PMID- 18060381
OWN - NLM
STAT- MEDLINE
DCOM- 20081222
LR  - 20211020
IS  - 0012-186X (Print)
IS  - 0012-186X (Linking)
VI  - 51
IP  - 2
DP  - 2008 Feb
TI  - Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 
      confers partial protection against lipid-induced insulin resistance in rodent 
      skeletal muscle.
PG  - 336-46
AB  - AIMS/HYPOTHESIS: A role for increased activity of the innate immune system in the 
      pathogenesis of insulin resistance is supported by a number of studies. The 
      current study assessed the potential role of the lipopolysaccharide receptor 
      known as Toll-like receptor-4 (TLR-4), a component of the innate immune system, 
      in mediating lipid-induced insulin resistance in skeletal muscle. METHODS: The 
      effects of TLR-4 inhibition/deletion on lipid-induced insulin resistance was 
      determined in skeletal muscle of TLR-4 null mice in vivo and in rat L6 myotubes 
      in vitro. RESULTS: In mice, acute hyperlipidaemia induced skeletal muscle insulin 
      resistance, but a deletion of TLR-4 conferred significant protection against 
      these effects. In L6 myotubes, inhibition of TLR-4 activity substantially reduced 
      the capacity of the saturated fatty acid palmitate to induce insulin resistance. 
      Importantly, palmitate activated the nuclear factor kappaB (NFkappaB) pathway in 
      L6 myotubes and mouse skeletal muscle, and these effects were blocked by 
      inhibition of TLR-4 in L6 myotubes and absence of TLR-4 in skeletal muscle. 
      Furthermore, inhibition of the NFkappaB pathway downstream of TLR-4 in L6 
      myotubes also protected against the induction of insulin resistance by palmitate. 
      CONCLUSIONS/INTERPRETATION: Inhibition or absence of TLR-4 confers protection 
      against the detrimental effects of lipids on skeletal muscle insulin action, and 
      these effects are associated with a prevention of the activation of the NFkappaB 
      pathway by lipids. Importantly, inhibition of the NFkappaB pathway in myotubes 
      downstream of TLR-4 also protects against lipid-induced insulin resistance, 
      suggesting a mechanism by which reduced TLR-4 activity confers beneficial effects 
      on insulin action.
FAU - Radin, M S
AU  - Radin MS
AD  - Department of Medicine, Division of Endocrinology, University of Pittsburgh, 
      Pittsburgh, PA 15261, USA.
FAU - Sinha, S
AU  - Sinha S
FAU - Bhatt, B A
AU  - Bhatt BA
FAU - Dedousis, N
AU  - Dedousis N
FAU - O'Doherty, R M
AU  - O'Doherty RM
LA  - eng
GR  - R01 DK058855/DK/NIDDK NIH HHS/United States
GR  - T32-DK07052/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071201
PL  - Germany
TA  - Diabetologia
JT  - Diabetologia
JID - 0006777
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (NF-kappa B)
RN  - 0 (Palmitates)
RN  - 0 (RNA, Messenger)
RN  - 0 (Toll-Like Receptor 4)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Glucose/pharmacology
MH  - Glucose Transporter Type 4/metabolism
MH  - Hypoglycemic Agents/pharmacology
MH  - In Vitro Techniques
MH  - Insulin/pharmacology
MH  - *Insulin Resistance
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Muscle Fibers, Skeletal/*drug effects/metabolism
MH  - Muscle, Skeletal/*drug effects/metabolism/physiopathology
MH  - NF-kappa B/metabolism
MH  - Palmitates/*pharmacology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA, Messenger/genetics/metabolism
MH  - Rats
MH  - Toll-Like Receptor 4/genetics/*physiology
EDAT- 2007/12/07 09:00
MHDA- 2008/12/23 09:00
CRDT- 2007/12/07 09:00
PHST- 2007/07/31 00:00 [received]
PHST- 2007/08/23 00:00 [accepted]
PHST- 2007/12/07 09:00 [pubmed]
PHST- 2008/12/23 09:00 [medline]
PHST- 2007/12/07 09:00 [entrez]
AID - 10.1007/s00125-007-0861-3 [doi]
PST - ppublish
SO  - Diabetologia. 2008 Feb;51(2):336-46. doi: 10.1007/s00125-007-0861-3. Epub 2007 
      Dec 1.