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Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents

¹Diabetes and Obesity Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia;
²School of Health Sciences, University of Wollongong, Wollongong, NSW, Australia;
³Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
⁴St Vincent's Hospital Clinical School, University of New South Wales, Sydney, NSW, Australia.

Correspondence: n.turner{at}garvan.org.au

Objective:A reduced capacity for mitochondrial fatty acid oxidation in skeletal muscle has been proposed as a major factor leading to the accumulation of intramuscular lipids and their subsequent deleterious effects on insulin action. Here we examine markers of mitochondrial fatty acid oxidative capacity in rodent models of insulin resistance associated with an oversupply of lipid.

Research Design and Methods:C57BL/6J mice were fed a high-fat diet for either 5 wk or 20 wk. Several markers of muscle mitochondrial fatty acid oxidative capacity were measured including ¹⁴C-palmitate oxidation, palmitoyl-CoA oxidation in isolated mitochondria, oxidative enzyme activity (citrate synthase, ßHAD, MCAD, CPT1) and expression of proteins involved in mitochondrial metabolism. Enzyme activity and mitochondrial protein expression were also examined in muscle from other rodent models of insulin resistance.

Results:Compared with chow controls, muscle from fat-fed mice displayed elevated palmitate oxidation rate (5 wk +23%, p<0.05 and 20 wk +29%, p<0.05) and increased palmitoyl-CoA oxidation in isolated mitochondria (20 wk +49%, p<0.01). Furthermore, oxidative enzyme activity and protein expression of PGC-1, UCP3 and mitochondrial respiratory chain subunits were significantly elevated in fat-fed animals. A similar pattern was present in muscle of fat-fed rats, obese Zucker rats and db/db mice, with increases observed for oxidative enzyme activity and expression of PGC-1, UCP3 and subunits of the mitochondrial respiratory chain.

Conclusions:These findings suggest that high lipid availability does not lead to intramuscular lipid accumulation and insulin resistance in rodents by decreasing muscle mitochondrial fatty acid oxidative capacity.

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