PMID- 18614690
OWN - NLM
STAT- MEDLINE
DCOM- 20080812
LR  - 20220317
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 28
IP  - 28
DP  - 2008 Jul 9
TI  - The role of hypothalamic mammalian target of rapamycin complex 1 signaling in 
      diet-induced obesity.
PG  - 7202-8
LID - 10.1523/JNEUROSCI.1389-08.2008 [doi]
AB  - The mammalian target of rapamycin (mTOR) kinase is a key regulator of several 
      cellular functions, including cell growth and differentiation. Because 
      hypothalamic mTOR complex 1 (mTORC1) signaling has been implicated as a target of 
      leptin in the regulation of energy balance, we investigated its role in 
      obesity-induced leptin resistance. In contrast to rats maintained on a low-fat 
      (LF) diet for 3 weeks, rats maintained on a high-fat (HF)-diet had no anorexic 
      response to intracerebroventricular leptin. Western blot analysis revealed that 
      leptin was unable to modulate hypothalamic mTORC1 signaling in the HF group, 
      whereas it significantly induced phosphorylation of both S6 kinase 1 (S6K1) and 
      S6 ribosomal protein (S6) in the LF group. Similar to leptin, the cytokine 
      ciliary neurotrophic factor (CNTF) induces hypophagia and increases signal 
      transduction activator of transcription 3 phosphorylation. However, CNTF and its 
      analog CNTF(Ax15) activate leptin-like pathways in the hypothalamus, even in 
      leptin-resistant states, including diet-induced obesity. Intracerebroventricular 
      CNTF(Ax15) decreased 24 h food intake and body weight in rats on HF or LF diets 
      and increased the phosphorylation of hypothalamic S6K1 and S6 in a comparable way 
      in both diets. Importantly, mice lacking the expression of S6K1 (S6K1(-/-)) did 
      not respond to the anorectic action of either leptin or CNTF(Ax15), implying a 
      crucial role for S6K1 in modulating the actions of these two cytokines. Finally, 
      exposure to HF diet decreased mTORC1 signaling within the hypothalamus. Overall, 
      these findings point strongly to the possibility that reduced hypothalamic mTORC1 
      signaling contributes to the development of hyperphagia, weight gain, and leptin 
      resistance during diet-induced obesity.
FAU - Cota, Daniela
AU  - Cota D
AD  - Department of Psychiatry, University of Cincinnati, Genome Research Institute, 
      Cincinnati, Ohio 45237, USA. daniela.cota@inserm.fr
FAU - Matter, Emily K
AU  - Matter EK
FAU - Woods, Stephen C
AU  - Woods SC
FAU - Seeley, Randy J
AU  - Seeley RJ
LA  - eng
GR  - DK 17844/DK/NIDDK NIH HHS/United States
GR  - R01 DK017844/DK/NIDDK NIH HHS/United States
GR  - R01 DK073505-01A1/DK/NIDDK NIH HHS/United States
GR  - P01 DK056863-01A10003/DK/NIDDK NIH HHS/United States
GR  - P01 DK056863/DK/NIDDK NIH HHS/United States
GR  - R01 DK073505/DK/NIDDK NIH HHS/United States
GR  - 5P01 DK 56863/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, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Ciliary Neurotrophic Factor)
RN  - 0 (Crtc1 protein, rat)
RN  - 0 (Dietary Fats)
RN  - 0 (Leptin)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
SB  - IM
MH  - Animals
MH  - Behavior, Animal
MH  - Ciliary Neurotrophic Factor/pharmacology
MH  - *Dietary Fats
MH  - Disease Models, Animal
MH  - Eating/drug effects/physiology
MH  - Feeding Behavior/physiology
MH  - Leptin/pharmacology
MH  - Male
MH  - Median Eminence/*physiopathology
MH  - Mice
MH  - Mice, Knockout
MH  - *Obesity/chemically induced/metabolism/pathology
MH  - Rats
MH  - Rats, Long-Evans
MH  - Ribosomal Protein S6 Kinases/deficiency
MH  - Signal Transduction/drug effects/*physiology
MH  - Transcription Factors/*metabolism
PMC - PMC2597379
MID - NIHMS67722
EDAT- 2008/07/11 09:00
MHDA- 2008/08/13 09:00
PMCR- 2009/01/09
CRDT- 2008/07/11 09:00
PHST- 2008/07/11 09:00 [pubmed]
PHST- 2008/08/13 09:00 [medline]
PHST- 2008/07/11 09:00 [entrez]
PHST- 2009/01/09 00:00 [pmc-release]
AID - 28/28/7202 [pii]
AID - 3374903 [pii]
AID - 10.1523/JNEUROSCI.1389-08.2008 [doi]
PST - ppublish
SO  - J Neurosci. 2008 Jul 9;28(28):7202-8. doi: 10.1523/JNEUROSCI.1389-08.2008.