Modulation of ambient temperature promotes inflammation and initiates atherosclerosis in wild type C57BL/6 mice

Abstract

ObjectivesObesity 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.MethodsApoE−/− 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.ResultsHousing 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.ConclusionsIn 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.

Warming the mouse to model human diseases

“…This increase in atherogenesis was associated with inflammatory changes in and around the vessel wall, as evidenced by increased infiltration of vessel wall and perivascular fat by inflammatory macrophages and dendritic cells. A similar increase in lesion area was observed by Giles et al, who found that Apoe -/- mice housed at thermoneutrality had larger atherosclerotic lesions in their aortic roots 70 . These investigators also tested whether thermoneutral housing might induce atherogenesis in C57BL/6J mice, which are normally resistant to development of atherosclerosis.…”

“…Because thermoneutral housing accelerated the onset of metabolic inflammation during obesity 62 , two recent studies asked whether it might potentiate vascular inflammation and atherosclerosis 62,70 . Using the Apoe -/- mice, Tian et al found that thermoneutral housing enhanced the development of atherogenic lesions in the aortas of mice fed the western diet 62 .…”

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

“…Aortic sinus disease, which we quantified in the present study along with aortic disease at multiple time points, was not examined by Tian et al Giles et al failed to find a major shift in plasma cholesterol but nonetheless reported that enhanced atherosclerosis was worsened in Apoe −/− mice fed a high fat diet, but there was no disease change in Apoe −/− mice fed a chow diet. They then went on to report that, surprisingly, WT C57BL/6 mice developed modest, but measureable, atherosclerosis when fed a high fat diet and housed at thermoneutrality 54 . For unclear reasons as of yet, these two studies appear directly at odds with the conclusions from our work and that of Dong et al 21 .…”

Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice

“…TG quantification was performed as reported . Briefly, 200 μL of triglyceride reagent (Pointe Scientific) was added to 10 μL of serum in a 96‐well, clear, flat‐bottom plate (Costar).…”