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Housing temperature as a variable in the study of mouse models.
Mice remain an attractive organism to model human disease including inborn errors of metabolism. Although thermoneutrality for mice is around 30 °C, most mouse studies are conducted at temperatures around 22 °C. At this temperature almost 50% of the animal’s energy expenditure is for the purpose of generating heat (Fischer et al 2018). This is very different from the situation in humans, who spend most of their day under thermoneutral conditions. Using high time-resolution calorimetry, Fisher et al examined energy expenditure of mice housed at different temperatures. This analysis provided the currently most accurate determination of the resting metabolic rate, which was lower than previously estimated (Fischer et al 2018). The authors established that under thermoneutral conditions the mean diurnal energy expenditure rate is 1.8 times higher than basal metabolism, which closely resembles the human situation. At housing temperatures below thermoneutrality, this ratio exceeds the human value.
A recent analysis of the molecular response of brown adipose tissue (BAT) to different environmental temperatures sketches a similar picture (Sanchez-Gurmaches et al 2018). In mice, BAT is of particular importance for the regulation of body temperature. Sanchez-Gurmaches et al compared BAT function of mice not only housed at room temperature (22 °C) and in severe cold (6 °C), but also at thermoneutral conditions. They show that shifting mice from thermoneutral to room temperature had a more profound impact on the BAT transcriptome than a further shift to severe cold. Somewhat unexpectedly, fatty acid synthesis was the most affected pathway with pronounced upregulation already evident at room temperature. Although not a novel observation, this highlights the interesting paradox that in active BAT, both fatty acid synthesis and fatty acid oxidation are activated. Sanchez-Gurmaches et al further demonstrate that the increase in lipogenesis was not required to maintain normal body temperature, but affected long-term adaptation to cold (Sanchez-Gurmaches et al 2018). The robust induction of lipogenesis by cold exposure and the relatively subtle physiological consequences when impaired remain enigmatic and deserve further study.
From these and other recent reports it is clear that housing temperature should be considered as a relevant variable in mouse studies. By now many physiological parameters and phenotypes have been demonstrated to be affected by ambient temperature including heart rate, obesity, atherosclerosis, infection, and cancer (Ganeshan and Chawla 2017). It is highly likely that the phenotypes of mouse models for inborn errors of metabolism are also affected by temperature. This may be of particular importance when a disorder that affects energy homeostasis is modelled. For example, while fasting at 21 °C, mice with a mitochondrial fatty acid oxidation defect have lower energy expenditure and body temperature than control mice (Diekman et al 2014). Since both phenotypes will be affected by housing temperature, the clinical presentation of murine fatty acid oxidation defects may be different at thermoneutrality and is therefore interesting to analyze as well.
- Sanchez-Gurmaches J, Tang Y, Jespersen NZ et al (2018) Brown fat AKT2 is a cold-induced Kinase that stimulates ChREBP-mediated de novo Lipogenesis to optimize fuel storage and thermogenesis. Cell Metab 27:195–209Google Scholar