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(TNF-)-Induced Insulin Resistance: Evidence for Differential Regulation of Insulin Signaling by TNF-
Departments of Physiology (A.T.C.) and Medicine (J.F. and D.H.C.), Tulane University and Department of Medicine, Louisiana State University (J.K.K.), New Orleans, Louisiana; and Department of Medicine, University of Tennessee and Research Service, Veterans Administration Medical Center (D.R., M.B.A.), Memphis, Tennessee 38104
Address all correspondence and requests for reprints to: Michael Bryer-Ash, Department of Medicine-Room 340M, University of Tennessee College of Medicine, 951 Court Avenue, Memphis, Tennessee 38163. E-mail: mbryerash{at}utmem1.utmem.edu
Tumor necrosis factor-
(TNF-) 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- contributes to the pathogenesis of impaired insulin
signaling, using obese and lean Zucker rats in which TNF- 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 ß-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-
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.
ß-galactosidase controls, whereas protein tyrosine phosphatase
activity in liver was unchanged. These results suggest that TNF- is
a mediator of insulin resistance in obesity and may modulate IR
signaling in skeletal muscle and liver through different pathways.
TNF- 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--induced insulin resistance in various
genetic models of obesity-linked diabetes.
is unclear, but the hyperglycemia that is its final clinical expression
results from a combination of insulin resistance in important metabolic
target tissues such as liver, muscle, and adipose tissue, as well as a
relative or absolute insulin secretory defect at the level of the
pancreatic ß-cell (1). The precise cause of insulin resistance is yet
to be determined, but its association with obesity has long been
established (2). Numerous recent data have implicated tumor necrosis
factor- (TNF-) as a link between insulin resistance and obesity
(3–5). However, the mechanism(s) whereby TNF- attenuates insulin
action in obese individuals is not well understood. Attempts have been
made to delineate the cellular mechanism involved using in
vitro systems, but these have yet to be studied in detail in
intact animals. Given the complexity of glucose homeostasis and the
fact that the pathogenesis of insulin resistance involves multiple
organs, an obese insulin-resistant animal model of DM devoid of TNF-
activity would be most valuable in elucidating how TNF- induces
insulin resistance.
The objective of this project was to further investigate the in
vivo cellular mechanism(s) whereby TNF- contributes to the
pathogenesis of impaired insulin signal transduction in obesity and DM2
using obese Zucker rats (fa/fa) in which effective blockade
of TNF- activity has been achieved through adenovirus 5
(Ad5)-mediated gene transfer. We show that TNF- inhibition improves
both hepatic and peripheral insulin sensitivity in vivo, and
that both tyrosine phosphorylation of insulin receptor (IR) and protein
tyrosine phosphatase (PTP) activity in skeletal muscle were increased
during glucose clamps, whereas in the liver they were unchanged. This
implies that TNF- may exert its effects on skeletal muscle and liver
through different mechanisms.
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