• An Erratum to this article was published on 01 October 2017

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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.

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  • 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.


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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


  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, Hepatology and Nutrition, Department of Pediatrics, 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


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Senad Divanovic.

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