PMID- 26344902
OWN - NLM
STAT- MEDLINE
DCOM- 20160824
LR  - 20220310
IS  - 1638-6183 (Electronic)
IS  - 0300-9084 (Linking)
VI  - 118
DP  - 2015 Nov
TI  - Palmitate activates mTOR/p70S6K through AMPK inhibition and hypophosphorylation 
      of raptor in skeletal muscle cells: Reversal by oleate is similar to metformin.
PG  - 141-50
LID - S0300-9084(15)00281-3 [pii]
LID - 10.1016/j.biochi.2015.09.006 [doi]
AB  - Excessive saturated free fatty acids (SFFAs; e.g. palmitate) in blood are a 
      pathogenic factor in diabetes, obesity, cardiovascular disease and liver failure. 
      In contrast, monounsaturated free fatty acids (e.g. oleate) prevent the toxic 
      effect of SFFAs in various types of cells. The mechanism is poorly understood and 
      involvement of the mTOR complex is untested. In the present study, we demonstrate 
      that oleate preconditioning, as well as coincubation, completely prevented 
      palmitate-induced markers of inflammatory signaling, insulin resistance and 
      cytotoxicity in C2C12 myotubes. We then examined the effect of palmitate and/or 
      oleate on the mammalian target of rapamycin (mTOR) signal path and whether their 
      link is mediated by AMP-activated protein kinase (AMPK). Palmitate decreased the 
      phosphorylation of raptor and 4E-BP1 while increasing the phosphorylation of 
      p70S6K. Palmitate also inhibited phosphorylation of AMPK, but did not change the 
      phosphorylated levels of mTOR or rictor. Oleate completely prevented the 
      palmitate-induced dysregulation of mTOR components and restored pAMPK whereas 
      alone it produced no signaling changes. To understand this more, we show 
      activation of AMPK by metformin also prevented palmitate-induced changes in the 
      phosphorylations of raptor and p70S6K, confirming that the mTORC1/p70S6K 
      signaling pathway is responsive to AMPK activity. By contrast, inhibition of AMPK 
      phosphorylation by Compound C worsened palmitate-induced changes and 
      correspondingly blocked the protective effect of oleate. Finally, metformin 
      modestly attenuated palmitate-induced insulin resistance and cytotoxicity, as did 
      oleate. Our findings indicate that palmitate activates mTORC1/p70S6K signaling by 
      AMPK inhibition and phosphorylation of raptor. Oleate reverses these effects 
      through a metformin-like facilitation of AMPK.
CI  - Copyright (c) 2015 Elsevier B.V. and Societe Francaise de Biochimie et Biologie 
      Moleculaire (SFBBM). All rights reserved.
FAU - Kwon, Bumsup
AU  - Kwon B
AD  - Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of 
      Brown University, Providence, RI 02903, USA.
FAU - Querfurth, Henry W
AU  - Querfurth HW
AD  - Department of Neurology, Rhode Island Hospital, Warren Alpert Medical School of 
      Brown University, Providence, RI 02903, USA. Electronic address: 
      henry_querfurth@brown.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150905
PL  - France
TA  - Biochimie
JT  - Biochimie
JID - 1264604
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Palmitates)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - 0 (Rptor protein, mouse)
RN  - 2UMI9U37CP (Oleic Acid)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Blotting, Western
MH  - Cell Line
MH  - Insulin Resistance/physiology
MH  - Metformin/pharmacology
MH  - Mice
MH  - Muscle, Skeletal/drug effects/*metabolism
MH  - Oleic Acid/metabolism/pharmacology
MH  - Palmitates/*metabolism/toxicity
MH  - Phosphorylation
MH  - Regulatory-Associated Protein of mTOR
MH  - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - TOR Serine-Threonine Kinases/*metabolism
OTO - NOTNLM
OT  - AMPK
OT  - Insulin resistance
OT  - Oleate
OT  - Plamitate
OT  - Raptor
OT  - mTOR
EDAT- 2015/09/08 06:00
MHDA- 2016/08/25 06:00
CRDT- 2015/09/08 06:00
PHST- 2015/07/15 00:00 [received]
PHST- 2015/09/02 00:00 [accepted]
PHST- 2015/09/08 06:00 [entrez]
PHST- 2015/09/08 06:00 [pubmed]
PHST- 2016/08/25 06:00 [medline]
AID - S0300-9084(15)00281-3 [pii]
AID - 10.1016/j.biochi.2015.09.006 [doi]
PST - ppublish
SO  - Biochimie. 2015 Nov;118:141-50. doi: 10.1016/j.biochi.2015.09.006. Epub 2015 Sep 
      5.