PMID- 9832430
OWN - NLM
STAT- MEDLINE
DCOM- 19981224
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 139
IP  - 12
DP  - 1998 Dec
TI  - An in vivo model for elucidation of the mechanism of tumor necrosis factor-alpha 
      (TNF-alpha)-induced insulin resistance: evidence for differential regulation of 
      insulin signaling by TNF-alpha.
PG  - 4928-35
AB  - Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce insulin 
      resistance in cultured cells as well as in animal models. The aim of this study 
      was to map the in vivo mechanism whereby TNF-alpha contributes to the 
      pathogenesis of impaired insulin signaling, using obese and lean Zucker rats in 
      which TNF-alpha activity was inhibited through adenovirus-mediated gene transfer. 
      We employed a replication-incompetent adenovirus-5 (Ad5) vector to endogenously 
      express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein consisting 
      of the extracellular domain of the human 55-kDa TNF receptor joined to a mouse 
      IgG heavy chain. Control animals consisted of rats infected with the same titer 
      of adenovirus carrying the lac-z complementary DNA, encoding for 
      beta-galactosidase. There was a significant reduction in plasma insulin and free 
      fatty acid levels in TNFi obese rats 2 days following Ad5 administration. The 
      peripheral insulin sensitivity index was 50% greater, whereas hepatic glucose 
      output was completely suppressed during hyperinsulinemic glucose clamps in TNFi 
      obese animals, with no differences observed between the two lean groups. The 
      improvement in peripheral and hepatic sensitivity to insulin seen in the obese 
      animals was independent of insulin receptor (IR) number and insulin binding 
      affinity for IR. However, TNF-alpha neutralization led to a 2.5-fold increase in 
      tyrosine phosphorylation of IR in skeletal muscle, whereas this was unchanged in 
      liver. There was also a 4-fold increase in particulate protein tyrosine 
      phosphatase activity of skeletal muscle in TNFi obese animals vs. 
      beta-galactosidase controls, whereas protein tyrosine phosphatase activity in 
      liver was unchanged. These results suggest that TNF-alpha is a mediator of 
      insulin resistance in obesity and may modulate IR signaling in skeletal muscle 
      and liver through different pathways. TNF-alpha may affect insulin action in the 
      liver either at sites distal to the IR or indirectly, possibly because of 
      increased provision of gluconeogenic substrates or altered counterregulation. In 
      addition, the Ad5-mediated gene delivery system employed here provides an in vivo 
      model that is efficient and economical for exploring mechanisms involved in 
      TNF-alpha-induced insulin resistance in various genetic models of obesity-linked 
      diabetes.
FAU - Cheung, A T
AU  - Cheung AT
AD  - Department of Physiology, Tulane University, New Orleans, Louisiana, USA.
FAU - Ree, D
AU  - Ree D
FAU - Kolls, J K
AU  - Kolls JK
FAU - Fuselier, J
AU  - Fuselier J
FAU - Coy, D H
AU  - Coy DH
FAU - Bryer-Ash, M
AU  - Bryer-Ash M
LA  - eng
GR  - DK-07405/DK/NIDDK NIH HHS/United States
GR  - P30 CA13148-26/CA/NCI NIH HHS/United States
GR  - R-29-AA-10384/AA/NIAAA NIH HHS/United States
GR  - etc.
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Insulin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatases)
SB  - IM
MH  - Animals
MH  - Blood Physiological Phenomena
MH  - Glucose Clamp Technique
MH  - Humans
MH  - Insulin/metabolism/*physiology
MH  - Insulin Resistance/*physiology
MH  - Liver/physiology
MH  - Mice
MH  - Obesity/metabolism
MH  - Phosphorylation
MH  - Protein Tyrosine Phosphatases/metabolism
MH  - Rats/blood
MH  - Rats, Zucker
MH  - Receptor, Insulin/metabolism
MH  - Reference Values
MH  - Signal Transduction/*physiology
MH  - Tumor Necrosis Factor-alpha/antagonists & inhibitors/*physiology
MH  - Tyrosine/metabolism
EDAT- 1998/12/01 00:00
MHDA- 1998/12/01 00:01
CRDT- 1998/12/01 00:00
PHST- 1998/12/01 00:00 [pubmed]
PHST- 1998/12/01 00:01 [medline]
PHST- 1998/12/01 00:00 [entrez]
AID - 10.1210/endo.139.12.6336 [doi]
PST - ppublish
SO  - Endocrinology. 1998 Dec;139(12):4928-35. doi: 10.1210/endo.139.12.6336.