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Role of malonyl-CoA in heart disease and the hypothalamic control of obesity Folmes CD; Lopaschuk GDCardiovasc Res 2007[Jan]; 73 (2): 278-87Obesity 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.|AMP-Activated Protein Kinases[MESH]|Acetyl-CoA Carboxylase/metabolism[MESH]|Acyl Coenzyme A/metabolism[MESH]|Animals[MESH]|Appetite Regulation/*physiology[MESH]|Carnitine O-Palmitoyltransferase/metabolism[MESH]|Energy Metabolism[MESH]|Heart Diseases/*metabolism[MESH]|Humans[MESH]|Hypothalamus/*physiology[MESH]|Malonyl Coenzyme A/*physiology[MESH]|Multienzyme Complexes/metabolism[MESH]|Obesity/*metabolism[MESH]|Protein Serine-Threonine Kinases/metabolism[MESH] |