Chill factor: effect of thermoneutrality on thoracic perivascular adipose tissue and vascular reactivity

Clinical translation of basic science research relies on the generation of robust animal models reflective of human disease. A hot topic in balancing animal welfare with generation of robust models is the housing temperature of rodents. Guidelines on the housing of rodents in animal research facilities recommend 20°C–24°C [1], however, this temperature is closer to the thermoneutral zone of humans. Thermoneutrality, the zone in which heat does not need to be produced or lost to maintain core temperature is accepted to be 30°C in mice [2]. Thus, mice spend a substantial amount of energy to maintain their body temperature in most vivariums. This may have considerable consequences for research into adipose tissue function and cardiovascular diseases. Brown adipose tissue, which in humans is located in cervical, supraclavicular and paravertebral regions [3], can participate in thermogenesis and is activated by cold exposure. Many studies have shown that activation of this process in humans and rodents will confer metabolic and cardiovascular improvements (reviewed by [4]). Therefore, modelling these diseases in rodents housed at 20°C–24°C may be somewhat an uphill battle. In health, perivascular adipose tissue (PVAT) modulates vascular contractility and insulin sensitivity by release of several vasoactive adipokines. In obesity, PVAT becomes pathologically whitened, inflamed and dysfunctional, contributing to the development of hypertension and type II diabetes (reviewed by [5]). The exact mechanisms remain unclear, and given the increasing global prevalence of obesity, further research is critical. In 2022, Keller et al.[6] published a study within the Journal of Hypertension demonstrating that housing rats at thermoneutrality may be a simple and effective tool in modelling vascular impairment, with a focus on endothelial dysfunction. One limitation of this original study was that the endogenous PVAT had been removed from the vessels. However, in the current issue, this research group have published a follow-up study expanding their research into the important field of PVAT. Henckel et al.[7] here report that thermoneutral housed rats exhibited remodelling of thoracic aortic PVAT (tPVAT). In rodents, tPVAT contains a mixture of white and brown adipocytes, however, thermoneutral housing induced a pathological whitening of this depot. Interestingly, the vasodilator adipokine, adiponectin, appeared reduced in thermoneutral rats, although this was not significant. The functional consequence of this whitening of tPVAT was impaired response to acetylcholine in aortic segments. Importantly, application of tPVAT from room-temperature house rats onto aortae from thermoneutral rats restored the vasodilator response to acetylcholine in females only. Authors found that endothelial nitric oxide synthase expression was reduced in thermoneutral PVAT and found mitochondrial dysfunction. Surprisingly, thermoneutral animals weighed less than their room-temperature counterparts, which is consistent with the group's previous study, although both studies demonstrated changes in insulin sensitivity/levels. These findings contrast with that of others who have reported increased weight gain in thermoneutral rodents [8,9], which would be expected given that the animals no longer need to expend as much energy in maintaining core temperature. Further research is needed into the effects of thermoneutral on adipose tissue expansion. To my knowledge, Henckel et al.[10] are the first to study the functional effects of thermoneutrality on PVAT in terms of vascular contractility; however, one study has reported that thermoneutral housing in mouse increases inflammation of epididymal fat pads without any effects on body weight, although this group did not find any effects on insulin. However, they did find that thermoneutral housing exacerbates atherosclerosis development. It has been reported that thermoneutral housing dramatically and reversibly increases blood pressure in rodents [11]. One limitation of the Henckel et al. [7] study is that only the aorta was studied, which plays little role in determining blood pressure. Given the findings of their study and the reports of increased blood pressure, it would be intriguing and important to study the effects of thermoneutral on PVAT surrounding resistance arteries. Resistance arteries are a critical determinant of blood pressure, and many have shown that dysfunction of PVAT depots around resistance arteries in obese and hypertensive models increases vascular tone (reviewed by [5]). As previously mentioned, the mechanisms remain unclear and are complicated by various conflicting and contrasting studies. These contrasts are likely due to variations in animal models such as the high calorie diets chosen, duration of feeding, etc. Therefore, the use of thermoneutral housing as a simplified model is intriguing and I look forward to further updates in this exciting field. ACKNOWLEDGEMENTS Dr Saxton is supported by British Heart Foundation grant PG/22/11044 and British Heart Foundation and Rosetrees Trust PG/22/11044. Conflicts of interest There are no conflicts of interest.