Abstract
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.
Highlights
Thermogenesis is an important homeostatic mechanism essential for survival and normal physiological functions in mammals
We recently reported that skeletal muscle— based thermogenesis can compensate for loss of brown adipose tissue (BAT) thermogenesis in UCP1Ϫ/Ϫ mice [13]
SLNϪ/Ϫ and UCP1Ϫ/Ϫ mice consumed less oxygen compared with the WT, suggesting that they contribute to the basal metabolic rate
Summary
Several earlier studies have shown that, cold adaptation comes at a significant energy cost. Even mild cold adaptation induced significant changes in mitochondrial architecture, with a greater density of cristae, in SLNϪ/Ϫ mice compared with WT littermates (Fig. 3). We observed that loss of UCP1/BAT activity led to an up-regulation of SLN expression in red gastrocnemius and soleus muscle under mild and severe cold (Fig. 4, B and C). These data suggest increased reliance on muscle-based NST in UCP1Ϫ/Ϫ mice even under mild cold. CD31 staining shows that skeletal muscle from cold-adapted UCP1Ϫ/Ϫ mice has greater blood vessel density compared with WT littermates (Fig. 5, D and E).
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