Thermogenesis is an important homeostatic mechanism essential for survival and 
normal physiological functions in mammals. Both brown adipose tissue (BAT) (i.e. 
uncoupling protein 1 (UCP1)-based) and skeletal muscle (i.e. sarcolipin 
(SLN)-based) thermogenesis processes play important roles in temperature 
homeostasis, but their relative contributions differ from small to large 
mammals. In this study, we investigated the functional interplay between 
skeletal muscle- and BAT-based thermogenesis under mild versus severe cold 
adaptation by employing UCP1-/- and SLN-/- mice. Interestingly, adaptation of 
SLN-/- mice to mild cold conditions (16 °C) significantly increased UCP1 
expression, suggesting increased reliance on BAT-based thermogenesis. This was 
also evident from structural alterations in BAT morphology, including 
mitochondrial architecture, increased expression of electron transport chain 
proteins, and depletion of fat droplets. Similarly, UCP1-/- mice adapted to mild 
cold up-regulated muscle-based thermogenesis, indicated by increases in muscle 
succinate dehydrogenase activity, SLN expression, mitochondrial content, and 
neovascularization, compared with WT mice. These results further confirm that 
SLN-based thermogenesis is a key player in muscle non-shivering thermogenesis 
(NST) and can compensate for loss of BAT activity. We also present evidence that 
the increased reliance on BAT-based NST depends on increased autonomic input, as 
indicated by abundant levels of tyrosine hydroxylase and neuropeptide Y. Our 
findings demonstrate that both BAT and muscle-based NST are equally recruited 
during mild and severe cold adaptation and that loss of heat production from one 
thermogenic pathway leads to increased recruitment of the other, indicating a 
functional interplay between these two thermogenic processes.