Perspective
A Novel Pathway to the Manifestations of
Metabolic Syndrome
Gabriele E. Sonnenberg, Glenn R. Krakower, and Ahmed H. Kissebah
Abstract
SONNENBERG, GABRIELE E., GLENN R.
KRAKOWER, AND AHMED H. KISSEBAH. A novel
pathway to the manifestations of metabolic syndrome. Obes
Res. 2004;12:180–186.
Pathways leading from obesity to the manifestations of
metabolic syndrome involve a number of metabolic risk
factors, as well as adipokines, mediators of inflammatory
response, thrombogenic and thrombolytic parameters, and
vascular endothelial reactivity. Increased adipose tissue
mass contributes to augmented secretion of proinflammatory
adipokines, particularly tumor necrosis factor-(TNF), along
with diminished secretion of the “protective” adiponectin. In
our view, TNF and adiponectin are antagonistic in
stimulating nuclear transcription factor-B (NF-B) activation.
Through this activation, TNFinduces oxidative stress, which
exacerbates pathological processes leading to oxidized low-
density lipoprotein and dyslipidemia, glucose intolerance,
insulin resistance, hypertension, endothelial dysfunction,
and atherogenesis. NF-B activation further stimulates the
formation of additional inflammatory cytokines, along with
adhesion molecules which promote endothelial dysfunction.
Elevated free fatty acid, glucose, and insulin levels enhance
this NF-B activation and further downstream modulate
specific clinical manifestations of metabolic syndrome.
Key words: adiponectin, TNF, NF-B, oxidative stress
Introduction
The understanding of metabolic syndrome as representing
the combined manifestation of insulin resistance and
hyperinsulinemia, impaired glucose tolerance, dyslipide-
Received for review June 17, 2003.
Accepted in final form December 9, 2003.
1
, tumor
Nonstandard abbreviations: NO, nitric oxide; ROS, reactive oxygen species; TNF necrosis
factor-; NF-B, nuclear transcription factor-B; IL-6, interleukin-6; IGF-1, insulin-like growth
factor 1; IKK-, inhibitory subunit I--B kinase, subunit; oxLDL, oxidized low-density
180 OBESITY RESEARCH Vol. 12 No. 2 February 2004
mia, and elevated blood pressure has been extended
considerably in recent years. In addition to advances in
elucidating mechanisms underlying hepatic and peripheral
insulin resistance, knowledge about the contributions of
cytokines, adhesion molecules, nitric oxide (NO), 1 and
reactive oxygen species (ROS) has soared. Adipose tissue
secretes numerous factors (adipokines) known to markedly
influence lipid and glucose/insulin metabolism, oxidative
stress, and cardiovascular integrity. Among these adipokines
are the proinflammatory cytokine tumor necrosis factor-
(TNF) and the “protective” adipose tissue-specific protein,
adiponectin, which we consider highly significant in the
development of metabolic syndrome (1). In this review, we
highlight the pathophysiological relevance of these
circulating adipokines and extend recently postulated
mechanisms leading to the clinical manifestations of the
metabolic syndrome. We propose that TNF-stimulated
activation of nuclear transcription factor-B (NF-B) augments
production of cytokines and adhesion molecules and
increases oxidative stress, whereas adiponectin inhibits
activation of NF-B and, thereby, promotes a more protective
metabolic profile. The central role of the NF-B pathway and
its regulation could guide in the search for innovative and
effective therapeutic agents to delay or prevent the clinical
manifestations of metabolic syndrome.
TNF and Adiponectin
Whereas adipose tissue secretes a number of hormones
with multifaceted biological actions (1), two seem key in
influencing many of the biological events related to
metabolic syndrome. The proinflammatory adipokine, TNF,
lipoprotein; CRP, C-reactive protein; FFA, free fatty acid; PPAR,
peroxisome proliferator activated receptor; LXR, liver X receptor.
Pathway to Metabolic Syndrome, Sonnenberg, Krakower, and Kissebah
The costs of publication of this article were defrayed, in part, by the payment of page charges.
18 U.S.C. Section 1734 solely to indicate this fact.
Department of Medicine, Division of Endocrinology, Metabolism
Address correspondence to Gabriele E. Sonnenberg, Department of Medicine, Division of
Endocrinology, Metabolism and Clinical Nutrition, 9200 W. Wisconsin Ave., Milwaukee WI
53226.
E-mail: gsonnen@mcw.edu
Copyright © 2004 NAASO
plays
This article must, therefore, be hereby marked “advertisement” in accordance with
a primary role in stimulating the production of leptin, in
addition to interleukin-6 (IL-6) and other inflammatory
mediators (2–5). Expression of TNF is increased during
weight gain and reduced with weight loss (6,7). TNF
stimulates lipolysis, and levels are closely associated with
both hyperinsulinemia and insulin resistance, as well as
systolic blood pressure (8–12). TNF may also contribute to
enhanced adipogenesis (13,14). In addition, the
neutralization of TNF in obese mice has been demonstrated
to significantly improve insulin sensitivity (15).
On the other hand, obesity is associated with low levels of
the gene product of apM1, adiponectin, whereas weight loss
increases adiponectin levels (16–18). A recent study
reporting that adiponectin inhibits pre-adipocyte
differentiation (19) suggests that it might contribute to the
regulation of fat tissue growth. Low levels of adiponectin are
closely associated with such manifestations of metabolic
syndrome as insulin sensitivity and type 2 diabetes (20–22).
Administration of adiponectin (or its 30-kDa cleavage
product) has been shown to ameliorate the insulin resistance
of mice by reducing levels of triglycerides in muscle and
liver through increases in fatty acid transport and -oxidation
(23–25). In addition, low serum adiponectin is also
correlated with high blood pressure and dyslipidemia (26–
29). Furthermore, adiponectin seems to ameliorate the
endothelial inflammatory response by inhibiting expression
of adhesion molecules on aortic endothelial cells (30) and by
suppressing human aortic smooth muscle cell proliferation
(31). Adiponectin deficiency also reversibly aggravates
neointimal thickening in mechanically injured arteries
(32,33). Adiponectin expression and secretion are reduced
by TNF (34,35), possibly through stimulated production of
IL-6 (36), which also inhibits adiponectin secretion (37).
We view increased secretion of TNFand reduced
expression of adiponectin as highly important in relating
adiposity to the development of metabolic syndrome,
although such other adipokines as leptin, IL-6, insulin-like
growth factor 1 (IGF-1), and resistin likely contribute to this
pathobiology. Adiponectin is seen to be “protective,” not
only in its inverse relationship with features of metabolic
syndrome (38), but also through its antagonism of TNF
action (39). The following section suggests one mechanism
by which this could occur.
NF-B and Oxidative Stress
and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin.
Many peripheral actions of adipokines are mediated
through activation of the ubiquitous NF-B, promoted by a
number of proinflammatory cytokines, hormones, and
metabolites (40). This pathway proceeds through the
phosphorylation and subsequent ubiquitination of the
subunit of the inhibitory subunit I--B kinase (IKK-). This
modified moiety, still associated with NF-B in the
cytoplasm, is then selectively degraded, thus freeing the
active NF-B to translocate to the nucleus and bind its target
genes to initiate transcription. Through this pathway, such
proinflammatory adipokines as TNFstimulate the
transcription of cytokines and adhesion molecules in
peripheral tissues. Adiponectin, on the other hand,
suppresses TNF-induced NF-B signaling at a step just before
IKK- activation (39). Adiponectin has been shown to inhibit
TNF-induced expression of endothelial adhesion molecules
in this manner
(30,41).
Inflammation is associated with increased oxidative
stress, which has been implicated in the development of
hypertension, atherosclerosis, diabetes, and, more recently,
in obesity per se (42,43). Adipokine-stimulated activation of
NF-B increases production of NO (44), which serves as a
substrate for the formation of ROS. ROSs likely mediate
some facets of this pathophysiology, including insulin
resistance and diminished insulin secretion (45,46), as well
as the atherogenic properties of the associated lipemic profile
(47,48). ROSs serve as a precursor to the formation of
oxidized low-density lipoproteins (oxLDLs), essential to the
development of atherosclerotic lesions through their
progressive uptake by macrophages. oxLDL is closely
associated with such manifestations of metabolic syndrome
as elevated plasma lipid levels and unfavorable LDL density
distributions, as well as increases in plasma glucose and
insulin levels (49–52). Moreover, oxLDL also contributes to
NF-B activation, thereby stimulating production of
additional ROSs (53,54).
Pathways to Metabolic Syndrome
A significant extension to the broadened view of
metabolic syndrome is represented by the occurrence of
endothelial dysfunction and intimal-medial thickening, as
well as elevations of plasma C-reactive protein (CRP) and
adhesion molecules. These are closely related to measures of
OBESITY RESEARCH Vol. 12 No. 2 February 2004 181
Pathway to Metabolic Syndrome, Sonnenberg, Krakower, and Kissebah

obesity and visceral fat accumulation, abnormalities in lipid

metabolism, essential hypertension, insulin resistance, and
type 2 diabetes (55–60). Activation of NF-B has been linked
to atherogenesis through inflammatory cytokines and
adhesion molecules and to endothelial dysfunction through
increased NO production (61). CRP levels are elevated in
obesity, insulin resistance, and coronary heart disease
(62,63), along with TNF levels (which induce production of
IL-6, the primary regulator of CRP production) (64), and are
negatively correlated with adiponectin (65). CRP enhances
uptake of LDL and also stimulates macrophages to express
cytokines (66), whereas plasma levels of CRP are closely
correlated with levels of adhesion molecules (67), which
contribute to endothelial dysfunction and worsen intimal-
medial thickening. Adhesion molecules, whose secretion is
also stimulated by cytokines through NF-B, are elevated
along with plasma lipids in atherosclerosis and diabetes (68–
70).
Increasing evidence suggests that adipokine-stimulated
NF-B activation contributes to the development of insulin
resistance and impaired insulin secretion (71). Cytokines
induced through this pathway play important direct roles in
-cell function and glucose/insulin metabolism. As described
above, elevation in TNF is associated with both liver and
muscle tissue insulin resistance (72,73); patients with
diabetes have elevated levels of TNF, IL-6, and CRP

182 OBESITY RESEARCH Vol. 12 No. 2 February 2004

Pathway to Metabolic Syndrome, Sonnenberg, Krakower, and Kissebah

Figure 1: The roles of adipose tissue secretory products and NF-B in the pathways leading to the clinical manifestations of metabolic
syndrome. oxidative stress because of increased mitochondrial
uncoupling and -oxidation, resulting in increased production
of ROSs (45). Moreover, hyperglycemia and FFAinduced
(74,75). Such other NF-B–induced cytokines as IL-1and -
oxidative stress activate signaling pathways that worsen both
interferon antagonize insulin signaling and inhibit glucose-
secretion and action of insulin.
stimulated insulin secretion (76,77). However, glucose, free
The model outlined in Figure 1 extends several hypotheses
fatty acids (FFAs), and insulin also play important roles in
(1,45,78–82) toward a view in which the development of
this pathophysiology, in part by activating the NF-B
metabolic syndrome is mediated by fat tissue mass and its
pathway. Elevated FFAs are also proposed to promote

OBESITY RESEARCH Vol. 12 No. 2 February 2004 183

Pathway to Metabolic Syndrome, Sonnenberg, Krakower, and Kissebah
dual relationships with the inflammatory adipokines,
primarily TNF, and the protective actions of adiponectin.
Through activation of NF-B, levels of the inflammatory
adipokines stimulate the formation of ROSs, inflammatory
cytokines, and adhesion molecules, which exacerbate
pathological processes, leading to LDL oxidation and
dyslipidemia, insulin resistance, and glucose intolerance, as
well as endothelial dysfunction and atherogenesis.
Elevations in plasma FFAs, glucose, and insulin
concentrations further activate NF-B in addition to their
other actions on pathways, leading to the clinical
manifestations of metabolic syndrome. By inhibiting NF-B
activation (39), adiponectin reduces both oxidative stress
and the stimulation of peripheral cytokine production,
thereby protecting against the development of long-term
morbidities such as coronary artery disease, hypertension,
and type 2 diabetes.
Support for this pathway is also provided by genetics
studies. We have localized several chromosomal regions
exhibiting strong evidence for linkage with obesity
phenotypes. The quantitative trait locus at chromosome
3q27, which has been replicated in genome-wide scanning
studies in a number of different ethnic groups, harbors the
apM1 gene. We also localized a quantitative trait locus for
plasma adiponectin on chromosome 14q11.2–13, a region
that includes the gene for the NF-B inhibitory protein
(83,84). The development of well-designed studies and
innovative genetic approaches could aid in the goal of
unraveling the pathobiology and genetic basis of obesity and
metabolic syndrome.
Guidance toward Therapeutic Interventions
This model could guide the search for preventive and
therapeutic interventions. Rather than limiting treatment
modalities to the specific clinical manifestations of
metabolic syndrome, this centralized pathway offers a means
for preventing or delaying their onset. Numerous sites along
this pathway have the potential for pharmacological
intervention, particularly the inhibition of the nuclear
translocation of NF-B. A number of commonly used anti-
inflammatory drugs inhibit NF-B activation (85), including
salicylates (86,87) and glucocorticoids (88,89), in addition to
experimental anti-inflammatory prostaglandins (90,91),
whereas a new generation of NF-B–specific inhibitors is
under development. Another potential therapeutic target is
represented by the NF-B inhibitory function of adiponectin,
which has already been suggested as a useful treatment
modality for both type 2 diabetes and atherosclerosis (92,93).
Treatment with thiazolidinediones, ligands for peroxisome
proliferator activated receptor (PPAR), increases serum
adiponectin levels (35,94,95); inhibition of NF-B by
adiponectin could explain PPAR regulation of the
184 OBESITY RESEARCH Vol. 12 No. 2 February 2004
production of cytokines and adhesion molecules (96).
Another target for intervention is represented by the liver X
receptors (LXRs), a class of nuclear receptors activated by
oxLDL. The LXRs mediate lipid-inducible gene expression;
because many of the genes inhibited by LXR are targets of
NF-B signaling, LXR agonists could, therefore, exhibit
important anti-inflammatory functions. The formation of
ROSs might also represent a means for intervention. In some
studies, antioxidants have been shown to inhibit NF-B
activation and prevent cytokine formation or block
formation of ROSs and, thereby, improve endothelial
function (47,48,97). However, other studies have failed to
demonstrate the efficacy of antioxidant supplementation in
preventing or delaying atherosclerosis or other
manifestations of metabolic syndrome.
Summary
This view is by no means complete and raises a number of
new questions. The relative contributions of subcutaneous
and visceral fat to adipokine secretion are just beginning to
be understood (98,99). In addition, pathways leading from
cytokines and mediators of oxidative stress toward the
clinical manifestations of metabolic syndrome remain to be
elucidated. It is likely that glucose, FFAs, and insulin, all
activators of NF-B, contribute significantly to these
pathways, whereas cross-talk between insulin and cytokine
signaling pathways could amplify this response (80). A
number of such other adipose tissue–derived
proinflammatory factors as IL-6 may also contribute, but
their specific functions are uncertain. Do these other
adipokines complement and magnify the responses evoked
by TNF? Or do they act to counter its actions (100)? More
detailed examination of these questions will greatly advance
our understanding of the pathobiological pathways toward
metabolic syndrome and guide our search for agents with a
potential for prevention and treatment.
Acknowledgments
This study was supported by National Institutes of Health
Grants DK54026 and RR00058.
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