Fatty acid oxidation in human skeletal muscle.

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 1). These data are the best evidence to date that changes in intramyocellular malonyl-CoA participate in the regulation of LCFA oxidation in humans. Intracellular fatty acid trafficking As noted, insulin normally inhibits lipolysis (3), thereby lowering plasma FFA concentrations and depriving cells of the primary source of circulating lipid fuel. In addition, insulin drives glucose into cells, stimulating both glucose storage and oxidation. This increase in intracellular glucose metabolism leads to the synthesis of malonylCoA and generates increased amounts of glycerol-3-phosphate, a compound used by cells to esterify intracellular LCFA-CoA (but not MCFA) (Figure 1). Thus, hyperinsulinemia, such as that which normally occurs after meal ingestion, drastically limits the availability of FFA to muscle, further inhibits LCFA oxidation even if LCFAs enter the cell, and makes available more glycerol-3-phosphate for LCFA esterification into triglyceride. The opposite situation occurs in circumstances such as starvation, where plasma insulin concentrations drop dramatically. Plasma FFA concentrations can increase dramatically (4) (3,000 μmol/l is not unheard of), and FFAs are readily taken up by muscle (5). The reduced uptake of glucose by muscle is thought to lower malonyl-CoA concentrations (2), permitting greater LCFA entry into the mitochondria. Exercise also increases FFA uptake into muscle, but in this case there is also increased glucose uptake and oxidation. Under these circumstances, however, reduced activity of acetyl-CoA carboxylase-β (ACCβ) actually decreases malonyl-CoA concentrations, thus relieving any residual CPT-1 activity and increasing fatty acid oxidation. One might question the utility of an intracellular regulator of LCFA entry into the mitochondria, given the 100fold range of possible plasma FFA concentrations. Shouldn’t this range be more than sufficient to regulate muscle LCFA oxidation? It is clear, however, that intracellular events can magniCOMMENTARY