Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
School of Applied Science, University of Campinas, Limeira, SP, Brazil.
Diabetologia. 2023 Mar;66(3):567-578. doi: 10.1007/s00125-022-05838-8. Epub 2022 Dec 1.
AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content.
C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle.
We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine on the insulin receptor kinase (IRK), and reductions in insulin-stimulated IRK phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively.
CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.
目的/假设：尽管肌肉内三酰甘油含量增加，运动员仍表现出肌肉胰岛素敏感性增加。这种现象被称为“运动员悖论”，目前了解甚少。最近的研究结果表明，质膜中 sn-1,2-二酰基甘油（DAG）的亚细胞分布导致新型蛋白激酶 C（PKC）的激活是诱导胰岛素抵抗的关键途径。在这里，我们假设定期有氧运动可以通过防止质膜 sn-1,2-DAG 的增加和 PKCε和 PKCθ 的激活来维持肌肉胰岛素敏感性，尽管这会促进肌肉三酰甘油含量的增加。
将 C57BL/6J 小鼠分为三组（常规饮食喂养[RC]；高脂肪饮食喂养[HFD]；RC 喂养和跑步轮运动[RC-EXE]）。我们使用一种新的 LC-MS/MS/细胞分离方法来评估骨骼肌五个亚细胞区室（质膜[PM]、内质网、线粒体、脂滴和细胞质）中 DAG 立体异构体。
我们发现，与 RC 小鼠相比，HFD 组多个亚细胞区室中的 sn-DAG 和神经酰胺含量更高，这与 PKCε和 PKCθ易位增加有关。然而，RC-EXE 组小鼠 PM sn-1,2-DAG 和神经酰胺含量明显低于 HFD 组小鼠。与 PM sn-1,2-DAG-新型 PKC 假说一致，我们观察到 HFD 组与 RC 和 RC-EXE 组相比，胰岛素受体激酶（IRK）上苏氨酸的磷酸化增加，胰岛素刺激的 IRK 磷酸化和 IRS-1 相关的磷酸肌醇 3-激酶活性降低，这些分别是 PKCε和 PKCθ作用的部位。
结论/解释：这些结果表明，RC-EXE 小鼠肌肉胰岛素敏感性的保留可以解释为 PKCθ/PKCε 活性和 sn-1,2-DAG 含量降低，尤其是在质膜区室中。
