In liver,
insulin and
glucose acutely increase the concentration of
malonyl-CoA by dephosphorylating and activating
acetyl-CoA carboxylase (ACC). In contrast, in incubated rat skeletal muscle, they appear to act by increasing the cytosolic concentration of
citrate, an allosteric activator of ACC, as reflected by increases in the whole cell concentrations of
citrate and
malate [Saha, A. K., D. Vavvas, T. G. Kurowski, A. Apazidis, L. A. Witters, E. Shafrir, and N. B. Ruderman. Am. J. Physiol. 272 (Endocrinol. Metab. 35): E641-E648, 1997]. We report here that sustained increases in plasma
insulin and
glucose may also increase the concentration of
malonyl-CoA in rat skeletal muscle in vivo by this mechanism. Thus 70 and 125% increases in
malonyl-CoA induced in skeletal muscle by infusions of
glucose for 1 and 4 days, respectively, and a twofold increase in its concentration during a 90-min euglycemic-hyperinsulinemic clamp were all associated with significant increases in the sum of whole cell concentrations of
citrate and/or
malate. Similar correlations were observed in muscle of the hyperinsulinemic fa/fa rat, in denervated muscle, and in muscle of rats infused with
insulin for 5 h. In muscle of 48-h-starved rats 3 and 24 h after refeeding, increases in
malonyl-CoA were not accompanied by consistent increases in the concentrations of
malate or
citrate. However, they were associated with a decrease in the whole cell concentration of long-chain
fatty acyl-CoA (LCFA-
CoA), an allosteric inhibitor of ACC. The results suggest that increases in the concentration of
malonyl-CoA, caused in rat muscle in vivo by sustained increases in plasma
insulin and
glucose or
denervation, may be due to increases in the cytosolic concentration of
citrate. In contrast, during refeeding after
starvation, the increase in
malonyl-CoA in muscle is probably due to another mechanism.