Verkerke Anthony R P, Ferrara Patrick J, Lin Chien-Te, Johnson Jordan M, Ryan Terence E, Maschek J Alan, Eshima Hiroaki, Paran Christopher W, Laing Brenton T, Siripoksup Piyarat, Tippetts Trevor S, Wentzler Edward J, Huang Hu, Spangenburg Espen E, Brault Jeffrey J, Villanueva Claudio J, Summers Scott A, Holland William L, Cox James E, Vance Dennis E, Neufer P Darrell, Funai Katsuhiko
Diabetes & Metabolism Research Center, University of Utah, Salt Lake City, UT, USA.
Department of Nutrition & Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
Nat Metab. 2019 Sep;1(9):876-885. doi: 10.1038/s42255-019-0111-2. Epub 2019 Sep 16.
The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins. Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca-ATPase (SERCA) to affect cellular metabolism. Recent evidence suggests that transport efficiency (Ca uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity. In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency. Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in 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 Ca-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.
膜磷脂的生物物理环境会影响膜结合蛋白的结构、功能和稳定性。肥胖会破坏膜脂，尤其是改变肌浆网/内质网（ER/SR）钙-ATP酶（SERCA）的活性，从而影响细胞代谢。最近的证据表明，骨骼肌SERCA的转运效率（钙摄取/ATP水解）可能会解偶联，以增加能量消耗并保护小鼠免受饮食诱导的肥胖。在分离的肌浆网囊泡中，已知膜磷脂组成会调节SERCA效率。在这里，我们表明骨骼肌肌浆网磷脂可被改变，以降低SERCA效率并提高全身代谢率。骨骼肌磷脂酰乙醇胺（PE）甲基转移酶（PEMT）的缺失会促进骨骼肌和全身代谢率的增加，从而保护小鼠免受饮食诱导的肥胖。代谢率的升高是由SERCA钙转运效率的降低引起的，而线粒体解偶联不受影响。我们的研究结果支持这样一种假设，即可以降低骨骼肌能量效率以促进对肥胖的预防。
