Fatty acid oxidation and the regulation of malonyl-CoA in human muscle

Questions concerning whether malonyl-CoA is regulated in human muscle and w hether malonyl-CoA modulates fatty acid oxidation are still unanswered. To address these questions, whole-body fatty acid oxidation and the concentrat ion of malonyl-CoA, citrate, and malate were determined in the vastus later alis muscle of 16 healthy nonobese Swedish men during a sequential euglycem ic-hyperinsulinemic clamp. Insulin was infused at rates of 0.25 and 1.0 mU . kg(-1) . min(-1), and glucose was infused at rates of 2.0 +/- 0.2 and 8.1 +/- 0.7 mg . kg(-1) . min(-1), respectively. During the low-dose insulin i nfusion, whole-body fatty acid oxidation, as determined by indirect calorim etry, decreased by 22% from a basal rate of 0.94 +/- 0.06 to 0.74 +/- 0.07 mg . kg(-1) . min(-1) (P = 0.005), but no increase in malonyl-CoA was obser ved. In contrast, during the high-dose insulin infusion, malonyl-CoA increa sed from 0.20 +/- 0.01 to 0.24 +/- 0.01 nmol/g (P < 0.001), and whole-body fatty acid oxidation decreased by an additional 41% to 0.44 +/- 0.06 mg . k g(-1) . min(-1) (P < 0.001). The increase in malonyl-CoA was associated wit h 30-50% increases in the concentrations of citrate (102 +/- 6 vs. 137 +/- 7 nmol/g, P < 0.001), an allosteric activator of the rate-limiting enzyme i n the malonyl-CoA formation, acetyl-CoA carboxylase, and malate (80 +/- 6 v s. 126 +/- 9 nmol/g, P = 0.002), an antiporter for citrate efflux from the mitochondria. Significant correlations were observed between the concentrat ion of malonyl-CoA and both glucose utilization (r = 0.53, P = 0.002) and t he sum of the concentrations of citrate and malate (r = 0.52, P < 0.001), a proposed index of the cytosolic concentration of citrate. In addition, an inverse correlation between malonyl-CoA concentration and fatty acid oxidat ion was observed (r = -0.32, P = 0.03). The results indicate that an infusi on of insulin and glucose at a high rate leads to increases in the concentr ation of malonyl-CoA in skeletal muscle and to decreases in whole-body and, presumably, muscle fatty acid oxidation. Furthermore, they suggest that th e increase in malonyl-CoA in this situation is due, at least in part, to an increase in the cytosolic concentration of citrate. Because cytosolic citr ate is also an inhibitor of phosphofructokinase, an attractive hypothesis i s that changes in its concentration are part of an autoregulatory mechanism by which glucose modulates its own use and the use of fatty acids as fuels for skeletal muscle.