Acute and chronic effects of leptin on skeletal muscle fatty acid metabolism

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Steinberg, Gregory R.

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University of Guelph

Abstract

Leptin reduces food intake and increases energy expenditure in rodents through actions on both central and peripheral tissues. In rodents, skeletal muscle is an important target of leptin and previous studies have demonstrated that leptin both acutely and chronically reduces intramuscular triacylglycerol (TG). Despite the pronounced effects of elevated leptin levels in rodents, high levels of leptin in obesity suggest the development of leptin resistance. Therefore, the objectives of this thesis were to (1) determine the mechanisms by which leptin chronically reduces intramuscular TG stores in rodents and (2) examine the development of leptin resistance in rodent and human skeletal muscle. Chronic leptin treatment (14 days) repartitioned FA towards oxidation and away from TG storage while also enhancing TG hydrolysis as measured in isolated soleus muscle using the pulse-chase technique. Increased oxidation rates and TG hydrolysis were not due to increased oxidative capacity or increased expression of hormone sensitive lipase respectively. Despite increased FA oxidation, FA transport in skeletal muscle was reduced due to reduced FA transport protein expression (FAT/CD36 and FABPpm) at the level of the plasma membrane. Thus, a reduced rate of FA transport combined with higher rates of FA oxidation and TG hydrolysis reduced intramuscular TG, possibly resulting in improved insulin sensitivity. Direct evidence for leptin resistance in peripheral tissues such as skeletal muscle did not previously exist. Therefore, we investigated whether leptin's acute stimulatory effects on skeletal muscle FA metabolism would be reduced following high-fat feeding. In both high-fat groups (safflower and fish oil), the stimulatory effect of leptin on muscle lipid oxidation and hydrolysis was eliminated. Partial substitution of fish oil resulted in the restoration of leptin's inhibition of TG esterification. Based on the above experimental results, we hypothesized that during the development of human obesity skeletal muscle also becomes resistant to leptin. We tested this hypothesis by measuring FA metabolism with and without leptin, in rectus abdominus muscle strips from lean and obese women. In lean women, leptin repartitioned FA towards oxidation and away from esterification. This effect was eliminated in the obese, thus providing the first evidence of leptin resistance in obese human skeletal muscle. We conclude that while leptin increases skeletal muscle FA metabolism in rodents and lean humans, it is ineffective in rodents fed high-fat diets and obese humans.

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mechanism, leptin, reduction, intramuscular, triacylglycerol, leptin resistance, rodents, human, skeletal muscle

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