The effects of lipid availability on skeletal muscle metabolism in lean and obese rodents and humans.

摘要

This thesis is an investigation of the effect of lipid exposure on FA metabolism, glucose transport and insulin signaling in skeletal muscle of rodents and lean and obese humans. This thesis also examined whether specific insulin sensitizing agents (globular adiponectin (gAd), exercise, ceramide synthesis inhibitor (fumonisin B1; (FB1)) could prevent the suspected deleterious effects of palmitate. Finally, this thesis examined whether the lipogenic capacity of muscle of obese humans is different compared to lean.;Skeletal muscle of obese humans is characterized by increased FA transport and TAG accumulation; however little is known about the role of lipogenesis in lipid accumulation in obesity. In the second study, the skeletal muscle lipogenic capacity, and proteins involved in ceramide metabolism were not different between lean and obese humans. Ceramide content and protein phosphatase 2A expression were significantly increased in muscle of obese humans. This research suggests that skeletal muscle of obese humans is not responding appropriately to increased FA transport. As a result excess FA are directed toward ceramide accumulation.;Finally, 4 hr of 2 mM palmitate exposure in soleus of sedentary (SED) rats impaired insulin-stimulated glucose transport and caused ceramide, diacylglycerol (DAG) and triacylglycerol (TAG) accumulation. A prior bout of exercise (EX) prevented the detrimental effects of palmitate on insulin signaling and caused a partial redistribution of FA toward TAG. EX also caused the largest absolute increase in ceramide accumulation, despite the maintenance of insulin sensitivity. The incubation of soleus from SED rats with FB1 (SED+FB1) prevented the detrimental effects of palmitate and caused a redirection of FA toward DAG and TAG accumulation. Therefore, inhibiting ceramide accumulation can prevent the detrimental effects of palmitate; however EX protects against palmitate-induced insulin resistance through a ceramide independent mechanism.;In the first study, 4 hrs of 2 mM palmitate exposure impaired insulin-stimulated glucose transport in skeletal muscle from obese but not lean individuals. The co-incubation of 2.5 mug/mL gAd did not prevent the effect of palmitate. Globular Ad stimulated fatty acid (FA) oxidation in lean and obese humans, suggesting that stimulating FA oxidation is not sufficient to prevent the detrimental effects of palmitate.