PMID- 14532332
OWN - NLM
STAT- MEDLINE
DCOM- 20040105
LR  - 20181113
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 100
IP  - 22
DP  - 2003 Oct 28
TI  - Hypothalamic malonyl-CoA as a mediator of feeding behavior.
PG  - 12624-9
AB  - Previous studies showed that i.p. administration of C75, a potent inhibitor of 
      fatty acid synthase (FAS), blocked fasting-induced up-regulation of orexigenic 
      neuropeptides and down-regulation of anorexigenic neuropeptides in the 
      hypothalami of mice. As a result, food intake and body weight were drastically 
      reduced. Here we provide evidence supporting the hypothesis that hypothalamic 
      malonyl-CoA, a substrate of FAS, is an indicator of global energy status and 
      mediates the feeding behavior of mice. We use a sensitive recycling assay to 
      quantify malonyl-CoA to show that the hypothalamic malonyl-CoA level is low in 
      fasted mice and rapidly (< or = 2 h) increases (approximately 5-fold) on 
      refeeding. Intracerebroventricular (i.c.v.) administration of C75 to fasted mice 
      rapidly (< or = 2 h) increased (by 4-fold) hypothalamic malonyl-CoA and blocked 
      feeding when the mice were presented with food. Moreover, prior i.c.v. 
      administration of an acetyl-CoA carboxylase inhibitor, 5-(tetradecyloxy)-2-furoic 
      acid, rapidly (although only partially) prevented the C75-induced rise of 
      hypothalamic malonyl-CoA and prevented the C75-induced decrease of food intake. 
      These effects correlated closely with the rapid (< or = 2 h) and reciprocal 
      effects of i.c.v. C75 on the expression of hypothalamic orexigenic (NPY and AgRP) 
      and anorexigenic (proopiomelanocortin) neuropeptide mRNAs. Previous results 
      showing that C75 administered i.c.v. rapidly activates hypothalamic neurons of 
      the arcuate and paraventricular nuclei are consistent with the results reported 
      in this paper. Together these findings suggest that level of hypothalamic 
      malonyl-CoA, which depends on the relative activities of acetyl-CoA carboxylase 
      and FAS, is an indicator of energy status and mediates feeding behavior.
FAU - Hu, Zhiyuan
AU  - Hu Z
AD  - Department of Biological Chemistry, Johns Hopkins University School of Medicine, 
      Baltimore, MD 21205, USA.
FAU - Cha, Seung Hun
AU  - Cha SH
FAU - Chohnan, Shigeru
AU  - Chohnan S
FAU - Lane, M Daniel
AU  - Lane MD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20031007
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (4-methylene-2-octyl-5-oxofuran-3-carboxylic acid)
RN  - 524-14-1 (Malonyl Coenzyme A)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
RN  - OL659KIY4X (4-Butyrolactone)
SB  - IM
MH  - 4-Butyrolactone/administration & dosage/*analogs & derivatives/*pharmacology
MH  - Animals
MH  - Fasting
MH  - Fatty Acid Synthases/antagonists & inhibitors
MH  - Feeding Behavior/drug effects/*physiology
MH  - Hypothalamus/drug effects/*physiology
MH  - Injections, Intraventricular
MH  - Male
MH  - Malonyl Coenzyme A/*physiology
MH  - Mice
MH  - Mice, Inbred BALB C
PMC - PMC240668
EDAT- 2003/10/09 05:00
MHDA- 2004/01/06 05:00
PMCR- 2004/04/28
CRDT- 2003/10/09 05:00
PHST- 2003/10/09 05:00 [pubmed]
PHST- 2004/01/06 05:00 [medline]
PHST- 2003/10/09 05:00 [entrez]
PHST- 2004/04/28 00:00 [pmc-release]
AID - 1834402100 [pii]
AID - 10012624 [pii]
AID - 10.1073/pnas.1834402100 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12624-9. doi: 
      10.1073/pnas.1834402100. Epub 2003 Oct 7.