The early development of leptin and adiponectin resistance in skeletal muscle - a possible protective mechanism

瘦素和脂联素是改善骨骼肌中胰岛素反应的脂肪因子，这种作用归因于它们刺激脂肪酸(FA)氧化和减少脂肪堆积的能力。发生胰岛素抵抗的情况，如肥胖，其特点是对瘦素和脂联素对脂肪酸氧化的刺激作用产生抵抗。对这些脂肪因子的抵抗可以在服用高脂肪饮食的几天内诱导，并先于肌肉内脂肪积累和胰岛素反应受损。因此，人们很容易推测，对这些脂肪因子的快速抵抗是肌肉中胰岛素信号受损早期发展的始动事件。然而，最近的研究结果挑战了线粒体FA氧化受损是肌肉中胰岛素反应受损的原因这一教条。另一些人则提出假设，脂质供应增加所导致的过量FA？氧化可能会产生各种有害物种，如活性氧物种(ROS)，这可能会损害许多细胞蛋白质，包括胰岛素信号转导系统中的蛋白质。值得注意的是，仅在高脂肪喂养3天后，肌肉中的ROS就会升高。我们认为，在高脂饮食过程中，瘦素和脂联素抵抗的快速发展并不是胰岛素信号受损的原因，而是一种保护机制，以限制过量的FA进入线粒体并随后产生ROS。接下来的一系列实验将检验我们的一般工作假设，即ROS的产生是瘦素和脂联素刺激线粒体FA摄取能力的重要控制因素。

Leptin and adiponectin are adipokines that improve insulin response in skeletal muscle, an effect attributed to their ability to stimulate fatty acid (FA) oxidation and decrease lipid accumulation. Conditions in which insulin resistance occurs, such as obesity, are characterized by a resistance to the stimulatory effects of leptin and adiponectin on FA oxidation. Resistance to these adipokines can be induced within days of administering a high fat diet, and precedes intramuscular lipid accumulation and impaired insulin response. Thus, it is tempting to speculate that the rapid development of resistance to these adipokines is an initiating event in the early development of impaired insulin signalling in muscle. However, findings of recent studies have challenged the dogma that impaired mitochondrial FA oxidation is the cause of impaired insulin response in muscle. Others have hypothesized that an excessive rate of FA ß-oxidation secondary to increased lipid availability may generate various deleterious species, such as reactive oxygen species (ROS), which can potentially damage many cellular proteins including those of the insulin signalling cascade. Notably, ROS are elevated in muscle after only 3 days of high fat feeding. It is our view that the rapid development of leptin and adiponectin resistance during the administration of a high fat diet is not the cause of impaired insulin signalling, but rather a protective mechanism to limit excessive FA entry into the mitochondrion and subsequent ROS production. The following series of experiments will test our general working hypothesis that ROS production is an important controller of leptin and adiponectin's ability to stimulate mitochondrial FA uptake.