A role for hypothalamic malonyl-CoA in the control of food intake.
The cellular level of malonyl-CoA, an intermediate in fatty acid biosynthesis, depends on its rate of synthesis catalyzed by acetyl-CoA carboxylase relative to its rate of utilization and degradation catalyzed by fatty acid synthase and malonyl-CoA decarboxylase, respectively. Recent evidence suggests that hypothalamic malonyl-CoA functions in the regulation of feeding behavior by altering the expression of key orexigenic and anorexigenic neuropeptides. Here we report that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a 5'-AMP kinase activator, rapidly lowers malonyl-CoA both in GT1-7 hypothalamic neurons and in the hypothalami of mice. These effects correlate closely with the phosphorylation of acetyl-CoA carboxylase, an established target of AMP kinase. Intracerebroventricular (i.c.v.) administration of AICAR rapidly lowers hypothalamic [malonyl-CoA] and increases food intake. Expression of an adenoviral cytosolic malonyl-CoA decarboxylase vector (Ad-cMCD) in hypothalamic GT1-7 cells decreases malonyl-CoA. When delivered by bilateral stereotaxic injection into the ventral hypothalamus (encompassing the arcuate nucleus) of mice, Ad-cMCD increases food intake and body weight. Ad-MCD delivered into the ventral hypothalamus also reverses the rapid suppression of food intake caused by i.c.v.-administered C75, a fatty acid synthase inhibitor that increases hypothalamic [malonyl-CoA]. Taken together these findings implicate malonyl-CoA in the hypothalamic regulation of feeding behavior.
Hu
Zhiyuan
Z
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Dai
Yun
Y
Prentki
Marc
M
Chohnan
Shigeru
S
Lane
M Daniel
MD
D000256:Adenoviridae / Q000235:genetics; D000263:Adenylate Kinase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000737:chemistry; D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism; D002384:Catalysis; D002478:Cells, Cultured; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005247:Feeding Behavior; D005822:Genetic Vectors; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007763:Lac Operon; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D051381:Rats; D012265:Ribonucleotides / Q000737:chemistry; D013997:Time Factors
D018076:DNA, Complementary; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D010455:Peptides; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008316:Malonyl Coenzyme A; D064429:Fatty Acid Synthases; D000263:Adenylate Kinase; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; C031143:AICA ribonucleotide