Regulation of fat metabolism in skeletal muscle

ABSTRACT: Regulation of carbohydrate and fat utilization by skeletal muscle at rest and during exercise has been the subject of investigation since the early 1960s when Randle et al. proposed the so-called glucose–fatty acid cycle to explain the reciprocal relationship between carbohydrate and fat metabolism. The suggested mechanisms were based on the premise that an increase in fatty acid (FA) availability would result in increased fat metabolism and inhibition of carbohydrate metabolism. Briefly, accumulation of acetyl-CoA would result in inhibition of pyruvate dehydrogenase (PDH), accumulation of citrate would inhibit phosphofructokinase (PFK), and accumulation of glucose-6-phosphate (G6P) would reduce hexokinase (HK) activity. Ultimately, this would inhibit carbohydrate metabolism with increasing availability and oxidation of FA. Although there is some evidence for the existence of the glucose-FA cycle at rest and during low-intensity exercise, it cannot explain substrate use at moderate to high exercise intensities. More recently, evidence has accumulated that increases in glycolytic flux may decrease fat metabolism. Potential sites of regu