An assessment of thermoneutral housing conditions on murine cardiometabolic function

Abstract

Mouse models are used to model human diseases and perform pharmacological efficacy testing to advance therapies to humans; most of these studies are conducted in room temperature conditions. At room temperature (22°C), mice are cold stressed and must utilize brown adipose tissue (BAT) to maintain body temperature. This cold stress increases catecholamine tone to maintain adipocyte lipid release via lipolysis, which will fuel adaptive thermogenesis. Maintaining rodents at thermoneutral temperatures (28°C) ameliorates the need for adaptive thermogenesis, thus reducing catecholamine tone and BAT activity. Cardiovascular tone is also determined by catecholamine levels in rodents, as beta adrenergic stimuli are primary drivers of not only lipolytic, but also ionotropic and chronotropic responses. As mice have increased catecholamine tone at room temperature, we investigated how thermoneutral housing conditions would impact cardiometabolic function. Here, we show a rapid and reversible effect of thermoneutrality on both heart rate and blood pressure in chow fed animals, which was blunted in animals fed high fat diet. Animals subjected to transverse aortic constriction displayed compensated hypertrophy at room temperature, while animals displayed less hypertrophy and trends towards worse systolic function at thermoneutrality. Despite these dramatic changes in blood pressure and heart rate at thermoneutral housing conditions, enalapril effectively improved cardiac hypertrophy and gene expression alterations. There were surprisingly few differences in cardiac parameters in high fat fed animals at thermoneutrality. Overall, these data suggest that thermoneutral housing may alter some aspects of cardiac remodeling in preclinical mouse models of heart failure.

Cardiometabolic Effects of DOCA-Salt in Mice Depend on Ambient Temperature

“…Before the initiation of DOCA-salt treatment, housing at TN alone resulted in expected reductions in BP and HR, as sympathetic stimulation of HR is withdrawn as mice move to TN housing. 7–9 Interestingly, although HR reductions in response to chlorisondamine were abolished by housing at TN, BP reductions were similar to mice housed at RT. These data reinforce the concept that TN housing selectively reduces autonomic stimulation of the heart 8,9 but perhaps not the vasculature.…”

“…28 Unfortunately, such documenting and appreciating the impact of environmental variables (such as ambient temperature) upon cardiovascular physiology in both humans and rodent models lags behind efforts to incorporate these factors into studies of bioenergetics and obesity. 1,2,29,30 Recent studies have highlighted the impact of ambient temperature upon cardiovascular functions in mice, [7][8][9] but there remains a general lack of appreciation for the complex interactions among ambient temperature and cardiometabolic stimuli upon fluid and electrolyte balance, energy homeostasis, and BP control in experimental models.…”

“…6 Along these lines, recent studies have demonstrated a major modulatory effect of ambient temperature upon blood pressure (BP) regulation in mice, as housing at thermoneutrality causes rapid, large, reversible reductions in heart rate (HR) and BP and altered pathogenesis of cardiac remodeling. [7][8][9] Further, some of these effects such as the dramatic HR reductions are attenuated after diet-induced obesity, 7 underscoring the interactions among body composition, thermoregulation, and cardiovascular control. As obesity and hypertension represent the greatest ongoing impediments to continued advances in cardiovascular health, 10 there is an urgent need to better understand the mechanisms that integrate and coordinate cardiometabolic control.…”

Leptin and environmental temperature as determinants of bone marrow adiposity in female mice

“…Thermoneutral housing alters many, but not all, metabolic responses ( 67 – 70 ). Regarding bone, compared to room temperature, thermoneutral housing prevents premature cancellous bone loss, attenuates risperidone-induced trabecular bone loss, has modest effects on cortical response to mechanical loading, and does not impact polyethylene-particle induced osteolysis ( 46 , 71 , 72 ).…”

Guidelines on models of diabetic heart disease

“…Of relevance, female mice are highly resistant to obesity-induced nonalcoholic fatty liver disease and subsequent steatohepatitis, but this resistance is extinguished if the mice are housed at thermoneutrality ( 296 ). More recently, studies in male mice housed at either room temperature or thermoneutrality have demonstrated that thermoneutrality lowers heart rate and mean arterial pressures in lean mice, whereas these actions are blunted in mice subjected to high-fat diet-induced obesity ( 252 ). Taken together, as the field continues to collaborate and refine the current models of diabetes, while also developing new models, this should result in further improvements in our ability to clinically manage diabetes-related cardiovascular disease.…”