International Journal of Obesity (2003) 27, S53S55

& 2003 Nature Publishing Group All rights reserved 0307-0565/03 $25.00
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PAPER
Inflammatory pathways and insulin action
GS Hotamisligil1*
1

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, USA

Obesity and type 2 diabetes are associated with a state of abnormal inflammatory response. While this correlation has also been
recognized in the clinical setting, its molecular basis and physiological significance are not yet fully understood. Studies in recent
years have provided important insights into this curious phenomenon. The state of chronic inflammation typical of obesity and
type 2 diabetes occurs at metabolically relevant sites, such as the liver, muscle, and most interestingly, adipose tissues. The
biological relevance of the activation of inflammatory pathways became evident upon the demonstration that interference with
these pathways improve or alleviate insulin resistance. The abnormal production of tumor necrosis factor alpha (TNF-a) in
obesity is a paradigm for the metabolic significance of this inflammatory response. When TNF-a activity is blocked in obesity,
either biochemically or genetically, the result is improved insulin sensitivity. Studies have since focused on the identification of
additional inflammatory mediators critical in metabolic control and on understanding the molecular mechanisms by which
inflammatory pathways are coupled to metabolic control. Recent years have seen a critical progress in this respect by the
identification of several downstream mediators and signaling pathways, which provide the crosstalk between inflammatory and
metabolic signaling. These include the discovery of c-Jun N-terminal kinase (JNK) and Ikappabkinase (IkK) as critical regulators of
insulin action activated by TNF-a and other inflammatory and stress signals, and the identification of potential targets. Here, the
role of the JNK pathway in insulin receptor signaling, the impact of blocking this pathway in obesity and the mechanisms
underlying JNK-induced insulin resistance will be discussed.
International Journal of Obesity (2003) 27, S53S55. doi:10.1038/sj.ijo.0802502
Keywords: JNK; TNF-a; IRS-1; signaling pathways; metabolism; diabetes; inflammation

Obesity is associated with a state of chronic inflammation

characterized by abnormal production of proinflammatory
cytokines and acute phase reactants.1 Several cell types, such
as adipocytes and macrophages, are involved in this
abnormal cytokine production. This seemingly surprising
ability of fat cells to mount an immune response is likely to
be a function of its common features with macrophages2 and
critical in systemic insulin action.3
Insulin signaling is a very complex process that involves
multiple pathways and cascades of phosphorylation events.
For the purposes of this short review, these pathways will not
be described; however, readers could refer to excellent recent
reviews on these pathways.4,5 Over the past decade, it is well
established that insulin receptor signaling is defective at
multiple levels in type 2 diabetes both in experimental
models and humans and this defective signaling is central to
pathogenesis of type 2 diabetes. One such pathway that
involves phosphorylation and signaling via the members of
the insulin-receptor substrate (IRS) family of proteins will be

*Correspondence: Dr GS Hotamisligil, Department of Genetics and

Complex Diseases, Harvard School of Public Health, 665 Huntington
Av., Boston, MA 02115, USA.
E-mail: ghotamis@hsph.harvard.edu

the focus of the present discussion, since it is particularly

relevant to insulin-mediated glucose metabolism and crosstalk with inflammatory pathways.4
Phosphorylation of tyrosine (tyr) residues of IRS-1 upon
activation of the insulin receptor constitutes a critical step in
the transmission of the insulin signal to downstream
effectors and biological outcomes. Several laboratories have
demonstrated that insulin-stimulated tyr phosphorylation of
IRS-1 as well as other proximal substrates of the insulin
receptor is reduced in obesity, and such reduction is believed
to be at the core of the development of insulin resistance.5
We and others have shown that the proinflammatory
cytokine tumor necrosis factor alpha (TNF-a), which promotes insulin resistance in several insulin-responding cells
and tissues, inhibits tyr phosphorylation of IRS-1 resulting in
a state reminiscent of type 2 diabetes and obesity.6 Interestingly, the same phenomenon is observed in the presence of
an increase in intracellular fatty acids,7 which also promote
insulin resistance, showing that both cytokines and fatty
acids may act via common pathways to block insulin action.
Under these conditions, cytokines and fatty acids stimulate
phosphorylation of IRS-1 on its serine (ser) residues.810 In
contrast to tyr phosphorylation, which results in the
transmission of the insulin signal, ser phosphorylation

Inflammation and insulin action

GS Hotamisligil

S54
blunts insulin signaling.810 In experimental systems, when
ser phosphorylation is prevented, the deleterious action of
TNF-a and possibly fatty acids on insulin signaling might be
prevented as well, further indicating the critical importance
of this modification in insulin-resistant states.
We and others have been investigating the molecular basis
and functional consequences of IRS-1 ser phosphorylation
and the responsible kinase(s). The inhibition of insulin
signaling by TNF-a and fatty acids in adipocytes and
hepatocytes involves activation of a kinase utilizing IRS-1
as a substrate.8,9 Once serine is phosphorylated, IRS-1
becomes a poor substrate for the insulin receptor, and
preventing such serine phosphorylation restores IRS-1mediated insulin receptor signaling in vitro. Of physiological
significance is the fact that in obesity and type 2 diabetes,
such an inhibitory phosphorylation of IRS-1 exists, in the
adipocyte and also in other metabolically important tissues.6
However, the identification of this kinase(s) and of its site(s)
of action on IRS-1 has been difficult due to the presence of
multiple phosphorylation sites on IRS-1, the existence in
cells of multiple distinct kinases that can act on IRS in vitro,4
and by the fact that TNF-a-mediated phosphorylation of IRS1 is a relatively weak phenomenon and therefore uneasy to
quantify.8,9,11 Despite such constraints, recent work has shed
light on IRS-1 phosphorylation sites as well as kinases
relevant to insulin resistance. Among others, biochemical
analysis has led to the identification of several serine
phosphorylation sites on IRS-1, of which ser-307 appears to
be of major importance and targeted by c-Jun N-terminal
kinase (JNK) in vitro.10 In cell-based systems and whole
animals, JNK serves as a sensing juncture for cellular stress
and the inflammatory status.12 JNK also phosphorylates IRS1 at the ser-307 site robustly. It is likely that other sites are
also targeted by this kinase, some simultaneously with serine
307, some depending on the stimulus and context. Phosphorylation of IRS-1 at ser-307 inhibits tyrosine phosphorylation, thereby inactivating further transmission of the
insulin signal. Serine phosphorylation can also be involved
in the targeting of IRS-1 for proteasome-mediated acute
degradation under certain but not all conditions. Of
relevance is the fact that JNK activity is elevated in the
tissues of several obesity models, including obesity resulting
from high-fat feeding and the genetic deficiency of leptin.12
In these mice, there is also elevation of ser-307 phosphorylation of IRS-1 and decreased tyrosine phosphorylation upon
insulin stimulation.
These observations indicated that JNK might be a key
molecule leading to insulin resistance and type 2 diabetes.
This was tested and validated in models where obesity is
generated in genetic deficiency of JNK isoforms, JNK1 and
JNK2.12 The JNK1 and JNK2 isoforms are expressed in most
tissues at different levels and ratios, whereas JNK3 is
primarily present in the central nervous system.13 In
experiments with complete deficiency of JNK1 or JNK2,
most of the obesity-related increase in JNK activity and
the metabolic consequences are attributable to the JNK1
International Journal of Obesity

isoform.12 JNK1 knockout mice gain less weight when fed

either a regular low-fat diet or a high-fat diet. Compared to
wild-type mice, adipose tissue of the JNK1 / mice is
morphologically normal, with smaller adipocytes, and the
liver contains dramatically less fat. Overall, there is a 10%
reduction in total body adipose mass in JNK1 / compared
to wild-type controls with no alterations in the lean body
mass.12 Other tissues do not appear to be affected by lack of
JNK1. Interestingly, the volumes of subcutaneous and
visceral but not gonadal fat depots are reduced in JNK1 /
mice. Plasma levels of adiponectin are increased while those
of resistin are reduced in JNK1-deficient mice on a high-fat
diet.12 JNK1 deficiency also dramatically enhances insulin
sensitivity and confers protection against diet-induced
insulin resistance as well as insulin resistance associated
with the ob/ob model of genetic obesity,12 although to a
lesser extent in the latter. It may seem counterintuitive at
first glance that the improvement in insulin sensitivity,
which should increase the anabolic action of insulin, leads
instead to reduced fat accretion. The reasons for such an
effect remain elusive at this time but suggest that the impact
of the JNK pathway on insulin action is not dependent on its
potentially distinct effects on whole-body adiposity. The
physiological relevance of the JNK1 isoform is further
illustrated by the fact that it is specifically increasedFin
liver, adipose tissue and skeletal muscleFin obesity resulting
in increased total JNK activity and increased IRS-1 serine
phosphorylation at these sites.12 In JNK1-deficient mice,
obesity-related ser-307 phosphorylation of IRS-1 is substantially reduced demonstrating that JNK1 is the predominant
ser kinase activity in obesity acting on IRS-1.12 Both TNF-a
and fatty acids increase JNK1 activity as well as ser
phosphorylation of IRS-1, and ser-307 phosphorylation is
reduced in JNK1 knockout mice. It must be mentioned that
JNK1 is not likely to be the sole serine kinase involved in the
development of insulin resistance. Several studies have
indeed underlined the importance of other kinases such as
protein kinase c (PKC) and IkK.14,15 The interactions
between these various kinases is complex and understanding
of these networks and mechanisms remain incomplete.16
The above discussion has focused on findings in cultured
cells and murine models, but there is evidence that JNK
might be highly relevant to human health. Indeed, human
mutations in the gene coding for JNK-binding protein, a
natural inhibitor of JNK activity, causes type 2 diabetes.17 It
is therefore not unreasonable to suggest that increased JNK
activity more generally plays a role in the development
of insulin resistance and type 2 diabetes in humans. If
JNK inhibitors turn out to be effective in improving
insulin sensitivity as much as gene targeting in experimental
models, they may offer attractive possibilities of developing effective means for the treatment of human insulin
resistance.
I should like to conclude this review with some thoughts
regarding the evolutionary reasons and advantages of the
remarkable overlap and correlations between the metabolic

Inflammation and insulin action

GS Hotamisligil

S55
and inflammatory signaling pathways. To this end, I will
allude to the fruit fly Drosophila melanogaster. This lowly and
distant cousin of ours bears a rather unique organ, called the
fat body, which functions at once as liver and hematopoietic/immune system.18 This site also appears as the mammalian homologue of adipose tissue.19 Remarkably, the GATA
family of transcription factors, which influences adipocyte
differentiation in mammals, is involved in the development
of the fat body of Drosophila.19 In the course of evolution,
the individualization of the hepatic, adipose and hematopoietic/immune organs occurred, while the function of a
common network of functional and molecular pathways
were retained in all. This might explain why there are so
many overlapping pathways in the hepatocyte, adipocyte,
macrophage and lymphocyte. The same molecules assume
both metabolic and inflammatory roles. Depending on the
cell type, the action of these overlapping pathways will
produce end points, such as insulin resistance (adipocyte),
atherosclerosis (macrophage) or hyperlipidemia (hepatocyte).
What could be the selective advantage of such a strong
overlap between metabolic and inflammatory signaling
pathways? One such advantage is that a strong immune
response confers higher odds of surviving infection, and
would therefore have been favored by natural selection. At
the same time however, in absence of starvation, a strong
immune response primes the system for an equally strong
metabolic response (eg insulin resistance) to stimuli such as a
high-energy and -fat intake. A survival advantage in hard
times hence becomes deleterious in times of plenty.

Acknowledgements
I thank Julie Gound and Gurol Tuncman for help in preparing this manuscript. Gokhan S Hotamisligil is supported

by grants from the National Institutes of Health and

American Diabetes Association.

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International Journal of Obesity