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

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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.