Warming the mouse to model human diseases

Abstract

Humans prefer to live within their thermal comfort or neutral zone, which they create by making shelters, wearing clothing and, more recently, by regulating their ambient temperature. These strategies enable humans to maintain a constant core temperature (a trait that is conserved across all endotherms, including mammals and birds) with minimal energy expenditure. Although this primordial drive leads us to seek thermal comfort, we house our experimental animals, laboratory mice (Mus musculus), under conditions of thermal stress. In this Review, we discuss how housing mice below their thermoneutral zone limits our ability to model and study human diseases. Using examples from cardiovascular physiology, metabolic disorders, infections and tumour immunology, we show that certain phenotypes observed under conditions of thermal stress disappear when mice are housed at thermoneutrality, whereas others emerge that are more consistent with human biology. Thus, we propose that warming the mouse might enable more predictive modelling of human diseases and therapies.

Figure 1. Scholander plots of energy expenditure at different ambient temperatures for animals

For mammals and birds, changes in ambient temperature below the thermoneutral zone result in a linear increase in metabolic rate (oxygen consumption). (a) For mice, the thermoneutral zone lies between 29-31°C (depicted in by the grey zone). The black line depicts changes in metabolic rate as the ambient temperature drops below the thermoneutral zone of mice. Note that the metabolic rate is ~2-fold higher at T_a of 20°C than at T_a of 30°C. The slope of this line is directly proportional to the thermal conductance of the animal. (b) Animals with a lower thermal conductance (more insulated by fur and subcutaneous fat), such as artic animals, have a larger thermoneutral zone and a smaller rise in metabolic rate at lower temperatures (red line). (c) Conversely, animals with higher thermal conductance (less insulated), such as equatorial animals or nude mice, have a rightward shift in their thermoneutral zone and a larger increase in metabolic rate at lower temperatures (blue line). Although less well studied, temperatures higher than the thermoneutral zone also result in an increase in metabolic rate, reflecting energy required to dissipate heat. Within a given species, the thermoneutral zone changes during the life of a species. A number of factors can alter the thermoneutral zone, including age, muscle mass, locomotor activity, pregnancy, lactation, and insulation. Dotted line represents basal metabolic rate (BMR). Although hypothetical, when BMR is zero, heat loss is zero and the core or defended temperature is equal to T_a. Thus, when dashed black (a), red (b), and blue (c) lines cross the x-axis at zero, the T_a is the defended or core temperature of the animal.

Figure 2. Effects of ambient temperature on oxygen consumption and food intake in mice

(a) Changes in oxygen consumption (energy expenditure) in C57BL/6J female mice housed at different ambient temperatures. Note that oxygen consumption changes in real time as the ambient temperature is changed between 20 and 30°C (n=5). Red and blue dashed lines mark basal metabolic rate (BMR) of C57BL/6J female mice housed at T_a=30°C and the resting metabolic rate (RMR) at T_a=20°C, respectively. RMR at T_a=20°C is ~2-fold higher than the BMR at T_a=30°C. Black bars on x-axis denote the night cycle. (b) Cumulative food intake by C57BL/6J female mice housed at different ambient temperatures (n=5).