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Molecular mechanisms of inflammation in obesity-linked insulin resistance

Authors:
PAPER
Molecular mechanisms of inflammation in obesity-
linked insulin resistance
A Marette
1
*
1
Department of Anatomy and Physiology, Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy, Que
´
bec,
Canada
International Journal of Obesity (2003) 27, S46–S48. doi:10.1038/sj.ijo.0802500
It is now well established that obesity is a chronic
inflammatory disorder. First proposed in pioneering studies
from Hotamisligil and Spiegelman
1
more than a decade ago,
there is now convincing experimental evidence for the
existence of an inflammatory link between obesity and the
occurrence of the insulin resistance dyslipidemic syndrome
commonly known as the ‘metabolic syndrome’. An ever-
increasing number of molecules that are best known for their
role in immune and inflammatory cells are now considered
as key modulators of energy metabolism in insulin target
tissues. In fact, several of those molecules (eg tumor necrosis
factor (TNF)-a, interleukine (IL)-6 and IL-1) are expressed and
secreted by fat cells in the expanded adipose tissue of obese
subjects. Those immune/inflammatory mediators as well as
adipose-specific cytokines (eg leptin and resistin) dubbed
‘adipokines’ exert their actions via a complex interplay of
signal transduction mechanisms that we are just beginning
to appreciate. The last few years have witnessed a burst of
studies providing strong experimental and genetic support
to the pathogenic role of some inflammatory pathways in
the development of insulin resistance in obesity. The goal of
this session of the symposium was to shed light on key
inflammatory pathways thought to promote insulin resis-
tance and the molecular mechanisms by which they are
believed to interfere with insulin signaling.
The use of salicylates for the treatment of diabetes mellitus
was first reported more than a century ago and the glucose-
lowering action of aspirin was confirmed in the 1950s.
Steven Shoelson presented recent experimental work sup-
porting the hypothesis that high-dose aspirin exerts its
beneficial effects through inhibition of the proinflammatory
pathway Ikappa B kinase (IKK)/NF-kB, a known target of
high-dose salicylates. In a series of elegant studies, Shoelson
and colleagues have found that the IKK/NF-kB pathway is
activated in insulin target tissues of obese insulin-resistant
animals and that high-dose aspirin/salicylates improve
insulin sensitivity and glucose tolerance in such animals.
2
To gain further genetic evidence for the role of the IKK/NF-
kB axis in obesity-linked insulin resistance, they have
performed additional studies in heterozygous Ikkb
þ /
mice
fed a high-fat diet or crossed with obese ob/ob mice. In both
models, a 50% decrease in the Ikkb gene led to reductions in
blood glucose levels and improved insulin sensitivity. High-
dose salicylates and heterozygous Ikkb gene deletion also
protected against the insulin-resistant effects of lipid infu-
sion in rats. Shoelson concluded his talk by proposing future
directions that are intended to answer important questions
such as the identification of target sites of IKK/NF-kB-
induced insulin resistance. A more provocative question is
whether salicylates should be reconsidered for the treatment
of type 2 diabetic subjects. Recent data confirmed that high-
dose salicylates improve peripheral insulin action in diabetic
patients, but additional studies using lower doses of salsalate,
a less irritating head-to-tail dimer of salicylate, are currently
underway to determine the efficacy of this drug in alleviat-
ing insulin resistance and improving glucose control.
Salsalate may turn out to be an effective insulin sensitizer,
and rejuvenate a 100-y-old concept that salicylates exert
antidiabetic effects.
Inflammatory cytokines also activate the MAP kinase
pathway in several cell types. As reported by Gohka
¨
n
Hotamisligil at this meeting, c-Jun N-terminal kinase (JNK)
activity is elevated in tissues of dietary and genetic models of
obesity. JNK1 but not JNK2 gene invalidation in mice
protects from high-fat-induced obesity and insulin resis-
tance.
3
It appears that JNK1 may cause insulin resistance by
promoting serine phosphorylation of insulin receptor sub-
strate-1 (IRS-1), which converts this protein into an inhibitor
of insulin signaling. Indeed, JNK1 invalidation reduces IRS-1
phosphorylation on serine 307, a well-known site of
heterologous inhibition of IRS-1 signaling. Genetic evidence
*Correspondence: Dr A Marette, Department of Physiology & Lipid
Research Unit, Laval University Hospital Research Center, 2705, Laurier
Bld, Ste-Foy, Que
´
bec, Canada G1V 4G2.
E-mail:andre.marette@crchul.ulaval.ca
International Journal of Obesity (2003) 27, S46S48
&
2003 Nature Publishing Group All rights reserved 0307-0565/03
$
25.00
www.nature.com/ijo
linking increased JNK activity to human diabetes was also
discussed. Indeed, loss-of-function mutations in JIP1, a
natural inhibitor of JNK, causes type 2 diabetes in humans.
Hotamisligil concluded his talk on some evolutionary
concepts, alluding to the fat body of the fruit fly Drosophila
melanogaster. This tissue concomitantly functions as a
hepatic, adipose, and hematopoietic/immune organ and
key proteins, including the fly equivalent of JNK, assume
both metabolic and inflammatory functions. This offers a
selective advantage in providing a strong immune response
to overcome infections, but it brings about an equally strong
metabolic response (eg insulin resistance), which, in the
context of plenty, favors the expression of contemporary
metabolic diseases such as diabetes and atherosclerosis.
Proinflammatory cytokines may also cause insulin resis-
tance by transcriptional mechanisms. Recent studies have
shown that cytokine-induced expression of inducible nitric
oxide synthase (iNOS)
4
and the suppressors of cytokine
signaling family (SOCS),
5
can lead to impaired insulin
signaling in muscle and fat tissues. In his talk, Emmanuel
Van Obberghen summarized recent work from his group
showing that SOCS3 is overexpressed in fat of murine
models of acquired and genetic obesity and that exposure
to TNF-a also induces SOCS3 expression in this tissue.
Conversely, SOCS3 levels are decreased in the adipose tissue
of ob/ob mice lacking TNF- a receptors. Hyperinsulinemia
may also be involved in the negative action of SOCS3 on
insulin signaling since insulin itself can promote its activa-
tion by tyrosine phosphorylation. SOCS3 may interfere with
insulin signaling by competing with the ability of the insulin
receptor to increase IRS-1 tyrosine phosphorylation and
downstream signaling to PI 3-kinase,
5
or by favoring IRS-1/2
degradation through the ubiquitin-mediated degradation
pathway as recently reported by White and colleagues.
6
Van
Obberghen also brought into perspective the fact that many
insulin-resistant factors or pathways converge at the level of
IRS proteins, either by uncoupling IRS-mediated downstream
signals, and/or through promoting their degradation, at least
in part by enhancing their serine phosphorylation.
Yehiel Zick’s presentation brought us even deeper into the
signal transduction mechanisms leading to ser/thr phos-
phorylation of IRS proteins. He reminded us that ser/thr
phosphorylation is not necessarily negative as the insulin-
responsive protein kinase Akt/PKB also phosphorylates
serines within the PTB domain of IRS-1 but that this protects
from the action of protein tyrosine phosphatases and keeps
IRS-1 in a tyrosine phosphorylated active state.
7
In contrast,
other insulin-sensitive kinases, such as the mammalian
target of rapamycin (mTOR),
8,9
as well as atypical PKCz,
10
can also phosphorylate IRS-1 on serine residues and
terminate insulin signaling at the level of PI 3-kinase. This
may represent an efficient feedback regulatory mechanism of
insulin signaling and the starting point may be located at the
level of PI 3-kinase itself since its inhibitor, wortmannin,
blocks the negative effects of the above IRS serine kinases. In
inflammatory conditions such as obesity-linked diabetes,
this feedback control loop may over-ride the normal
activation of insulin signaling and thus promote insulin
resistance. Interestingly, IKKb has been shown to be a
substrate of PKCz and to be activated by a functional PKCz,
leading to the hypothesis that IKKb may be a downstream
mediator of PKCz-mediated inhibition of insulin signaling.
This is supported by the observation that TNF-a activates
both PKCz and IKKb. Zick concluded by asking an important
question, that is, are the same or different pathways being
utilized by insulin and inflammatory mediators to regulate
the activity of IRS serine kinases? Clearly, overlapping
pathways are likely to contribute to the modulation of ser/
thr phosphorylation of IRS proteins and the contribution of
each of those pathways may well vary between individual
target tissues.
This symposium thus identified key signal transduction
pathways activated by inflammatory mediators that can
interfere with insulin receptor signaling in insulin target
cells. A majority of these complex and inter-related pathways
appear to converge at the level of IRS-1, by promoting its
serine phosphorylation to mediate heterologous inhibition
of IRS-1 signaling to counter-regulate the insulin response.
The future challenge is to integrate reductionist models into
reality and describe networks of signal transduction path-
ways in complex biosystems. A detailed knowledge of this
complexity is a daunting task that will require a multifaceted
approach, which is, nevertheless, necessary for the develop-
ment of effective means for the treatment of insulin
resistance, a pathognomonic syndrome in chronic metabolic
disorders such as obesity, diabetes, and associated cardiovas-
cular diseases.
Acknowledgements
I would like to express my gratitude to Dr Yves Deshaies for
editing and critically revising several manuscripts of this
symposium.
References
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