The role of skeletal muscle in nonshivering thermogenesis (NST) is not well 
understood. Here we show that sarcolipin (Sln), a newly identified regulator of 
the sarco/endoplasmic reticulum Ca(2+)-ATPase (Serca) pump, is necessary for 
muscle-based thermogenesis. When challenged to acute cold (4 °C), Sln(-/-) mice 
were not able to maintain their core body temperature (37 °C) and developed 
hypothermia. Surgical ablation of brown adipose tissue and functional knockdown 
of Ucp1 allowed us to highlight the role of muscle in NST. Overexpression of Sln 
in the Sln-null background fully restored muscle-based thermogenesis, suggesting 
that Sln is the basis for Serca-mediated heat production. We show that ryanodine 
receptor 1 (Ryr1)-mediated Ca(2+) leak is an important mechanism for 
Serca-activated heat generation. Here we present data to suggest that Sln can 
continue to interact with Serca in the presence of Ca(2+), which can promote 
uncoupling of the Serca pump and cause futile cycling. We further show that loss 
of Sln predisposes mice to diet-induced obesity, which suggests that 
Sln-mediated NST is recruited during metabolic overload. These data collectively 
suggest that SLN is an important mediator of muscle thermogenesis and whole-body 
energy metabolism.