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

An Erratum to this article was published on 01 October 2017

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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.

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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.

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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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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.

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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.

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Correspondence to Senad Divanovic.

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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

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