PMID- 17227768
OWN - NLM
STAT- MEDLINE
DCOM- 20070424
LR  - 20211203
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 11
DP  - 2007 Mar 16
TI  - MAP4K4 gene silencing in human skeletal muscle prevents tumor necrosis 
      factor-alpha-induced insulin resistance.
PG  - 7783-9
AB  - Tumor necrosis factor-alpha (TNF-alpha) induces skeletal muscle insulin 
      resistance by impairing insulin signaling events involved in GLUT4 translocation. 
      We tested whether mitogenic-activated protein kinase kinase kinase kinase isoform 
      4 (MAP4K4) causes the TNF-alpha-induced negative regulation of extracellular 
      signal-regulated kinase-1/2 (ERK-1/2), c-Jun NH2-terminal kinase (JNK), and the 
      insulin receptor substrate-1 (IRS-1) on the insulin signaling pathway governing 
      glucose metabolism. Using small interfering RNA (siRNA) to suppress the 
      expression of MAP4K4 protein 85% in primary human skeletal muscle cells, we 
      provide evidence that TNF-alpha-induced insulin resistance on glucose uptake was 
      completely prevented. MAP4K4 silencing inhibited TNF-alpha-induced negative 
      signaling inputs by preventing excessive JNK and ERK-1/2 phosphorylation, as well 
      as IRS-1 serine phosphorylation. These results highlight the MAPK4K4/JNK/ERK/IRS 
      module in the negative regulation of insulin signaling to glucose transport in 
      response to TNF-alpha. Depletion of MAP4K4 also prevented TNF-alpha-induced 
      insulin resistance on Akt and the Akt substrate 160 (AS160), providing evidence 
      that appropriate insulin signaling inputs for glucose metabolism were rescued. 
      Silencing of MAP2K1 and MAP2K4, signaling proteins downstream of MAP4K4, 
      recapitulated the effect of MAP4K4 siRNA in TNF-alpha-treated cells. Thus, 
      strategies to inhibit MAP4K4 may be efficacious in the prevention of 
      TNF-alpha-induced inhibitory signals that cause skeletal muscle insulin 
      resistance on glucose metabolism in humans. Moreover, in myotubes from 
      insulin-resistant type II diabetic patients, siRNA against MAP4K4, MAP2K4, or 
      MAP2K1 restored insulin action on glucose uptake to levels observed in healthy 
      subjects. Collectively, our results demonstrate that MAP4K4 silencing prevents 
      insulin resistance in human skeletal muscle and restores appropriate signaling 
      inputs to enhance glucose uptake.
FAU - Bouzakri, Karim
AU  - Bouzakri K
AD  - Department of Molecular Medicine and Surgery, Karolinska University Hospital, 
      Karolinska Institutet, S-171 77 Stockholm, Sweden.
FAU - Zierath, Juleen R
AU  - Zierath JR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070116
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Interleukin-6)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9G2MP84A8W (Deoxyglucose)
RN  - EC 2.7.1.11 (MAP4K4 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Cell Differentiation
MH  - Deoxyglucose/metabolism
MH  - *Gene Silencing
MH  - Humans
MH  - *Insulin Resistance
MH  - Interleukin-6/metabolism
MH  - Intracellular Signaling Peptides and Proteins
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Muscle Fibers, Skeletal/metabolism
MH  - Muscle, Skeletal/*metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*genetics/*metabolism
MH  - Signal Transduction
MH  - Tumor Necrosis Factor-alpha/*metabolism
EDAT- 2007/01/18 09:00
MHDA- 2007/04/25 09:00
CRDT- 2007/01/18 09:00
PHST- 2007/01/18 09:00 [pubmed]
PHST- 2007/04/25 09:00 [medline]
PHST- 2007/01/18 09:00 [entrez]
AID - S0021-9258(20)63783-8 [pii]
AID - 10.1074/jbc.M608602200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 Mar 16;282(11):7783-9. doi: 10.1074/jbc.M608602200. Epub 2007 
      Jan 16.