Obesity and Inflammation: Epidemiology, Risk Factors, and Markers of Inflammation

Abstract

Obesity is a public health problem that has reached epidemic proportions with an increasing worldwide prevalence. The global emergence of obesity increases the risk of developing chronic metabolic disorders. Thus, it is an economic issue that increased the costs of the comorbidities associated. Moreover, in recent years, it has been demonstrated that obesity is associated with chronic systemic inflammation, this status is conditioned by the innate immune system activation in adipose tissue that promotes an increase in the production and release of pro-inflammatory cytokines that contribute to the triggering of the systemic acute-phase response which is characterized by elevation of acute-phase protein levels. On this regard, low-grade chronic inflammation is a characteristic of various chronic diseases such as metabolic syndrome, cardiovascular disease, diabetes, hypertension, non-alcoholic fatty liver disease, and some cancers, among others, which are also characterized by obesity condition. Thus, a growing body of evidence supports the important role that is played by the inflammatory response in obesity condition and the pathogenesis of chronic diseases related.

Full text

Hindawi Publishing Corporation
International Journal of Endocrinology
Volume 2013, Article ID 678159, 11 pages
http://dx.doi.org/10.1155/2013/678159
Review Article
Obesity and Inflammation: Epidemiology, Risk Factors,
and Markers of Inflammation
Heriberto Rodríguez-Hernández,1,2 Luis E. Simental-Mendía,1
Gabriela Rodríguez-Ramírez,1and Miguel A. Reyes-Romero2
1Biomedical Research Unit of the Mexican Social Security Institute at Durango, Predio Canoas 100, Los Angeles,
34067 Durango, DGO, Mexico
2Faculty of Medicine and Nutrition, Ju´
arez University of Durango State, Av. Universidad and Fanny Anit´
ua s/n,
Zona Centro, 34000 Durango, DGO, Mexico
Correspondence should be addressed to Luis E. Simental-Mend´
ıa; luis simental81@hotmail.com
Received 14 January 2013; Accepted 27 March 2013
Academic Editor: Abdelfattah El Ouaamari
Copyright © 2013 Heriberto Rodr´
ıguez-Hern´
andez et al. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Obesity is a public health problem that has reached epidemic proportions with an increasing worldwide prevalence. e global
emergence of obesity increases the risk of developing chronic metabolic disorders. us, it is an economic issue that increased the
costs of the comorbidities associated. Moreover, in recent years, it has been demonstrated that obesity is associated with chronic
systemic inammation, this status is conditionedby the innate immune system activation in adipose tissue that promotes an increase
in the production and release of pro-inammatory cytokines that contribute to the triggering of the systemic acute-phase response
which is characterized by elevation of acute-phase protein levels. On this regard, low-grade chronic inammation is a characteristic
of various chronic diseases such as metabolic syndrome, cardiovascular disease, diabetes, hypertension, non-alcoholic fatty liver
disease, and some cancers, among others, which are also characterized by obesity condition. us, a growing body of evidence
supports the important role that is played by the inammatory response in obesity condition and the pathogenesis of chronic
diseases related.
1. Epidemiology and Obesity
Obesity is actually an epidemic problem in the world; it has
become truly a global problem aecting countries rich and
poor. An estimated 500 million adults worldwide are obese
and 1.5 billion are overweight or obese [1]. Particularly the
prevalence of obesity or combined overweight and obesity
has increased in Brazil, Canada, Mexico, and United States
[2]. Much of the information about obesity among adults rest
in the use of body mass index (BMI) to dene obesity, which
willbedenedasaBMI30kg/m
2or greater unless otherwise
stated [3]. An examination of national data through 1991
conrmed that signicant increases in the United States
populationhadtakesplacebothinadultsandchildrenand
adolescents [4,5]. e most recent data from 2005-2006 show
that 33.3% of men and 35.3% of women were obese [6]. In
Canada, the prevalence of obesity based on measured height
and weight has almost doubled in the last two decades and
now aects 23% of the adult population [7].
Obesityisaconsequenceofmanyriskfactors,as
increased energy consumption and reduced physical exercise.
Many studies also implicate chronic low grade inammation
in the interplay between obesity and metabolic complica-
tions, as many chronic degenerative disorders, including
atherosclerosis, and are also commonly associated with
hypertension, which itself has also been linked recently
to inammation [8,9]. Obesity and inammation have
been associated with type 2 diabetes, cardiovascular disease,
hypertension, stroke, and gallbladder disease, some forms
of cancer, osteoarthritis, and psychosocial problems [10]. In
obesity subjects, this problem is commonly associated with
other metabolic disorders as hyperglycemia and hypertriglyc-
eridemia, which are well-known risk factors for developing
chronic liver disease, as nonalcoholic fatty liver disease

2International Journal of Endocrinology
(NAFLD) [11,12]. e prevalence of NAFLD reaches 14%
to21%,butisitashighas90%–95%inobesepersons
and up to 70% in diabetic patients [13]. Liver inammation
can be induced by the metabolically active intraabdominal
fat, and that the high BMI and large waist circumference
are signicantly associated with the elevation of aspartate
aminotransferase (AST) and alanine aminotransferase (ALT)
levels [14,15]. Patients with obesity can have elevationof AST
and ALT levels, and the reduction of body weight can be
achieved with combining diet and physical activity strategies,
and reduced levels of aminotransferase [16]. NAFLD and
cardiovascular disease have common metabolic risk factors
and have 3.7% on mortality; individuals with NAFLD were
older, predominantly males, and more likely to be Hispanic.
ey also had a higher prevalence of all components of
metabolic syndrome and cardiovascular disease; however,
patients with NAFLD disease did not increase cardiovascular
mortality in over 14 years [17].
For example, within the context of chronic HCV and
HBV infection, the presence of cirrhosis is the most impor-
tant risk factor in the development of hepatocellular carci-
noma [18].erearesomenonmodiableriskfactorsinclud-
ing older age, male gender, and family history, and several
modiable risk factors in hepatocelular carcinoma, of which
the most important are alcohol and tobacco [19]. However,
identifying additional modiable risk factors, including diet,
is important, including coee and tea, fructose, iron, red and
with meats, types of fat, selenium, and vitamins D and E [20].
Diet and life style play a crucial role in the development
of some cancers. Actually in Mexico and others countries,
more than one-third of cancer deaths can be avoided
through dietary modication. Dierent mechanisms, includ-
ing antioxidant, anti-inammatory, and antiestrogenic pro-
cesses, have been proposed to explain the protective nature
of certain dietary components [21].
2. Obesity and Chronic Inflammation
Inammation is a physiological response necessary to restore
homeostasis altered by diverse stimuli; however, inamma-
tion state chronically established or an excessive response can
involve deleterious eects. In overweight and obesity, there
exists low-grade chronic inammation; recent studies have
unveiled some of the intracellular pathways of inammation
associated with these conditions; studies in mice and humans
evidence that consumption of nutrients may acutely evoke
inammatory responses; so, it is thought that the starting
signal of inammation is overfeeding and the pathway origins
in tissues involved in metabolism, that is, adipose tissue,
liver, and muscle, which in response of this stimulus triggers
the inammatory response [22,23]. Compared with lean
control, in obese men and women, tissue and liver tissues
display an increased activation of kinases such as c-jun N-
terminal kinase and the inhibitor of k kinase, which are
able to induce the expression of inammatory cytokines
[24,25]. ese kinases regulate downstream transcriptional
programs through the transcription factors activator protein-
1, nuclear factor 𝜅B, and interferon regulatory factor, inducing
upregulation of inammatory mediator gene expression.
e increase in cytokines exacerbates receptor activation by
establishing a positive feedback loop of inammation and the
inhibitory signaling of metabolic pathways [26].
Likewise, inammasome and the Toll-like receptors
(TLRs) of the innate immune system are activated as well
[27,28]. Now, strong evidences indicate a prominent role of
the inammasome signaling in the development of a chronic
proinammatory state that impairs insulin sensitivity [24].
3. The Inflammasome
Inammasome is a macromolecular innate immune cell sen-
sor that initiates the inammatory response. Recognition of
diverse noxious signals by the inammasome results in acti-
vation of caspase-1, which subsequently induces secretion of
potent proinammatory cytokines, particularly interleukin-
1𝛽(IL-1𝛽). In this way, inammasome-mediated processes
are important in regulating metabolic processes [24,29].
e inammasome is a heptamer formed by monomers
containing Nod-like receptors (NLRs), the adaptor protein
ASC (apoptosis-associated speck-like protein containing a
caspase-recruitment domain), and the enzyme caspase-1.
NLRs are characterized by a structure composed of a central
domain that mediates nucleotide-binding and oligomeriza-
tion (NOD or NBS domain), a C-terminal leucine-rich
domain (LRR), and a variable N-terminal region required for
protein-protein interactions. When assembled as inamma-
some, NLR activates caspase-1, which converts pro-IL-1𝛽into
active IL-1𝛽[30,31].
In the human being, the NLR family consists of 22 mem-
bers, classied in 4 subfamilies, NLRA, NLRB, NLRC, and
NLRP, on basis of their N-terminal domain conguration.
ey interact with the inammasome-associated proteins
ASC and caspase-1 [32].
A member of the NLRP, named NLRP3, has been
linked to metabolic stress, insulin resistance, and type 2
diabetes. NLRP3 inammasome activation in obesity pro-
motes macrophage-mediated T cell activation in adipose
tissue and impairs insulin sensitivity creating a chronic pro-
inammatory state that impairs insulin sensitivity. Inam-
masome activation can be induced by hyperglycemia, reac-
tive oxygen species, palmitate, lipopolysaccharides, and uric
acid, among other substances [24]. ese ndings highlight
the potential molecular intervention in pathways regulating
caspase-1 activation for management of chronic inamma-
tion [29–31,33].
Recent studies show that a protein upregulated by glu-
cose, the thioredoxin interacting protein (TXNIP), interacts
with NLRP3, leading to IL-1𝛽secretion and hampering of
pancreatic 𝛽-cell function [34,35].
4. Inflammatory Cytokines
e origin of inammation during obesity and the underlying
molecular mechanisms that explain its occurrence are not
yet fully understood, but pro-inammatory cytokines play
acentralrole.Inobesity,therearehighercirculatingcon-
centrations of inammatory cytokines than in lean beings,

International Journal of Endocrinology 3
and it is believed that they play a role in causing insulin
resistance. e main source of pro-inammatory cytokines
inobesityistheadiposetissue;theyaremainlyproducedby
inltrating macrophages, although adipocytes play a role. In
this way, blood concentrations of these cytokines are lowered
following weight loss [22,23]. e main cytokines responsible
of chronic inammation are tumor necrosis factor-𝛼(TNF𝛼),
interleukin-6 (IL-6), and the inammasome-activated IL-1𝛽
mentioned earlier.
TNF-𝛼is a pleiotropic molecule that plays a central role in
inammation, immune system development, apoptosis, and
lipid metabolism, with numerous eects in adipose tissue,
including lipid metabolism and insulin signaling. Circulating
TNF-𝛼is increased in obesity and decreased with weight
loss. TNF-𝛼promotes the secretion of other powerful pro-
inammatory cytokine, IL-6, and reduces anti-inammatory
cytokines like adiponectin. TNF-𝛼induces adipocytes apop-
tosis and promotes insulin resistance by the inhibition of the
insulin receptor substrate 1 signaling pathway [36,37].
IL-6 is a cytokine that plays important roles in acute phase
reactions, inammation, hematopoiesis, bone metabolism,
and cancer progression. IL-6 regulates energy homeostasis
and inammation; it is capable of suppressing lipoprotein
lipase activity, and it controls appetite and energy intake
at hypothalamic level [38]. IL-6 is important in the tran-
sition from acute inammation to chronic inammatory
disease. It contributes to chronic inammation in conditions
such as obesity, insulin resistance, inammatory bowel dis-
ease, inammatory arthritis, and sepsis when deregulated
[39].
IL-1𝛽is a pyrogenic cytokine. It is mainly produced
by blood monocytes in response to infection, injury, or
immunologic challenge; it causes fever, hypotension, and
production of additional pro-inammatory cytokines, such
as IL-6. IL-1𝛽is formed from its pro-IL-1𝛽inactive precursor
by the inammasome. In this way, IL-1𝛽has now emerged as
a prominent instigator of the pro-inammatory response in
obesity [24].
Important advances have been reached in the last decade
in the understanding the role of cytokines and the inam-
masome in obesity, chronic inammation, insulin resistance,
and type 2 diabetes. However, further research is required
to better understand the underlying mechanisms as they are
potential intervention points in the search of new therapeu-
ticallymodalitiesfortheseglobalhealthproblems.
5. Markers of Inflammation
Several chronic diseases involve an inammatory response
characterized by the increase of cytokines and serum con-
centrations of acute-phase reactants (markers of active
inammation) such as brinogen, C-reactive protein (CRP),
complement, serum amyloid A, haptoglobin, sialic acid and
low albumin concentrations [40]. Acute-phase reactants are
synthesizedintheliver,anditsproductionisregulatedby
cytokines, including IL-6 and TNF-alpha [41–44]. e CRP,
consideredes the classic sensitive acute-phase reactant, is
a very sensitive systemic marker of inammation, and its
serum concentration increases rapidly in response to a variety
of stimuli. is protein is present in low concentrations under
normal conditions [45,46].
Visceraladiposetissuemayproduceinammatorymedi-
ators, which induce the production of acute-phase reactants
in hepatocytes and endothelial cells [47]. In fact, because it
has been shown that adipocytes express and secrete TNF-
alpha, adipose body mass may be an important mediator to
explain the relation between obesity and inammation [48].
Some studies have shown that abdominal adiposity is associ-
ated with elevation of CRP levels, independent of body mass
index (BMI), which is a measure of general adiposity. e
proportion of people with elevated hs-CRP was signicantly
higher in those individuals with abdominal adiposity than
control subjects, although they had a similar BMI [49]. IL-6
is a pro-inammatory cytokine synthesized by adipose tissue,
endothelial cells, macrophages, and lymphocytes. e CRP
is synthesized in the liver largely in response to IL-6 stimuli
[50]. Individuals with obesity are at increased risk for various
chronic diseases, several of which are also characterized by
elevated CRP concentrations. Because adipose tissue is a
major source of pro-inammatory cytokines such as IL-6
and TNF-alpha, both cytokines increase hepatic lipogenesis
[51,52] and trigger a systemic acute-phase response [41].
In recent years, it has been demonstrated that obesity is
associated with low-grade inammatory process character-
ized by the increase in circulating levels of pro-inammatory
cytokinessuchasIL-6,TNF-alpha,andacute-phaseproteins
(CRP and haptoglobin) in healthy obese subjects [53–56].
is phenomenon is also observed in obese children who
have higher CRP levels than normal weight children [57].
Some studies have reported that weight loss, through diet,
is associated with reduction in circulating levels of IL-
6, TNF-alpha, CRP, and other markers of inammation,
independently of age, sex, and BMI [58,59]. Similarly, weight
reductionobservedinsubjectsaergastricbypassshows
decrease of CRP and IL-6 levels [60].
6. Metabolic Syndrome
e metabolic syndrome is characterized as the presence
of three or more of the following features: obesity, hyper-
glycemia, hypertension, low HDL cholesterol levels, and/or
hypertriglyceridemia [61–64]. Although pathogenic mech-
anisms are poorly understood, a central role has been
attributed to the pro-inammatory cytokines TNF-alpha
[65]andIL-6[66], since both are synthesized by adipose
tissue. is syndrome has been associated with markers of
inammatory activity, such as CRP [67–75], IL-6 [76,77],
serum amyloid A [78,79], and soluble adhesion molecules
[73,75,80,81].
Risk Factors. Low-grade chronic inammation is associated
with metabolic syndrome [82] and some features of insulin
resistance [83]. Other studies have demonstrated signicant
correlation between CRP levels with features of the metabolic
syndrome, including adiposity, hyperinsulinemia, insulin
resistance, hypertriglyceridemia, and low HDL cholesterol
[84,85]. Few studies have reported the association between

4International Journal of Endocrinology
CRP and development of metabolic syndrome [50,86]. In
addition, it has been observed that elevated hs-CRP levels
are associated with increased risk for incident cardiovascular
events among individuals as having the metabolic syndrome
[87]. Inammation has been proposed as common part
of dierent metabolic disturbances of insulin, glucose, and
lipids that inuence the underlying development of metabolic
syndrome [50].
Also, it has shown that CRP adds independent prognostic
information on severity of metabolic syndrome [87]. Given
the evidence, it has been proposed that CRP is an additional
component of metabolic syndrome [88]. In one study, it was
reported that elevated levels of CRP (≥3 mg/L) may increase
the risk of metabolic syndrome mediated through obesity and
factors related to insulin resistance [50].
Tre atme nt. Observational studies have shown that dietary
patterns similar to the Mediterranean diet, rich in fruit
and vegetables and high in monounsaturated fats and ber,
resulted in decrease prevalence of the metabolic syndrome
[89–91]. In addition, interventional studies also demon-
strated a decrease in markers of inammation in subjects with
metabolic syndrome consuming Mediterranean diet and/or
national dietary guidelines [92,93].
Studies that evaluate markers of inammation in individ-
uals with metabolic syndrome are scarce; however, some have
shown anti-inammatory eects of statin therapy [94,95].
Because subjects with metabolic syndrome exhibit increased
inammation, aer therapeutic lifestyle changes, statins
could be a therapeutic option.
7. Cardiovascular Disease
In the last years, dierent markers of inammation (such as
CRP, IL-6, and TNF-alpha, among others) have been studied
in prediction of coronary events; on this regard, CRP is the
most important marker for cardiovascular disease [96].
Risk Factors. Circulating elevated levels of inammatory
markers, such as CRP, TNF-alpha, and IL-6, are associated
with increased risk of developing cardiovascular disease [97–
102]; even some acute-phase reactants may also contribute
to their pathogenesis [103]. ough in mild degree, chronic
elevation of CRP levels, even within normal value range,
is an independent predictor of future cardiovascular events
[99,104]. Stratied ranges of high-sensitivity CRP levels
of <1, 1–3, and >3mg/L correspond to low, moderate, and
high risks for future cardiovascular events. Previously, some
studies have found a signicative association between CRP
and cardiovascular risk [105,106]. is nding was observed
for the rst time over 50 years ago, where increased CRP
level, aer myocardial infarction, was identied as marker of
poor prognostic [87]. Later, the European Concerted Action
on rombosis and Disabilities Angina Pectoris Study Group
reported that CRP concentrations were higher in the patients
who had coronary events than in those without such events
[107]. In addition, the Cholesterol and Recurrent Events
Trial showed that elevated CRP levels are associated with
major risk of coronary events aer myocardial infarction
[108]. A growing body of evidence has corroborated that
inammation is a strong predictor of future cardiovascular
events [96–99,104,109–114].
Furthermore, hsCRP is better marker of cardiovascular
disease than others acute-phase reactants, cytokines, and
soluble adhesion molecules [115]. us, supported by a large
number of observational studies and meta-analyses, CRP
is considered as a mediator of cardiovascular disease [116],
independently of age, smoking, cholesterol levels, blood
pressure, and diabetes among others traditional risk factors
evaluated in the clinical setting [117]. us, CRP is one of the
most well-documented emerging cardiovascular disease risk
factors [118,119].
Tre atme nt. Some interventional studies using Mediterranean
diet and others characterized by increased intake of mustard
or soybean oil, fruits, vegetables, nuts, and whole grains
reduced the rate of cardiovascular disease with signicant
anti-inammatory eect [120,121]. Also, various observa-
tional and interventional studies found that intake of omega-
3 and omega-6 fatty acids and alpha-linolenicacid resulted in
lower risk of cardiovascular disease and lower concentrations
of markers of inammation [122–128]. Moreover, several
studies have shown that statin therapy is associated with
reduced inammation and cardiovascular risk reduction
[108,129–141].
8. Diabetes
Several studies have shown that subclinical systemic inam-
mation,asmeasuredbyelevatedlevelsofCRPandIL-6,
predicts the development of diabetes [142–149]. In fact, IL-
6 may interfere with insulin signalling through induction
of proteins that bind to the insulin receptor [150]. On this
regard, a growing body of evidence supports the hypothesis
that chronic systemic inammation contributes to decrease
of insulin sensitivity at peripheral tissues [40,45,151,152].
Risk Factors. Several studies in healthy subjects have con-
rmed that elevated levels of CRP and cytokines IL-6 and
TNF-alpha are associated with insulin resistance [84,85,153–
155]. In addition, it has been shown that in the individuals
with impaired glucose tolerance [156,157], the low-grade
chronic inammation is related to glucose metabolic distur-
bances.
It has been reported that TNF-alpha is overexpressed in
the adipose and muscle tissues of obese and insulin-resistant
nondiabetic subjects, overexpression that is positively cor-
related with insulin resistance [48,158–160]. Interestingly,
circulating TNF-alpha levels are higher in type 2 diabetes
[161–163] as compared with IFG/IGT [156]. In addition,
several cross-sectional studies have shown an increase of CRP
levels in patients with diabetes [142,143,164] and the increase
of CRP, IL-6, and TNF-alpha in subjects with IGT [40,165].
Moreover, in obesity there are elevated levels of several
kinases such as protein kinase C isoforms, I Kappa B Kinase-
𝛽, and c-jun-terminal kinase, and these kinases have been
implicated in alteration of insulin signaling by promoting
serine phosphorylation of insulin receptor substrate which

International Journal of Endocrinology 5
is associated with suppression of tyrosine phosphorylation of
this substrate [166]. Also, various studies have demonstrated
thatnutrientexcessandobesityareassociatedwithelevated
levels of free fatty acids, which can induce both insulin
resistance in peripheral tissues and activation of innate
immunity [28,167–172].
Furthermore, it is dicult to set cut-point values to
predict risk of development disease because intermediate
values of CRP are at moderate risk for metabolic disturbances.
However, it has been reported that patients with diabetes
and CRP values >3 mg/L have 51% higher risk of all-cause
mortality and 44% higher risk of cardiovascular mortality
than subjects with diabetes and CRP <3 mg/L of similar age
and sex, independently of classical risk factors such as lipids,
blood pressure, and glycemia [173].
Tre atme nt. In clinical eld, there are dierent therapeutic
options, such as genetic, biochemical, and pharmacological
targeting of inammatory signalling pathways improving
insulin action, a central problem in the pathophysiology of
type 2 diabetes [174]. Existing evidence about inhibiting spe-
cic inammatory kinases pathway improves insulin action
in animal models [175,176]. Pharmacological therapeutics
using thiazolidinediones exhibited anti-inammatory eects
inhibiting both adipocyte and macrophage function in obe-
sity and type 2 diabetes [177]. Various clinical studies, using
anti-inammatory drugs to treat type 2 diabetes and even
prediabetes, showed improvements in beta-cell function and
insulin sensitivity, reducing glucose levels [34,178–182]. In
addition, others studies in patients with type 2 diabetes taking
statins have demonstrated a benecial and additive eect
on markers of inammation [183–186], which could be an
alternative therapeutic for this disease; however, the clinical
practice recommendations should be considered about the
appropriate use of statin therapy because basic studies have
documented controversial results regarding the benecial
andadverseeectsoninsulinsecretionandsensitivity[187].
9. Conclusion
e origin of inammation during obesity and the underlying
molecular mechanisms that explain its occurrence are not
still fully understood, but pro-inammatory cytokines play
acentralrole.Inobesity,therearehighercirculatingcon-
centrations of inammatory cytokines than in lean beings,
and it is believed that they play a role in causing insulin
resistance. e main source of proinammatory cytokines
in obesity is the adipose tissue; they are mainly produced
by inltrating macrophages, although adipocytes play a role.
Obesityisaconsequenceofmanyriskfactors,asincreased
energy consumption and reduced physical exercise. Many
problems ecist in patients with obesity, as cardiovascular
disease, diabetes, metabolic syndrome, and NAFLD, among
others, predicting the risk of future cardiovascular events
and mortality. Dierent mechanisms, including antioxidant,
anti-inammatory, ber diet, and antiestrogenic processes,
have been proposed to explain the protective nature of
certain dietary components, particularly, components of
Mediterranean diet which could be an important therapeutic
lifestyle change which allows to avoid the development of
metabolic diseases.
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