Malonyl-CoA, fuel sensing, and insulin resistance

Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase (C PT) I, the enzyme that controls the transfer of long-chain fatty acyl (LCFA )-CoAs into the mitochondria where they are oxidized. In rat skeletal muscl e, the formation of malonyl-CoA is regulated acutely (in minutes) by change s in the activity of the beta-isoform of acetyl-CoA carboxylase (ACC(beta)) . This can occur by at least two mechanisms: one involving cytosolic citrat e, an allosteric activator of ACC(beta) and a precursor of its substrate cy tosolic acetyl-CoA, and the other involving changes in ACC(beta) phosphoryl ation. Increases in cytosolic citrate leading to an increase in the concent ration of malonyl-CoA occur when muscle is presented with insulin and gluco se, or when it is made inactive by denervation, in keeping with a diminishe d need for fatty acid oxidation in these situations. Conversely, during exe rcise, when the need of the muscle cell for fatty acid oxidation is increas ed, decreases in the ATP/AMP and/or creatine phosphate-to-creatine ratios a ctivate an isoform of an AMP-activated protein kinase (AMPK), which phospho rylates ACC(beta) and inhibits both its basal activity and activation by ci trate. The central role of cytosolic citrate links this malonyl-CoA regulat ory mechanism to the glucose-fatty acid cycle concept of Randle et al. (P. J. Randle, P. B. Garland. C. N. Hales, and E. A. Newsholme. Lancet 1: 785-7 89, 1963) and to a mechanism by which glucose might autoregulate its own us e. A similar citrate-mediated malonyl-CoA regulatory mechanism appears to e xist in other tissues, including the pancreatic p-cell, the heart, and prob ably the central nervous system. It is our hypothesis that by altering the cytosolic concentrations of LCFA-CoA and diacylglycerol, and secondarily th e activity of one or more protein kinase C isoforms, changes in malonyl-CoA provide a link between fuel metabolism and signal transduction in these ce lls. It is also our hypothesis that dysregulation of the malonyl-CoA regula tory mechanism, if it leads to sustained increases in the concentrations of malonyl-CoA and cytosolic LCFA-CoA, could play a key role in the pathogene sis of insulin resistance in muscle. That it may contribute to abnormalitie s associated with the insulin resistance syndrome in other tissues and the development of obesity has also been suggested. Studies are clearly needed to test these hypotheses and to explore the notion that exercise and some p harmacological agents that increase insulin sensitivity act via effects on malonyl-CoA and/or cytosolic LCFA-CoA.