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Nat Med. 2017 Jul;23(7):829-838. doi: 10.1038/nm.4346. Epub 2017 Jun 12.

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

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.
2
Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
3
Department of Infectious Diseases and Microbiology, University of Lübeck, Lübeck, Germany.
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.
5
Institute of Nutritional Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
6
Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA.
7
Institute for Diabetes and Obesity, Helmholtz Diabetes Center and German Center for Diabetes Research (DZD), Helmholtz Zentrum München, Neuherberg, Germany.
8
Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan.
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.
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.
11
Bill &Melinda Gates Foundation, Seattle, Washington, USA.
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.
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.
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.

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.

PMID:
28604704
PMCID:
PMC5596511
DOI:
10.1038/nm.4346
[Indexed for MEDLINE]
Free PMC Article

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