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Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice
OBJECTIVES: 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 mic...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081423/ https://www.ncbi.nlm.nih.gov/pubmed/27818938 http://dx.doi.org/10.1016/j.molmet.2016.09.008 |
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author | Giles, Daniel A. Ramkhelawon, Bhama Donelan, Elizabeth M. Stankiewicz, Traci E. Hutchison, Susan B. Mukherjee, Rajib Cappelletti, Monica Karns, Rebekah Karp, Christopher L. Moore, Kathryn J. Divanovic, Senad |
author_facet | Giles, Daniel A. Ramkhelawon, Bhama Donelan, Elizabeth M. Stankiewicz, Traci E. Hutchison, Susan B. Mukherjee, Rajib Cappelletti, Monica Karns, Rebekah Karp, Christopher L. Moore, Kathryn J. Divanovic, Senad |
author_sort | Giles, Daniel A. |
collection | PubMed |
description | OBJECTIVES: 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. METHODS: ApoE(−/−) and WT mice were housed at either standard (T(S)) or thermoneutral (T(N)) 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. RESULTS: Housing mice at T(N), 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. CONCLUSIONS: 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. |
format | Online Article Text |
id | pubmed-5081423 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-50814232016-11-04 Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice Giles, Daniel A. Ramkhelawon, Bhama Donelan, Elizabeth M. Stankiewicz, Traci E. Hutchison, Susan B. Mukherjee, Rajib Cappelletti, Monica Karns, Rebekah Karp, Christopher L. Moore, Kathryn J. Divanovic, Senad Mol Metab Brief Communication OBJECTIVES: 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. METHODS: ApoE(−/−) and WT mice were housed at either standard (T(S)) or thermoneutral (T(N)) 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. RESULTS: Housing mice at T(N), 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. CONCLUSIONS: 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. Elsevier 2016-09-21 /pmc/articles/PMC5081423/ /pubmed/27818938 http://dx.doi.org/10.1016/j.molmet.2016.09.008 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Brief Communication Giles, Daniel A. Ramkhelawon, Bhama Donelan, Elizabeth M. Stankiewicz, Traci E. Hutchison, Susan B. Mukherjee, Rajib Cappelletti, Monica Karns, Rebekah Karp, Christopher L. Moore, Kathryn J. Divanovic, Senad Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title | Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title_full | Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title_fullStr | Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title_full_unstemmed | Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title_short | Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice |
title_sort | modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type c57bl/6 mice |
topic | Brief Communication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081423/ https://www.ncbi.nlm.nih.gov/pubmed/27818938 http://dx.doi.org/10.1016/j.molmet.2016.09.008 |
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