Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice.
Obesity and obesity-associated inflammation is central to a variety of end-organ sequelae including atherosclerosis, a leading cause of death worldwide. Although mouse models have provided important insights into the immunopathogenesis of various diseases, modeling atherosclerosis in mice has proven difficult. Specifically, wild-type (WT) mice are resistant to developing atherosclerosis, while commonly used genetically modified mouse models of atherosclerosis are poor mimics of human disease. The lack of a physiologically relevant experimental model of atherosclerosis has hindered the understanding of mechanisms regulating disease development and progression as well as the development of translational therapies. Recent evidence suggests that housing mice within their thermoneutral zone profoundly alters murine physiology, including both metabolic and immune processes. We hypothesized that thermoneutral housing would allow for augmentation of atherosclerosis induction and progression in mice.



ApoE-/-and WT mice were housed at either standard (TS) or thermoneutral (TN) temperatures and fed either a chow or obesogenic "Western" diet. Analysis included quantification of (i) obesity and obesity-associated downstream sequelae, (ii) the development and progression of atherosclerosis, and (iii) inflammatory gene expression pathways related to atherosclerosis.



Housing mice at TN, in combination with an obesogenic "Western" diet, profoundly augmented obesity development, exacerbated atherosclerosis in ApoE-/-mice, and initiated atherosclerosis development in WT mice. This increased disease burden was associated with altered lipid profiles, including cholesterol levels and fractions, and increased aortic plaque size. In addition to the mild induction of atherosclerosis, we similarly observed increased levels of aortic and white adipose tissue inflammation and increased circulating immune cell expression of pathways related to adverse cardiovascular outcome.



In sum, our novel data in WT C57Bl/6 mice suggest that modulation of a single environmental variable, temperature, dramatically alters mouse physiology, metabolism, and inflammation, allowing for an improved mouse model of atherosclerosis. Thus, thermoneutral housing of mice shows promise in yielding a better understanding of the cellular and molecular pathways underlying the pathogenesis of diverse diseases.
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA.
Daniel A
DA
Giles
Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA; Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
Bhama
B
Ramkhelawon
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Elizabeth M
EM
Donelan
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Traci E
TE
Stankiewicz
Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
Susan B
SB
Hutchison
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Rajib
R
Mukherjee
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Monica
M
Cappelletti
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Rebekah
R
Karns
Discovery & Translational Sciences, The Bill & Melinda Gates Foundation, Seattle, WA 98109, USA.
Christopher L
CL
Karp
Department of Medicine, Marc and Ruti Bell Program for Vascular Biology and Disease, The Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
Kathryn J
KJ
Moore
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA. Electronic address: senad.divanovic@cchmc.org.
Senad
S
Divanovic
D000818:Animals; D050197:Atherosclerosis / Q000276:immunology*; D006801:Humans; D007249:Inflammation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013696:Temperature
Atherosclerosis; Inflammation; Thermoneutrality