Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids

Abstract

GW501516, an agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta), increases lipid combustion and exerts antidiabetic action in animals, effects which are attributed mainly to direct effects on skeletal muscle. We explored such actions further in isolated rat skeletal muscle. Specimens of rat skeletal muscle were pretreated with GW501516 (0.01-30 mumol/l) for 0.5, 4 or 24 h and rates of fuel metabolism were then measured. In addition, effects on mitochondrial function were determined in isolated rat liver mitochondria. At concentrations between 0.01 and 1 mumol/l, GW501516 dose-dependently increased fatty acid oxidation but reduced glucose utilisation in isolated muscle. Thus after 24 h of preincubation with 1 mumol/l GW501516, palmitate oxidation increased by +46+/-10%, and the following decreased as specified: glucose oxidation -46+/-8%, glycogen synthesis -42+/-6%, lactate release -20+/-2%, glucose transport -15+/-6% (all p<0.05). Reduction of glucose utilisation persisted independently of insulin stimulation or muscle fibre type, but depended on fatty acid availability (the effect on glucose transport in the absence of fatty acids was an increase of 30+/-9%, p<0.01), suggesting a role for the glucose-fatty acid cycle. At higher concentrations, GW501516 uncoupled oxidative phosphorylation by direct action on isolated mitochondria. GW501516-induced activation of PPAR-delta reduces glucose utilisation by skeletal muscle through a switch in mitochondrial substrate preference from carbohydrate to lipid. High concentrations of GW501516 induce mitochondrial uncoupling independently of PPAR-delta.