title: Role of malonyl-CoA in heart disease and the hypothalamic control of obesity.
abstract: Obesity is an important contributor to the risk of developing insulin resistance, diabetes, and heart disease. Alterations in tissue levels of malonyl-CoA have the potential to impact on the severity of a number of these disorders. This review will focus on the emerging role of malonyl-CoA as a key "metabolic effector" of both obesity and cardiac fatty acid oxidation. In addition to being a substrate for fatty acid biosynthesis, malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase (CPT) 1, a key enzyme involved in mitochondrial fatty acid uptake. A decrease in myocardial malonyl-CoA levels and an increase in CPT1 activity contribute to an increase in cardiac fatty acid oxidation. An increase in malonyl-CoA degradation due to increased malonyl-CoA decarboxylase (MCD) activity may be one mechanism responsible for this decrease in malonyl-CoA. Another mechanism involves the inhibition of acetyl-CoA carboxylase (ACC) synthesis of malonyl-CoA, due to AMP-activated protein kinase (AMPK) phosphorylation of ACC. Recent studies have demonstrated a role of malonyl-CoA in the hypothalamus as a regulator of food intake. Increases in hypothalamic malonyl-CoA and inhibition of CPT1 are associated with a decrease in food intake in mice and rats, while a decrease in hypothalamic malonyl-CoA increases food intake and weight gain. The exact mechanism(s) responsible for these effects of malonyl-CoA are not clear, but have been proposed to be due to an increase in the levels of long chain acyl CoA, which occurs as a result of malonyl-CoA inhibition of CPT1. Both hypothalamic and cardiac studies have demonstrated that control of malonyl-CoA levels has an important impact on obesity and heart disease. Targeting enzymes that control malonyl-CoA levels may be an important therapeutic approach to treating heart disease and obesity.
authors.affiliation: Cardiovascular Research Group, Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Clifford D L
authors.initials: CD
authors.lastname: Folmes
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004734:Energy Metabolism; D006331:Heart Diseases / Q000378:metabolism*; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D008316:Malonyl Coenzyme A / Q000502:physiology*; D009097:Multienzyme Complexes / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D009097:Multienzyme Complexes; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase