Divergent selection for basal metabolic rate in mice affects the abundance of UCP1 protein: implications for translational studies.

Abstract

Low basal metabolic rate (BMR) is a risk factor for obesity, whereas elevation of non-shivering thermogenesis (NST) is a promising means to combat obesity. Because heat generated by NST covers thermogenic needs not fulfilled by BMR, one can expect the presence of a negative relationship between both parameters. Understanding of the mechanisms underlying this relationship is therefore important for interpretation of the results of translational experiments and the development of anti-obesity treatments. We studied two lines of laboratory mice divergently selected for high or low level of BMR, raised at 23°C and subsequently acclimated to different ambient temperatures (30, 23 and 4°C). Mice selected for low BMR accumulated more fat but simultaneously showed higher NST capacity and more uncoupling protein-1 (UCP1) in interscapular brown adipose tissue (iBAT), to compensate for their lower heat production through BMR. The between-line difference in UCP1 protein abundance was significant even in mice acclimated to 30°C when the level of UCP1 is very low. Differences in NST capacity between selected lines and acclimation temperatures were explained by UCP1 iBAT abundance. Our results reveal that BMR is inversely correlated with UCP1 protein abundance and NST, even after acclimation to thermoneutrality. Thus, low values of BMR can increase both obesity risk and the magnitude of NST, i.e. the process whose activation has been proposed to mitigate obesity risk. All these effects should be taken into account in the design and interpretation of translational studies on mice models of metabolic diseases. KEY POINTS: Basal metabolic rate (BMR) and non-shivering thermogenesis (NST) based on the activity of uncoupling protein-1 (UCP1) are two main sources of heat in laboratory mice. Both BMR and UCP1 can affect obesity risk in laboratory rodents and humans. Here we studied BMR, NST, and the abundance of UCP1 in laboratory mice selected divergently towards either high or low BMR. We showed that BMR is negatively correlated with UCP1 abundance and this effect is not removed even after acclimation to thermoneutrality. The pattern described reveals that BMR can affect not only obesity risk but also the magnitude of UCP1-mediated NST. Since activation of NST was proposed to mitigate obesity risk, variation in BMR should be taken into account in translational studies of mouse models of metabolic diseases.