International Journal of Obesity (2004) 28, 674–679

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PAPER
Obesity is the major determinant of elevated
C-reactive protein in subjects with the metabolic
syndrome
D Aronson1*, P Bartha2, O Zinder3, A Kerner1, W Markiewicz1, O Avizohar4,5, GJ Brook4,5 and
Y Levy2
1
Department of Cardiology; 2Department of Internal Medicine D; 3Department of Laboratory Medicine; 4Center for
Preventive Medicine, Rambam Medical Center, Haifa, Israel; and 5Rappaport Faculty of Medicine, Rambam Medical Center,
Haifa, Israel

OBJECTIVE: To investigate the relationship between C-reactive protein (CRP) and various characteristics of the metabolic
syndrome.
DESIGN: Population-based cross-sectional study.
SUBJECTS: A total of 1929 subjects undergoing a medical examination in a preventive medicine clinic (age, 50710 y; 63%
males).
RESULTS: The proportion of subjects with CRP levels above the cut point generally used to indicate an obvious source of
infection or inflammation (410 mg/l) was 3, 7, and 15% in subjects who were normal weight, overweight, and obese,
respectively. Subjects with obesity had markedly higher CRP level compared to patients without obesity regardless of whether
they had the metabolic syndrome. However, there was no significant difference in CRP levels between nonobese subjects
without the metabolic syndrome and subjects in whom the diagnosis of the metabolic syndrome was based on criteria other
than obesity (adjusted geometric mean CRP 1.75 vs 2.08 mg/l, P ¼ 0.79). Similarly, CRP levels did not differ among obese
subjects with and without the metabolic syndrome (adjusted geometric mean CRP 3.22 vs 3.49 mg/l, P ¼ 0.99). There was a
linear increase in CRP levels with an increase in the number of metabolic disorders (Ptrend o0.0001), which was substantially
diminished after controlling for body mass index (BMI) (Ptrend ¼ 0.1). Stepwise multivariate linear regression analysis identified
BMI, triglyceride levels, HDL cholesterol levels (inversely), and fasting glucose as independently related to CRP levels. However,
BMI accounted for 15% of the variability in CRP levels, whereas triglycerides, HDL cholesterol and fasting glucose levels
accounted for only B1% of the variability in CRP levels.
CONCLUSION: Obesity is the major factor associated with elevated CRP in individuals with the metabolic syndrome. CRP levels
in the range suggesting a source of infection or inflammation (410 mg/l) are more common among obese subjects than in
nonobese subjects.
International Journal of Obesity (2004) 28, 674–679. doi:10.1038/sj.ijo.0802609
Published online 2 March 2004

Keywords: C–reactive protein; obesity; inflammation; metabolic syndrome

Introduction infarction, stroke, peripheral vascular disease, and sudden

Arterial inflammation has emerged as central to the initia-
tion and progression of atherosclerosis. 1,2 Of the markers of
inflammation, C-reactive protein (CRP) has been shown in
multiple prospective studies to predict incident myocardial
*Correspondence: Dr D Aronson, Department of Cardiology, Rambam
Medical Center, POB 9602, Haifa 31096, Israel.
E-mail: daronson@netvision.net.il
Received 11 August 2003; revised 3 January 2004; accepted 11 January
2004
cardiac death.3,4
The proportion of overweight adults in the US has been
steadily increasing in the past several decades. Presently, most
US adults are overweight (450%), and approximately one in
five are obese (body mass index (BMI)Z30 kg/m2).5 Each year,
an estimated 300 000 US adults die of causes related to
obesity.6 In particular, obesity is associated with the metabolic
syndrome, development of type II diabetes and coronary
heart disease.7 Obesity independently predicts coronary
atherosclerosis,8 coronary events, and coronary mortality.9,10

Recent studies have shown that elevated CRP is strongly
associated with various characteristics of the metabolic
syndrome.11–15 A growing body of evidence implicates
adipose tissue as a major regulator of inflammation,
coagulation, and fibrinolysis. Adipose tissue produces proin-
flammatory cytokines such as tumor necrosis factor-a and
interleukin-6,14,16 and is considered an important source of
basal production of interleukin-6, the chief stimulator of the
production of CRP in the liver.17
In the present cross-sectional study of middle-aged
subjects, we examine the relation between plasma CRP
concentrations, obesity, and other characteristics of the
metabolic syndrome.
Subjects and methods
Subjects
We studied 1929 middle-aged subjects who reported to the
Rambam Center for Preventive Medicine for investigation of
cardiovascular risk factors. Subjects with evidence for an
overt inflammatory disease were excluded. The participating
subjects came to the Rambam Medical Center for a medical
examination and health counseling. Some were sent by their
employers for these services, some were referred by their
personal physician, and others were self-referred.
A medical history was taken by a physician in all subjects.
The investigational review committee on human research
approved the study. Subjects enrolled in the study signed a
statement agreeing to use their medical information for
research purposes.
Definitions
BMI was used as an estimate of overall adiposity. Cigarette
smoking was dichotomized into ‘never’ or ‘ever’ (including
past and current) by use of standard questionnaire. Leisure
time physical activity was also dichotomized to never, rarely,
or regular physical activity.
Categories of overweight and obesity were constructed
based on the graded classification that applies to both men
and woman proposed by a World Health Organization expert
committee:18 normal BMI o25 kg/m2; overweight BMI 25.0–
29.9 kg/m2; class I obese BMI 30.0–34.9 kg/m2; class II obese
BMI 35.0–39.9 kg/m2; and class III obese BMI Z40.0 kg/m2.
Characteristics of the metabolic syndrome was based on
the recent Third Report of the National Cholesterol Educa-
tion Program Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults (ATP III)
Criteria 19 using the following cutoff limits: (1) blood
pressure Z135/85 mmHg, (2) triglyceride Z1.7 mmol/l
(150 mg/dl), (3) low HDL cholesterol r1.0 mmol/l (40 mg/
dl) for men and r1.3 mmol/l (50 mg/dl) for women, (4)
fasting glucose Z6.1 mmol/l (110 mg/dl). However, because
waist circumference was not measured in all subjects, we
used a BMI cut point of Z30 kg/m2 for obesity, as suggested
by the recent World Health Organization (WHO) criteria for
Obesity and CRP
D Aronson et al
675
diagnosis of the metabolic syndrome.20 Subjects with Z3 of
the above criteria were diagnosed as having the metabolic
syndrome. If the participants were using antihypertensive or
antidiabetic medications (oral agents or insulin), they were
considered as participants with high blood pressure or
diabetes, respectively.
Laboratory measurements
Venous blood samples were collected from each subject after
a 12-h fast and used for assay of glucose, total and HDL
cholesterol, triglycerides, and uric acid. Triglycerides were
determined by using a reagent kit from Boehringer Man-
nheim after enzymatic hydrolysis of the triglycerides and
subsequent determination of liberated glycerol by colorime-
try. Total cholesterol was measured with an automated
enzymatic method using a high-performance reagent kit
from Boehringer Mannheim. HDL cholesterol was measured
by the phosphotungstate method. Plasma glucose was
enzymatically determined with the glucose oxidase method
using AutoAnalyzer (Hitachi Inc., Tokyo, Japan). Complete
blood cell counts were performed with standard techniques.
CRP was measured with latex-enhanced immunonephelo-
metry on a Behring BN II Nephelometer (Dade Behring,
Newark, DE, USA). In this assay, polystyrene beads coated
with mouse monoclonal antibodies bind CRP present in the
serum sample, and form aggregates. The intensity of the
scattered light is proportional to the size of the aggregates
and thus reflects concentration of CRP present in the sample.
The intra-assay and interassay CVs for CRP were 3.3 and
3.2%, respectively. The lower detection limit of the assay was
0.15 mg/l. In nine subjects, CRP levels were lower than this
value. A value of 0.15 mg/l was assigned to these subjects.
Statistical methods
Differences between CRP levels in subjects with and without
each of the characteristics of the metabolic syndrome were
compared using the Mann–Whitney Rank Sum test. The
distribution of CRP levels was highly skewed. Therefore, CRP
values were transformed to their natural logarithm (ln CRP)
for all other analyses. The adjusted mean values of ln CRP in
relation to the number of metabolic disorders were calcu-
lated by analysis of covariance (ANCOVA), with results
expressed as geometric means. Using a general linear model,
we tested the significance of trends for increasing CRP levels
across the number of metabolic disorders.
The strength of the association between CRP and clinical
and biochemical variables was assessed by linear regression
of ln CRP on each variable separately. Subsequently, stepwise
linear regression models were fit for ln CRP as a dependent
variable, including all variables of interest as independent
variables to demonstrate the relative contribution of each of
these variables to the outcome variable. Only variables that
had a Pr0.05 were considered in the final fitted model.
Differences were considered significant at the Po0.05 level.
International Journal of Obesity
 Obesity and CRP
D Aronson et al
676
All statistical analyses were performed using the SPSS
statistical software (version 10.1).
Results
The study population included 1929 subjects (mean age
50710 y (range 32–78), 63% males). More than 95% of
subjects were Caucasian. The median plasma concentrations
of CRP were lowest among participants with normal BMI
(1.2, interquartile range 0.7–2.6 mg/l), higher among over-
weight individuals (1.9, interquartile range 1.0–4.2 mg/l),
and highest among individuals with obesity (4.0, interquar-
tile range 2.0–7.3 mg/l). CRP levels increased continuously
with increasing severity of obesity (Figure 1a).
The proportion of subjects with CRP levels above the cut
point, generally used to indicate an obvious source of
infection or inflammation (410 mg/l),21,22 increased with
higher levels of obesity, with a substantial proportion of
obese subjects having CRP above this cut point (Figure 1b).
The WBC count was significantly higher in subjects with
Figure 1 (a) Box and whisker plots of CRP level according to BMI category.
Normal BMI o25 kg/m2; overweight BMI 25.0–29.9 kg/m2; class I obese BMI
30.0–34.9 kg/m2; class II obese BMI 35.0–39.9 kg/m2; and class III obese BMI
Z40.0 kg/m2. The line within the box denotes the median and the box spans
the interquartile range (25–75th percentiles). Whiskers extend from the 10–
90th percentiles. (b) Percentages of patients with CRP levels Z10 mg/l
according to BMI category. Trend was evaluated by w2 test.
International Journal of Obesity
CRP 410 mg/l compared with subjects with CRP r10 mg/l
(6.771.7 vs 8.172.1 (  109 l1); Po0.0001).
Nonobese subjects without the metabolic syndrome had
the lowest CRP levels. Subjects with obesity had markedly
higher CRP level compared to patients without obesity
regardless of whether they had the metabolic syndrome
(Figure 2). However, there was no significant difference in
CRP levels between nonobese subjects without the metabolic
syndrome and subjects in whom the diagnosis of the
metabolic syndrome was based on criteria other than obesity
(P ¼ 0.79). Similarly, CRP levels did not differ among obese
subjects with and without the metabolic syndrome
(P ¼ 0.99).
CRP levels were significantly higher in subjects who had
each characteristic of the metabolic syndrome, compared to
those who did not (Table 1). The percentage of subjects
presenting with 0, 1, 2, 3, 4, or 5 components of the
metabolic syndrome was 44, 29, 16, 8, 2, and 1%,
respectively. There was a strong linear increase in ln CRP
with increasing number of metabolic disorders (Figure 3a).
BMI increased continuously with increasing number of
components of the metabolic disorders; the geometric mean
CRP for those with 0, 1, 2, 3, 4, and 5 components of the
metabolic syndrome were 1.48, 2.31, 2.66, 3.19, 3.42, and
3.86 mg/l, respectively. However, controlling for BMI sub-
stantially diminished the trend across characteristics of the
metabolic syndrome (Figure 3b).
There was a statistically significant unadjusted relation
correlation between ln CRP and all components of the
Figure 2 Adjusted geometric means CRP and 95% confidence intervals for
subjects without both the metabolic syndrome and obesity (MS, Ob),
subjects with the metabolic syndrome based on components other than
obesity (MS þ , Ob), subjects with obesity but without the metabolic
syndrome (MS, Ob þ ) and subjects with the diagnosis of the metabolic
syndrome when one of the components is obesity (MS þ , Ob þ ). CRP levels
were adjusted for age, sex, WBC count, serum albumin, physical activity,
smoking status, and HRT using ANCOVA. P-values are based on the Bonferroni
adjustment for multiple comparisons. *Po0.0001 compared with MS, Ob;
w
P ¼ 0.005 compared with MS þ , Ob; z Po0.0001 compared with MS þ ,
Ob;
 Obesity and CRP
D Aronson et al
677
Table 1 Median CRP levels (interquartile range) among 1929 subjects Table 2 Pearson’s correlation coefficients and regression coefficients
according to characteristics of the metabolic syndrome between variables of interest and ln CRP

Characteristic N (%) Absent Present P-value* Variable R Regression coefficient (s.e.) 95% CI

Obesity 349 (18) 1.5 (0.8–3.0) 3.4 (1.8–5.5) o0.0001 Coefficient (s.e.)
Hypertension 323 (17) 1.7 (0.8–3.4) 2.3 (1.2–4.5) o0.0001 BMI 0.39* 0.10 (0.01) 0.09, 0.11
Hypertriglyceridemia 632 (33) 1.5 (0.8–3.2) 2.2 (1.3–2.2) o0.0001 Hypertension 0.12* 0.34 (0.06) 0.21, 0.46
Low HDL 202 (10) 1.7 (0.8–3.4) 2.7 (1.4–4.9) o0.0001 Triglycerides (mmol/l) 0.18* 0.19 (0.02) 0.14, 0.24
Glucose intolerance 219 (11) 1.7 (0.8–3.5) 2.3 (1.3–4.7) o0.0001 HDL cholesterol (mmol/l) 0.12* 0.36 (0.07) 0.50, 0.23
Fasting glucose (mmol/l) 0.16* 0.13 (0.02) 0.09, 0.17
Data are median (interquartile range); *Mann-Whitney Rank Sum test HRT 0.08** 0.53 (0.15) 0.23, 0.82
Smoking habit 0.08* 0.19 (0.05) 0.09, 0.30
Physical activity 0.08** 0.12 (0.04) 0.18, 0.05
WBC count 0.31* 0.20 (0.01) 0.17, 0.22
Albumin 0.22* 1.1 (0.11) 1.29, 0.87

Regression coefficients at the *Po 0.0001 and **P ¼ 0.001, respectively.

BMI ¼ body mass index; HRT ¼ hormone replacement therapy; CI ¼ confi-
confidence interval.

analysis, all components of the metabolic syndrome re-

mained significantly and independently related to CRP
levels, except for hypertension (Table 3). However, although
triglycerides, HDL cholesterol, and glucose levels were
independently associated with ln CRP, they accounted for
B1% of the variability in ln CRP, whereas BMI accounted for
15% of the variability in CRP levels. Stepwise multivariate
linear regression analysis also identified hormone replace-
ment therapy, WBC count, and serum albumin as indepen-
dently associated with ln CRP levels (Table 3).

Figure 3 Adjusted geometric means CRP and 95% confidence intervals
(error bars) according to the number of metabolic disorders including (1)
obesity (BMI Z30 kg/m2), (2) hypertension (blood pressure Z135/
85 mmHg), (3) triglyceride Z150 mg/dl, (4) low HDL cholesterol r40 mg/
dl for men and r50 mg/dL for women, and (5) fasting glucose Z110 mg/dl.
(a) Geometric mean CRP adjusted for age, sex, WBC count, serum albumin,
physical activity, smoking status, and HRT using ANCOVA. (b) After further
adjustment for BMI.
metabolic syndrome, as well as with hormone replacement
therapy (HRT), smoking, and leisure time physical activity
(Table 2). The strongest correlation (r ¼ 0.39) was observed
between CRP and BMI. After adjustment for potential
confounders in a stepwise multivariate linear regression
Discussion
In this sample of middle-aged subjects, components of the
metabolic syndrome were strongly related to plasma con-
centrations of CRP, independent of other factors known to
influence CRP levels, such as smoking, HRT, and physical
activity. Levels of CRP increased continuously with increas-
ing number of metabolic disorders. However, BMI was the
dominant contributor to CRP levels among subjects with the
metabolic syndrome. In addition, CRP levels consistent with
active inflammation were common in obese subjects.
Previous studies have shown that components of the
metabolic syndrome cluster with elevation of acute phase
reactants.11–15,23 Our results confirm recent observations
that in middle-aged subjects, CRP levels are strongly
associated with various characteristics of the metabolic
syndrome. However, the association between measures of
metabolic risk and CRP was mainly related to overall obesity.
First, subjects with the metabolic syndrome had higher CRP
levels than subjects without the metabolic syndrome only if
they were obese. Subjects with obesity had markedly higher
CRP level compared to patients without obesity regardless of
whether they had the metabolic syndrome, and nonobese
patients had comparable CRP levels regardless of whether
they had the metabolic syndrome. Second, the effect of
increasing number of metabolic disorders on CRP levels

International Journal of Obesity

 Obesity and CRP
D Aronson et al
678
Table 3 Stepwise multiple linear regression analysis with ln CRP as the dependent variablea
Independent variable Regression coefficient (s.e.)
BMI (kg/m2) 0.07 (0.01)
Triglycerides (mmol/l) 0.06 (0.02)
HDL cholesterol (mmol/l) -0.16 (0.08)
Fasting glucose (mmol/l) 0.04 (0.02)
HRT 0.50 (0.14)
WBC count 0.15 (0.01)
Albumin -0.77 (0.10)
a
After forcing age, gender, white blood cell count, and serum albumin into the model, BMI, presence of hypertension, triglycerides, HDL cholesterol, fasting glucose,
exercise, smoking status, and HRT were analyzed as independent variables. BMI ¼ body mass index; HRT ¼ hormone replacement therapy.
described in previous studies12 was markedly attenuated
after accounting for BMI. Third, multivariate regression
analysis indicated that among the components of the
metabolic syndrome, BMI contributes most of the variance
in CRP levels.
Recent guideline suggest that if CRP level of 410 mg/l is
identified, there should be a search initiated for an obvious
source of infection or inflammation, and that the result of
the test should then be discarded.22 Although only 7.6% of
subjects had CRP values greater than the generally accepted
cutoff for inflammation, our results suggest that these values
are most frequently associated with overweight and espe-
cially with obesity. Therefore, CRP results should always be
interpreted in the context of the subject’s BMI, as very high
levels may be expected in severely obese subjects.
One of the explanations for increased CRP concentrations
in subjects with the metabolic syndrome relates to the
potential effect of body fat. Both tumor necrosis factor-a and
interleukin-6 are expressed in, and released by adipose
tissue.14,16 There is a close relationship between circulating
CRP and cytokine concentrations14 and between CRP
concentrations and anthropometric measures of obesity.14,15
Since the synthesis of CRP by the liver is predominantly
regulated by inteleukin-6,17 it is believed that interleukin-6
originating from adipose tissue contributes to the raised CRP
concentrations in obese insulin-resistance subjects. Tumor
necrosis factor-a does not induce CRP directly, but can
potentiate the induction of CRP by interleukin-6.24
This hypothesis is consistent with the strong relationship
between BMI and CRP levels.11–15,25 However, the existence
of an association between CRP and insulin resistance
independent of body mass is controversial. As obesity
induces insulin resistance and inflammatory cytokines are
secreted by adipose tissue, it is difficult to exclude the
possibility that the relationship between markers of systemic
inflammation and measures of insulin resistance reflects
residual confounding of the stronger relationship between
obesity and insulin resistance. For example, inflammatory
cytokines originating from adipose tissue induce insulin
resistance by direct action on the insulin-signaling cas-
cade26,27 and stimulate CRP production by the liver.17,24
Some studies describe an independent inverse association
International Journal of Obesity
95% CI P-value Adjusted R2 (%)
0.062, 0.084 o0.0001 15.0
0.007, 0.103 0.025 0.5
-0.309, -0.009 0.038 0.2
0.007, 0.075 0.012 0.1
0.24, 0.77 0.002 0.4
0.12, 0.17 o0.0001 5.9
-0.97, -0.65 o0.0001 3.4
between measures of insulin resistance and CRP.12,28
By contrast, other studies failed to identify a relationship
between serum markers of inflammation and measures
of insulin resistance after controlling for the effect of
obesity.29–31
Inflammation is a modifiable risk factor amenable to
improvement by drugs4 and lifestyle modifications. Weight
loss has been associated with a concomitant decrease in CRP
and cytokine levels.32,33 In the context of the present study,
it is important to emphasize that weight loss is probably the
most useful intervention to ameliorate the proinflammatory
state associated with the metabolic syndrome.
Study limitations
The prevalence of the metabolic syndrome has varied
between different studies, mostly because of the lack of
accepted criteria for the definition of the syndrome.
Recently, both the World Health Organization20 and the
ATP–III19 proposed unifying definitions for the syndrome.
We defined components of the metabolic syndrome based
on a combination of the ATP-III and WHO criteria. This
definition differs from the full ATP-III criteria in that obesity
is defined based on BMI rather than waist circumference.19,20
However, Ridker et al34 have recently found almost identical
results when using different definitions of the metabolic
syndrome for predicting cardiovascular disease. Further-
more, Lemieux et al15 have recently performed a study with
particular attention to the relation between CRP and
measures of abdominal fat accumulation including waist
girth, waist-to-hip ratio, and visceral adipose tissue accumu-
lation assessed by computed tomography. Measures of
abdominal fat accumulation were positively associated with
CRP in a univariate analysis. However, multivariate regres-
sion analysis reveled that after including body fat mass in the
model, no other variable contributed to the variance in CRP
levels. In a large study by Festa et al,12 waist circumference
was positively associated with CRP in a univariate analysis
but not in a multivariate analysis. Therefore, we believe that
inclusion of waist circumference instead of BMI in our
analysis would not likely have produced materially different
results.

Conclusion
Obesity is the major factor associated with elevated CRP in
individuals with the metabolic syndrome. CRP levels in the
range suggesting a source of infection or inflammation
(410 mg/l) are more common among obese subjects than in
nonobese subjects.
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