1316 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Finkelman, F., Morris, S., Orekhova, T. & Sehy, D. The in vivo cytokine capture assay for measurement of cytokine production in the mouse. Curr. Protoc. Immunol. 54, 6.28 (2003).

    Google Scholar 

  66. Divanovic, S. et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat. Immunol. 6, 571–578 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Castañeda, T.R. et al. Metabolic control by S6 kinases depends on dietary lipids. PLoS One 7, e32631 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wu, D. et al. Interleukin-13 (IL-13)/IL-13 receptor alpha1 (IL-13Rα1) signaling regulates intestinal epithelial cystic fibrosis transmembrane conductance regulator channel-dependent Cl− secretion. J. Biol. Chem. 286, 13357–13369 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Schloss, P.D. et al. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl. Environ. Microbiol. 75, 7537–7541 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Segata, N. et al. Metagenomic biomarker discovery and explanation. Genome Biol. 12, R60 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Caporaso, J.G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by NIH R01DK099222 and R01DK099222-S1 (to S.D.), the CCHMC Pediatric Diabetes and Obesity Center initiative (to S.D.), R01DK033201 (to C.R.K.), K12-HD000850 (to S.S.), NIH T32AI118697 (associated with D.A.G.), NIEHS Grant P30 ES006096 University of Cincinnati Center for Environmental Genomics (associated with D.A.G.), PHS Grant P30 DK078392 Pathology of the Digestive Disease Research Core Center at CCHMC (associated with S.D.) and German Research Foundation IRTG 1911 (projects A6 and B8 to C.S. and J.R.). We would also like to acknowledge C. Chougnet (CCHMC) for providing access to human PBMC samples and C. Woods (CCHMC) for technical assistance.

Author information

Authors and Affiliations

  1. Division of Immunobiology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Daniel A Giles, Maria E Moreno-Fernandez, Traci E Stankiewicz, Monica Cappelletti, Rajib Mukherjee, Calvin C Chan, Matthew J Lawson, Jared Klarquist & Senad Divanovic

  2. Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Daniel A Giles, Calvin C Chan & Jared Klarquist

  3. Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany

    Simon Graspeuntner & Jan Rupp

  4. Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    David Wu & Simon P Hogan

  5. Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

    Annika Sünderhauf & Christian Sina

  6. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA

    Samir Softic & C Ronald Kahn

  7. Institute for Diabetes and Obesity, Helmholtz Diabetes Center and German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany

    Kerstin Stemmer

  8. Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan

    Yoichiro Iwakura

  9. Division of Biomedical Informatics, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Bruce J Aronow

  10. Division of Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Rebekah Karns & Kris A Steinbrecher

  11. Bill & Melinda Gates Foundation, Seattle, Washington, USA

    Christopher L Karp

  12. Division of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Rachel Sheridan & Shiva K Shanmukhappa

  13. Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Damien Reynaud

  14. Division of Infectious Diseases, Department of Pediatrics, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    David B Haslam

Authors
  1. Daniel A Giles
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria E Moreno-Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Traci E Stankiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simon Graspeuntner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Monica Cappelletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rajib Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Calvin C Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Matthew J Lawson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jared Klarquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Annika Sünderhauf
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Samir Softic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. C Ronald Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Kerstin Stemmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yoichiro Iwakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Bruce J Aronow
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Rebekah Karns
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Kris A Steinbrecher
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Christopher L Karp
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Rachel Sheridan
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Shiva K Shanmukhappa
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Damien Reynaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. David B Haslam
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Christian Sina
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Jan Rupp
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Simon P Hogan
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Senad Divanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.A.G., M.E.M.-F., T.E.S., S.G., M.C., D.W., R.M., C.C.C., M.J.L., J.K., S.S., A.S. and D.R. participated in data generation. D.A.G., M.E.M.-F., S.G., D.R., R.K., B.J.A., S.K.S., R.S., K.A.S., D.B.H., J.R., S.P.H. and S.D. participated in data analysis and interpretation. S.S., K.S., Y.I., C.R.K., B.J.A., C.S. and C.L.K. provided materials and technical support and participated in critical review of the manuscript. D.A.G., S.S., C.R.K., J.R., C.S. and S.D. obtained the funding. D.A.G. and S.D. participated in the conception and design of the study, and wrote the manuscript.

Corresponding author

Correspondence to Senad Divanovic.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures and Table

Supplementary Figures 1–12 and Supplementary Table 1 (PDF 2090 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Giles, D., Moreno-Fernandez, M., Stankiewicz, T. et al. Thermoneutral housing exacerbates nonalcoholic fatty liver disease in mice and allows for sex-independent disease modeling. Nat Med 23, 829–838 (2017). https://doi.org/10.1038/nm.4346

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.4346

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing