PPAR‐alpha agonist increases skeletal muscle carnitine palmitoyltransferase‐1 activity and fatty acid oxidation in obese insulin‐resistant monkeys

Abstract

The selective PPAR‐alpha agonist K‐111 (Kowa Co. Ltd., Tokyo, Japan) decreases plasma triglycerides and improves insulin sensitivity in obese, insulin‐resistant rhesus monkeys. The purpose of this study was to determine whether K‐111 improves skeletal muscle fatty acid oxidation and enzymes involved in fatty acid metabolism. Five obese, insulin‐resistant adult monkeys were studied at baseline and again after treatment with K‐111 at 3 mg/kg μday for 7 weeks. Acyl‐CoA synthase (ACS), carnitine palmitoyltransferase‐1 (CPT‐1), β‐hydroxy‐acyl CoA dehydrogenase ( β‐HAD), citrate synthase (CS) and total fatty acid oxidation were measured in skeletal muscle homogenates at baseline and following K‐111. CPT‐1 activity significantly increased (0.012 ± 0.004 vs. 0.019 ± 0.004 pmol/min μ;mg protein, p<0.05) and total fatty acid oxidation tended to increase (2.1 ± 0.6 vs. 4.0 ± 1.1 pmol/min μmg protein, p<0.07) following treatment. ACS activity (128 ± 25 vs. 180 ± 11 pmol/min μmg protein), β‐HAD activity (0.182 ± 0.05 vs. 0.190 ± 0.03) and CS activity (0.108 ± 0.02 vs. 0.116 ± 0.01 µmol/min μmg protein) were not significantly affected by treatment. The change in total fatty acid oxidation was associated with the change in ß‐HAD and CS activity (p<0.01) but not to CPT‐1 activity. These results suggest that the mechanism by which PPAR‐alpha agonist treatment improves fatty acid oxidation is through changes in ß‐HAD and CS activity.