title: Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA.
abstract: Energy balance is monitored by the hypothalamus. Malonyl-CoA, an intermediate in fatty acid synthesis, serves as an indicator of energy status in the hypothalamic neurons. The cellular malonyl-CoA level is determined by its rate of synthesis, catalyzed by acetyl-CoA carboxylase (ACC), and rate of removal, by fatty acid synthase (FAS). Malonyl-CoA functions in the hypothalamic neurons that express orexigenic and anorexigenic neuropeptides. Inhibitors of FAS, administered systemically or intracerebroventricularly to mice, increase hypothalamic malony-CoA and suppress food intake. Recent evidence suggests that the changes of hypothalamic malonyl-CoA during feeding and fasting cycles are caused by changes in the phosphorylation state and activity of ACC mediated via 5'-AMP-activated protein kinase (AMPK). Stereotactic delivery of a viral malonyl-CoA decarboxylase (MCD) vector into the ventral hypothalamus lowers malonyl-CoA and increases food intake. Fasting decreases hypothalamic malonyl-CoA and refeeding increases hypothalamic malonyl-CoA, to alter feeding behavior in the predicted manner. Malonyl-CoA level is under the control of AMP kinase which phosphorylates/inactivates ACC. Malonyl-CoA is an inhibitor of carnitine palmitoyl-CoA transferase-1 (CPT1), an outer mitochondrial membrane enzyme that regulates entry into, and oxidation of fatty acids, by mitochondria. CPT1c, a recently discovered, brain-specific enzyme expressed in the hypothalamus, has high sequence similarity to liver/muscle CPT1a/b and binds malonyl-CoA, but does not catalyze the prototypical reaction. This suggests that CPT1c has a unique function or activation mechanism. CPT1c knockout (KO) mice have lower food intake, weigh less and have less body fat, consistent with the role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c protects against the effects of a high-fat diet. CPT1cKO mice exhibit decreased rates of fatty acid oxidation, consistent with their increased susceptibility to diet-induced obesity. We suggest that CPT1c may be a downstream target of malonyl-CoA that regulates energy homeostasis.
authors: Department of Biological Chemistry, Johns Hopkins University Medical School, Baltimore, MD 21205, USA. dlane@jhmi.edu
authors: M D
authors: MD
authors: Lane
authors: M
authors: M
authors: Wolfgang
authors: S-H
authors: SH
authors: Cha
authors: Y
authors: Y
authors: Dai
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D004435:Eating / Q000502:physiology*; D004734:Energy Metabolism / Q000502:physiology*; D064429:Fatty Acid Synthases / Q000378:metabolism; D007031:Hypothalamus / Q000201:enzymology* / Q000502:physiology; D008316:Malonyl Coenzyme A / Q000378:metabolism* / Q000502:physiology; D051379:Mice
chemical_list: D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D000103:Acetyl-CoA Carboxylase