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

骨骼肌中瘦素和脂联素抵抗的早期发展——一种可能的保护机制

• 批准号: 217437-2011
• 负责人: Dyck, David
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=523792
• 关键词: early; development; leptin; adiponectin; resistance

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.

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）氧化和减少脂质积累的能力。发生胰岛素抵抗的病症，如肥胖，其特征在于对瘦素和脂联素对FA氧化的刺激作用的抵抗。对这些脂肪因子的抗性可在施用高脂肪饮食的数天内诱导，并且先于肌内脂质积聚和受损的胰岛素反应。因此，很容易推测，对这些脂肪因子的抗性的快速发展是肌肉中受损的胰岛素信号传导的早期发展的起始事件。然而，最近的研究结果已经挑战了线粒体FA氧化受损是肌肉中胰岛素反应受损的原因的教条。其他人假设继发于脂质可用性增加的FA β-氧化的过度速率可能产生各种有害物质，例如活性氧物质（ROS），其可能损害许多细胞蛋白，包括胰岛素信号级联的那些蛋白。值得注意的是，仅在高脂肪喂养3天后，肌肉中的ROS升高。我们认为，在高脂饮食期间瘦素和脂联素抵抗的快速发展不是胰岛素信号传导受损的原因，而是限制过多FA进入胰岛素和随后ROS产生的保护机制。 下面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器。