Malonyl CoA is a regulator of
carnitine palmitoyl
transferase 1 (CPT1), the
enzyme that controls the transfer of long chain
fatty acyl CoA into mitochondria where it is oxidized. Recent studies indicate that in skeletal muscle the concentration of
malonyl CoA is acutely (minutes) regulated by changes in its fuel supply and energy expenditure. In response to changes in fuel supply, regulation appears to be due to alterations in the cytosolic concentration of
citrate, which is both an allosteric activator of
acetyl CoA carboxylase (ACC), the
enzyme that catalyzes
malonyl CoA synthesis and a source of its precursor, cytosolic
acetyl CoA. During exercise and immediately thereafter regulation by
citrate appears to be lost and
malonyl CoA levels diminish as the result of a decrease in ACC activity secondary to phosphorylation. Sustained increases in the concentration of
malonyl CoA have been observed in muscle of a number of
insulin-resistant rodents including the Zucker (fa/fa) and GK rats, KKAgy mice,
glucose-infused rats and rats in which muscle has been made
insulin resistant by
denervation. Available data suggest that
malonyl CoA could be linked to
insulin resistance in these rodents by virtue of its effects on the cytosolic concentration of long chain
fatty acyl CoA (LCFA
CoA) and one or more
protein kinase C isozymes. Whether similar alterations occur in other tissues and contribute to the pathophysiology of the
insulin resistance syndrome remains to be determined.