Fatty acid oxidation in human skeletal muscle.

Abstract

In this issue of the JCI, Rasmussen et al. (1) describe the functional regulation of fatty acid oxidation by hyperglycemia and hyperinsulinemia in human skeletal muscle. The authors report inhibition of long-chain fatty acid (LCFA) oxidation, but not medium-chain fatty acid (MCFA) oxidation, in association with increased intramyocellular malonyl-CoA concentrations. Normally, a glucose infusion designed to raise intramyocellular malonyl-CoA by creating hyperglycemia would suppress plasma FFA concentrations from the usual (∼500 μmol/l) to extremely low levels (<30 μmol/l) in normal, healthy volunteers, making measures of LCFA oxidation uninterpretable. By maintaining stable plasma FFA concentrations, the investigators could reasonably compare MCFA oxidation, a process not dependent upon carnitine palmitoyltransferase-1 (CPT-1), with LCFA oxidation, a process that is dependent upon CPT-1 activity. Malonyl-CoA is a potent inhibitor of CPT-1 activity (2), and thus increases in malonyl-CoA concentration should inhibit access of LCFAs into the mitochondria (Figure ​(Figure1).1). These data are the best evidence to date that changes in intramyocellular malonyl-CoA participate in the regulation of LCFA oxidation in humans. Figure 1 The major sites of regulation of fatty acid entry into myocellular mitochondria. Insulin inhibits (–) lipolysis, thus lowering FFA concentrations and limiting FFA availability for transport into muscle. Insulin stimulates (+) muscle glucose ...