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

• Published in: Nature medicine Vol. 23; no. 7; pp. 829 - 838
• Main Authors: Giles, Daniel A, Moreno-Fernandez, Maria E, Stankiewicz, Traci E, Graspeuntner, Simon, Cappelletti, Monica, Wu, David, Mukherjee, Rajib, Chan, Calvin C, Lawson, Matthew J, Klarquist, Jared, Sünderhauf, Annika, Softic, Samir, Kahn, C Ronald, Stemmer, Kerstin, Iwakura, Yoichiro, Aronow, Bruce J, Karns, Rebekah, Steinbrecher, Kris A, Karp, Christopher L, Sheridan, Rachel, Shanmukhappa, Shiva K, Reynaud, Damien, Haslam, David B, Sina, Christian, Rupp, Jan, Hogan, Simon P, Divanovic, Senad
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2017; Nature Publishing Group
• Subjects: 13/21; 45/91; 631/1647/767/1424; 631/250/256/2515; 64/60; 692/163/2743/2037; 692/420/2780; Amplification; Analysis; Animal models; Animals; Biomedicine; Cancer Research; Care and treatment; Cirrhosis; Clonal deletion; Cold Temperature; Corticosterone; Corticosterone - metabolism; Deactivation; Diet, High-Fat; Disease Models, Animal; Disease Progression; Dosage and administration; Fatty acids; Fatty liver; Female; Fibrosis; Flow Cytometry; Gastrointestinal Microbiome - immunology; Gene Expression Profiling; Gram-Negative Bacteria - immunology; Health aspects; Hematopoietic Stem Cells - metabolism; Hepatocellular carcinoma; High fat diet; Housing; Housing, Animal; Humans; Immune response; Immune system; Inactivation; Infectious Diseases; Inflammation; Interleukin 17; Interrogation; Intestinal Mucosa - metabolism; Intestine; Jejunum - metabolism; Liver; Liver cirrhosis; Liver diseases; Machine Learning; Male; Metabolic Diseases; Mice; Mice, Knockout; Microbiota (Symbiotic organisms); Molecular Medicine; Molecular modelling; Neurosciences; Non-alcoholic Fatty Liver Disease - immunology; Non-alcoholic Fatty Liver Disease - metabolism; Obesity - immunology; Obesity - metabolism; Pathogenesis; Patient outcomes; Permeability; Proteins; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Sex; Sex Factors; Stress, Physiological - immunology; Temperature; TLR4 protein; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Ohio
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4346

Current mouse models of nonalcoholic steatohepatitis are limited, making identification and preclinical testing of new treatments challenging. Housing mice at thermoneutrality leads to less stress, a stronger immune response and better modeling of this condition. 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.