The biophysical environment of membrane phospholipids affects the structure, function, and stability of membrane-bound proteins^,. Obesity can disrupt membrane lipids, and, in particular, alter the activity of sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) to affect cellular metabolism^{, –}. Recent evidence suggests that the transport efficiency (Ca²⁺ uptake and ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity^,. In isolated sarcoplasmic reticulum vesicles, membrane phospholipid composition is known to modulate SERCA efficiency^{, , –}. Here we show that skeletal muscle sarcoplasmic reticulum phospholipids can be altered to decrease SERCA efficiency and increase the whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine methyltransferase (PEMT) promotes an increase in the skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca²⁺-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity.