Uncoupling Protein 1 and Sarcolipin Are Required to Maintain Optimal Thermogenesis, and Loss of Both Systems Compromises Survival of Mice under Cold Stress

Leslie A Rowland,Naresh C Bal,Leslie P Kozak,Muthu Periasamy

doi:10.1074/jbc.m115.637603

Abstract

The importance of brown adipose tissue as a site of nonshivering thermogenesis has been well documented. Emerging studies suggest that skeletal muscle is also an important site of thermogenesis especially when brown adipose tissue function is lacking. We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA) pump, could contribute to heat production in skeletal muscle. In this study, we sought to understand how loss of UCP1 or SLN is compensated during cold exposure and whether they are both necessary for thermogenesis. Toward this goal, we generated a UCP1;SLN double knock-out (DKO) mouse model and challenged the single and DKO mice to acute and long-term cold exposures. Results from this study show that there is up-regulation of SLN expression in UCP1-KO mice, and loss of SLN is compensated by increased expression of UCP1 and browning of white adipose tissue. We found that the DKO mice were viable when reared at thermoneutrality. When challenged to acute cold, the DKO were extremely cold-sensitive and became hypothermic. Paradoxically, the DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake. These studies suggest that UCP1 and SLN are required to maintain optimal thermogenesis and that loss of both systems compromises survival of mice under cold stress.

Highlights

The mechanisms underlying uncoupling protein 1 (UCP1)-independent thermogenesis are not well understood
We recently showed that sarcolipin (SLN), an uncoupler of the sarco(endo)plasmic reticulum Ca2؉ ATPase (SERCA) pump, could contribute to heat production in skeletal muscle
We examined whether there is additional recruitment of subcutaneous white adipose tissue (WAT) to increase thermogenesis by what is known as “browning.” Interestingly, H&E staining of subcutaneous WAT in SLN-KO mice showed morphological characteristics consistent with browning: large areas of fat depletion and multilocular adipocytes (Fig. 2B)

Summary

Background

The mechanisms underlying UCP1-independent thermogenesis are not well understood. Results: Loss of both SLN and UCP1 results in compromised thermogenic ability and severe sensitivity to acute cold. The DKO mice were able to survive gradual cold challenge, but these mice lost significant weight and depleted their fat stores, despite having higher caloric intake These studies suggest that UCP1 and SLN are required to maintain optimal thermogenesis and that loss of both systems compromises survival of mice under cold stress. In many adult large mammals, BAT activity is limited to neonatal stages by becoming downregulated in the adult and is even absent in some endothermic species These animals, including humans, must rely on alternative thermogenic mechanisms to survive when exposed to cold environments (8 –13). Studies on large mammals, including rabbits, dogs, ruminants, marsupials, etc., suggest that muscle is the major site of heat production (8, 9, 13, 19 –21) These species have reduced BAT content in adulthood, especially when compared with rodents; they cannot rely entirely on BAT thermogenesis to maintain body temperature. Our studies highlight the compensatory and unique roles of these two thermogenic systems in a mouse model

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION