Malonyl CoA is an inhibitor of
carnitine palmitoyl
transferase 1 (CPT1), the
enzyme that regulates the transfer of long chain
fatty acyl CoA into mitochondria. By virtue of this effect, it is thought to play a key role in regulating
fatty acid oxidation. Thus, when the supply of
glucose to muscle is increased,
malonyl CoA levels increase in keeping with a decreased need for
fatty acid oxidation, and
fatty acids are preferentially esterified to form diaglycerol and
triglycerides. In contrast, during exercise, when the need for
fatty acid oxidation is increased,
malonyl CoA levels fall. Changes in
glucose supply regulate
malonyl CoA by modulating the concentration of cytosolic
citrate, an allosteric activator of
acetyl CoA carboxylase (ACC), the rate-limiting
enzyme for
malonyl CoA formation and a precursor of its substrate cytosolic
acetyl CoA. Conversely, exercise lowers the concentration of
malonyl CoA, by activating an
AMP-activated protein kinase, which phosphorylates and inhibits ACC. A number of reports have linked sustained increases in the concentration of
malonyl CoA in muscle to
insulin resistance. In this paper, we review these reports, as well as the notion that changes in
malonyl CoA contribute to the increases in long chain
fatty acyl CoA, (LCFA
CoA),
diacylglycerol and
triglyceride content and changes in
protein kinase C activity and distribution observed in
insulin-resistant muscle. We also review the implications of the
malonyl CoA/LCFA
CoA hypothesis to two other proposed mechanisms for
insulin resistance, the
glucose-
fatty acid cycle and the
hexosamine theory.