PMID- 18776140
OWN - NLM
STAT- MEDLINE
DCOM- 20081231
LR  - 20231003
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 57
IP  - 12
DP  - 2008 Dec
TI  - Fatty acid synthase inhibitors modulate energy balance via mammalian target of 
      rapamycin complex 1 signaling in the central nervous system.
PG  - 3231-8
LID - 10.2337/db07-1690 [doi]
AB  - OBJECTIVE: Evidence links the hypothalamic fatty acid synthase (FAS) pathway to 
      the regulation of food intake and body weight. This includes pharmacological 
      inhibitors that potently reduce feeding and body weight. The mammalian target of 
      rapamycin (mTOR) is an intracellular fuel sensor whose activity in the 
      hypothalamus is also linked to the regulation of energy balance. The purpose of 
      these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1) 
      signaling is involved in mediating the effects of FAS inhibitors. RESEARCH DESIGN 
      AND METHODS: We measured the hypothalamic phosphorylation of two downstream 
      targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6), after 
      administration of the FAS inhibitors C75 and cerulenin in rats. We evaluated food 
      intake in response to FAS inhibitors in rats pretreated with the mTOR inhibitor 
      rapamycin and in mice lacking functional S6K1 (S6K1(-/-)). Food intake and 
      phosphorylation of S6K1 and S6 were also determined after C75 injection in rats 
      maintained on a ketogenic diet. RESULTS: C75 and cerulenin increased 
      phosphorylation of S6K1 and S6, and their anorexic action was reduced in 
      rapamycin-treated rats and in S6K1(-/-) mice. Consistent with our previous 
      findings, C75 was ineffective at reducing caloric intake in ketotic rats. Under 
      ketosis, C75 was also less efficient at stimulating mTORC1 signaling. 
      CONCLUSIONS: These findings collectively indicate an important interaction 
      between the FAS and mTORC1 pathways in the central nervous system for regulating 
      energy balance, possibly via modulation of neuronal glucose utilization.
FAU - Proulx, Karine
AU  - Proulx K
AD  - Department of Psychiatry, University of Cincinnati, Genome Research Institute, 
      Cincinnati, OH, USA.
FAU - Cota, Daniela
AU  - Cota D
FAU - Woods, Stephen C
AU  - Woods SC
FAU - Seeley, Randy J
AU  - Seeley RJ
LA  - eng
GR  - R01 DK017844/DK/NIDDK NIH HHS/United States
GR  - P01 DK056863/DK/NIDDK NIH HHS/United States
GR  - DK-056863/DK/NIDDK NIH HHS/United States
GR  - DK-54890/DK/NIDDK NIH HHS/United States
GR  - DK-17844/DK/NIDDK NIH HHS/United States
GR  - R01 DK054890/DK/NIDDK NIH HHS/United States
GR  - R37 DK017844/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20080905
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Crtc1 protein, rat)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Transcription Factors)
RN  - 17397-89-6 (Cerulenin)
RN  - EC 2.3.1.85 (Fatty Acid Synthases)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (Rps6kb1 protein, rat)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Animals
MH  - Anorexia/physiopathology
MH  - Central Nervous System/drug effects/*physiology
MH  - Cerulenin/pharmacology
MH  - Diet, Ketogenic
MH  - Energy Intake
MH  - Energy Metabolism/*drug effects
MH  - Enzyme Inhibitors/*pharmacology
MH  - Fatty Acid Synthases/*antagonists & inhibitors
MH  - Gene Knockout Techniques
MH  - Hypothalamus/drug effects/enzymology/physiopathology
MH  - Leucine/blood
MH  - Male
MH  - Mice
MH  - Rats
MH  - Rats, Long-Evans
MH  - Ribosomal Protein S6 Kinases/deficiency/genetics/metabolism
MH  - Transcription Factors/*physiology
PMC - PMC2584128
EDAT- 2008/09/09 09:00
MHDA- 2009/01/01 09:00
PMCR- 2009/12/01
CRDT- 2008/09/09 09:00
PHST- 2008/09/09 09:00 [pubmed]
PHST- 2009/01/01 09:00 [medline]
PHST- 2008/09/09 09:00 [entrez]
PHST- 2009/12/01 00:00 [pmc-release]
AID - db07-1690 [pii]
AID - 57123231 [pii]
AID - 10.2337/db07-1690 [doi]
PST - ppublish
SO  - Diabetes. 2008 Dec;57(12):3231-8. doi: 10.2337/db07-1690. Epub 2008 Sep 5.