Mouse thermoregulation: Introducing the concept of the thermoneutral point

Abstract

Obesity affects over one third of adults and increases the risk of health conditions including heart disease, stroke, and type 2 diabetes. The mouse is a widely used model system for obesity and diabetes research. However, mouse and human thermal physiology differs, and a better understanding of mouse thermal physiology is needed to improve the utility of the mouse as a model for human diseases. Here we map the mouse light and dark phase thermoneutral zone (TNZ), focusing on its neglected upper boundary.Mouse thermal physiology was studied by indirect calorimetry with continuous measurement of core body temperature (Tb) over a range of ambient temperatures (Ta). Measurements included total energy expenditure (TEE), respiratory exchange ratio, food intake, and physical activity (infrared beam break). Segmented line regression with nonlinear mixed model was used for data analysis.In wild‐type C57BL/6J mice, light‐phase TEE decreased linearly with increasing Ta, until a plateau was reached. The Ta at the break point (the TNZ lower bound, called the lower critical temperature or Tlc) was 28.90 ± 0.15 °C. At warm Tas, the TEE began to increase with rising Ta starting at 33.91 ± 0.29 °C along with increased physical activity. We found no range of ambient temperatures over which both TEE and Tb were constant. Tb was constant at cool Ta and began to rise at Ta = 28.92 ± 0.11 °C with slope 0.337 ± 0.029 °CTb/°CTa. At Ta = 33.15 ± 0.08, Tb began to steeply increase with slope 0.780 ± 0.035 °CTb/°CTa, suggesting Tb regulation mechanisms are overwhelmed above this Ta. Thus, the Ta at which Tb starts to increase coincides with the Tlc, and the Ta at which TEE starts to rise with increasing Ta coincides with the initiation of steep Tb increase. The generality of this observation was reproduced in male, female, warm acclimated, C57BL/6J, 129, chow‐fed, diet‐induced obese, leptin deficient (ob/ob), and Trpv1−/−;Trpm8−/−;Trpa1−/− mice with thermal sensory channel deletions, and in both chamber and home cage indirect calorimetry systems. Different thermal physiology was observed at the dark phase, with the minimum TEE being restricted to a single point at 33.94 ± 0.14 °C. The Tb vs Ta graph also showed a single breakpoint at 32.77 ± 0.13 °C. These dark phase TEE and Tb break points were coincident with upper light phase break points ‐ where TEE start to rise and where Tb began to steeply increase. Importantly, slopes of TEE and Tb increase above these points were similar in dark and light phase.Based on our results, we propose the concept of a thermoneutral point (TNP), a discrete ambient temperature below which energy expenditure increases and above which body temperature increases. The mouse has different TNP in light and dark phase (under our conditions the light phase TNP is ~29 °C and dark phase TNP is ~33 °C). These mouse observations have implications for how thermoneutrality is defined and suggest changes for how mice are used to model human energy physiology and drug development.Support or Funding InformationZIA DK075063