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Regulation of food intake and energy expenditure by hypothalamic malonyl-CoA.
Lane, M D; Wolfgang, M; Cha, S-H; Dai, Y.
Afiliação
  • Lane MD; Department of Biological Chemistry, Johns Hopkins University Medical School, Baltimore, MD 21205, USA. dlane@jhmi.edu
Int J Obes (Lond) ; 32 Suppl 4: S49-54, 2008 Sep.
Article em En | MEDLINE | ID: mdl-18719599
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.
Assuntos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ingestão de Alimentos / Metabolismo Energético / Hipotálamo / Malonil Coenzima A Tipo de estudo: Health_economic_evaluation Limite: Animals Idioma: En Revista: Int J Obes (Lond) Assunto da revista: METABOLISMO Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Ingestão de Alimentos / Metabolismo Energético / Hipotálamo / Malonil Coenzima A Tipo de estudo: Health_economic_evaluation Limite: Animals Idioma: En Revista: Int J Obes (Lond) Assunto da revista: METABOLISMO Ano de publicação: 2008 Tipo de documento: Article País de afiliação: Estados Unidos