Vous êtes sur la page 1sur 11

Journal of

Dental Research
http://jdr.sagepub.com/

Obesity, Inflammation, and Periodontal Disease


N. Pischon, N. Heng, J.-P. Bernimoulin, B.-M. Kleber, S.N. Willich and T. Pischon
J DENT RES 2007 86: 400
DOI: 10.1177/154405910708600503
The online version of this article can be found at:
http://jdr.sagepub.com/content/86/5/400

Published by:
http://www.sagepublications.com

On behalf of:
International and American Associations for Dental Research

Additional services and information for Journal of Dental Research can be found at:
Email Alerts: http://jdr.sagepub.com/cgi/alerts
Subscriptions: http://jdr.sagepub.com/subscriptions
Reprints: http://www.sagepub.com/journalsReprints.nav
Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - May 1, 2007


What is This?

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Obesity, Inflammation, and Periodontal Disease


N. Pischon*, N. Heng, J.-P. Bernimoulin,
B.-M. Kleber, S.N. Willich1, and T. Pischon1,2
Dept. of Periodontology, Charit University Medical Center,
Campus Virchow, Augustenburger Platz 1, 13353 Berlin, Germany;
1 Institute for Social Medicine, Epidemiology and Health
Economics, Charit University Medical Center, Berlin, Germany;
and 2Dept. of Epidemiology, German Institute of Human Nutrition,
Potsdam-Rehbruecke, Germany; *corresponding author,
nicole.pischon@charite.de

J Dent Res 86(5):400-409, 2007

ABSTRACT
The prevalence of obesity has increased substantially over
the past decades in most industrialized countries. Obesity
is a systemic disease that predisposes to a variety of comorbidities and complications that affect overall health.
Cross-sectional studies suggest that obesity is also
associated with oral diseases, particularly periodontal
disease, and prospective studies suggest that periodontitis
may be related to cardiovascular disease. The possible
causal relationship between obesity and periodontitis and
potential underlying biological mechanisms remain to be
established; however, the adipose tissue actively secretes a
variety of cytokines and hormones that are involved in
inflammatory processes, pointing toward similar pathways
involved in the pathophysiology of obesity, periodontitis,
and related inflammatory diseases. We provide an
overview of the definition and assessment of obesity and
of related chronic diseases and complications that may be
important in the periodontist's office. Studies that have
examined the association between obesity and
periodontitis are reviewed, and adipose-tissue-derived
hormones and cytokines that are involved in inflammatory
processes and their relationship to periodontitis are
discussed. Our aim is to raise the periodontist's awareness
when treating obese individuals.
KEY WORDS: obesity, adipose tissue, inflammation,
periodontal disease.

INTRODUCTION

besity, defined as a body mass index (BMI) > 30.0 kg/m2, is a


major public health problem today. The prevalence of obesity
has increased substantially over the past decades in most
industrialized countries. In the year 2004, approximately 34.1% of
the US population was overweight (BMI 25.0-29.9 kg/m2), and
about 32.2% obese (Fig. 1) (Expert Panel, 1998; Mokdad et al.,
2003; Ogden et al., 2006). A further increase is expected in the
future (Seidell, 2000). Obesity is a risk factor for several chronic
diseases, most notably hypertension, type 2 diabetes, dyslipidemia,
and coronary heart disease (Table 1) (Must et al., 1999; Mokdad et
al., 2004; Flegal, 2006; Gregg et al., 2005). It is estimated that the
costs associated with the management of obesity and obesity-related
diseases account for about 5% of total healthcare expenditures in
most industrialized countries (Thompson and Wolf, 2001). The
relevance and consequences of the obesity epidemic have long been
recognized by the scientific community and public health policymakers, and expert committees have made recommendations on
how to assess, prevent, and treat the obesity epidemic (Expert
Panel, 1998). Since adiposity can be considered as a systemic
disease that predisposes to a variety of co-morbidities and
complications that affect overall health, obese persons require
awareness across the spectrum of health professionals, including
dentists. Further, recent studies have suggested that obesity is also
associated with oral diseases, particularly with periodontitis
(Perlstein and Bissada, 1977; Saito et al., 1998, 2001, 2005; AlZahrani et al., 2003; Wood et al., 2003; Dalla Vecchia et al., 2005;
Genco et al., 2005). In fact, the adipose tissue secretes several
cytokines and hormones that are involved in inflammatory
processes, suggesting that similar pathways are involved in the
pathophysiology of obesity and periodontitis.
The present article provides an overview of the definition and
assessment of obesity and of the major chronic diseases and
complications related to adiposity that may be of importance in the
periodontal office. Further, we present a summary of adiposetissue-derived hormones and cytokines that are involved in
inflammatory processes, and discuss their potential impact on
periodontitis. We also discuss potential effects of periodontitisrelated cytokines on obesity-associated diseases, and review studies
that have examined the association between obesity and
periodontitis. Our aim is to raise the periodontist's awareness when
treating obese individuals.

DEFINITION AND ASSESSMENT OF OBESITY

Received February 6, 2006; Accepted September 18, 2006

400

The definition of obesity is based on the body mass index (BMI,


also called Quetelet Index), which is the ratio of body weight (in
kg) to body height (in m) squared (Table 2) (Expert Panel, 1998).
BMI is highly correlated with fat mass and morbidity and mortality,
and therefore sufficiently reflects obesity-related disease risk in a
wide range of populations; however, there are some limitations. For
example, for the same BMI, older persons tend to have a higher
body fat composition, and, therefore, risk assessment by BMI is less
accurate in older people (over 65 yrs of age). Furthermore, current
BMI cut-off points for overweight and obesity are probably too

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

J Dent Res 86(5) 2007

Obesity, Inflammation, and Periodontal Disease

401

Table 1. Diseases for Which Sufficient Evidence Exists That Their Risk is
Increased by Obesity (Clinical guidelines on the identification,
evaluation, and treatment of overweight and obesity in adultsThe
evidence report. National Institutes of Health, 1998; Expert Panel, 1998;
Haslam and James, 2005; Overweight, obesity, and health risk.
National Task Force on the Prevention and Treatment of Obesity, 2000)*

Type 2 diabetes
Hypertension
Dyslipidemia
Coronary heart disease
Stroke
Gallbladder disease
Liver disease (non-alcoholic steatohepatitis)
Musculoskeletal disease (osteoarthritis)
Sleep apnea and pulmonary dysfunction
Cancer (colon cancer, endometrial cancer, post-menopausal
breast cancer, kidney cancer)
Reproductive abnormalities (menstrual irregularities, infertility)
*

Figure 1. Prevalence of overweight and obesity in the United States (US)


and in Europe. Numbers in parentheses indicate year of data
assessment. Data for the US are from the National Health and Nutrition
Examination Survey, 2003-2004, with measured height and weight, as
provided by the Centers for Disease Control and Prevention
(http://www.cdc.gov/; accessed April 28, 2006) (Ogden et al., 2006).
Data for Europe are from the national Health Interviews Surveys, round
2004, as provided by Eurostat, the official European Union's statistical
information service (http://epp.eurostat.cec.eu.int; accessed April 26,
2006). In addition to year of data collection, age range in surveys may
differ. Weight and height are based on self-reports of participants in
most countries, except the United States, Germany, and the United
Kingdom, where height and weight were measured.

high for Asian populations (Table 2) (Choo, 2002). More


importantly, the BMI does not assess body fat distribution. It is
well-known that abdominal (central, visceral, android) obesity,
which is usually observed in men, is associated with a higher
morbidity than the gluteofemoral (peripheral, gynoid) obesity
typically observed in women (Expert Panel, 1998). Body fat
distribution is assessed by the measurement of waist
circumference, with 102 cm in men and 88 cm in women,
respectively, being the cut-off point for abdominal obesity
associated with an increased risk of morbidity (Table 3) (Expert
Panel, 1998). Waist circumference shows a close correlation
with the amount of visceral adipose tissue, and visceral adipose
tissue has been shown to be metabolically more active and to
secrete far greater amounts of cytokines and hormones
compared with subcutaneous adipose tissue (Pouliot et al.,

The list is based on reviews by experts and expert committees about


obesity and its relation to chronic disease incidence. Sufficient
evidence indicates that associations between obesity and chronic
disease risk were observed in several prospective studies in
different populations and are supported by experimental models.

1994; Wajchenberg, 2000; Berg and Scherer, 2005). Further, a


higher influx of portal fatty acids, cytokines, and hormones into
the liver from omental adipose tissue may specifically distort
hepatic metabolism, including abnormal lipoprotein synthesis,
hepatic insulin resistance, and increased gluconeogenesis
(Eckel et al., 2005; Haslam and James, 2005). Recent large
studies have indicated that measurement of waist circumference
or waist-hip ratio may be a better disease risk predictor than
BMI (Wang et al., 2005; Yusuf et al., 2005), and there is still
intensive research ongoing as to whether BMI, waist
circumference, or both should be used to assess disease risk.
Several other diagnostic tools are available to assess body
fat composition, such as measurement of (subcutaneous) skin
fold by means of a caliper or ultrasound, bioelectrical
impedance analysis (BIA), densitometry, or imaging
procedures (CT, NMR); however, most of these procedures are
not readily available in clinical practice, and do not add
substantial information for risk assessment in an individual
beyond BMI and waist circumference (Heymsfield et al.,
1998).

OBESITY-RELATED DISEASES
Hypertension
Overweight and obesity have long been recognized as
important determinants of elevated blood pressure levels (Must
et al., 1999). It is well-established that weight gain is
consistently associated with increased blood pressure, and that
weight loss decreases blood pressure independent of changes in
sodium intake. Compared with normal-weight individuals,
obese persons have an up to 5 times higher risk of
hypertension, and up to 2/3 of cases of hypertension can be
attributed to excess weight (Wolf et al., 1997). Mechanisms
that have been implicated in the development of obesity-related
hypertension include increased sympathetic nerve activity,

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

Pischon et al.

402

Table 2. Classification and Definition of Overweight and Obesity (based


on Expert Panel, 1998)*

Classification
Underweight
Normal
Overweight
Obese - Class I
Obese - Class II
Obese - Class III
*

Table 3. Definition of the Metabolic Syndrome Based on the NCEP-ATPIII


Definition
Risk Factor*

Disease Risk Relative to Normal Weight


and Waist Circumference
Men < 102 cm
Men > 102 cm
BMI (kg/m2) Women < 88 cm Women > 88 cm
< 18.5
18.5-24.9
25.0-29.9
30.0-34.9
35.0-39.9
> 40

Increased
High
Very high
Extremely high

Abdominal obesity
Men
Women
Triglycerides
HDL cholesterol
Men
Women
Blood pressure
Fasting glucose

High
Very high
Very high
Extremely high

Established for non-Asian populations. The recently proposed


classification for Asian populations is: BMI < 18.5, underweight;
18.5-22.9, normal weight; 23.0-24.9, overweight; 25.0-29.9,
obese class I; > 30.0, obese class II (WHO/IASO/IOTF, 2000).
Disease risk for type 2 diabetes, hypertension, and cardiovascular
disease.

sodium and volume retention, renal abnormalities, insulin


resistance, hyperleptinemia, and increased secretion of
angiotensinogen from adipocytes (Kolanowski, 1999; Haslam
and James, 2005).

Type 2 Diabetes
The relationship between obesity and type 2 diabetes is
particularly close. Obese persons have a more than 10-fold
increased risk of developing type 2 diabetes compared with
normal-weight persons (Field et al., 2001). Type 2 diabetes
develops due to an interaction between insulin resistance and
beta cell failure (Stumvoll et al., 2005). Several factors,
including lipotoxicity and glucose toxicity as well as obesityderived cytokines, have been implicated in these processes
(Stumvoll et al., 2005).

Cardiovascular Disease and the Metabolic Syndrome


Obese persons have an about 1.5-fold increased risk for
cardiovascular disease (including coronary heart disease and
cerebrovascular disease), and between 10 and 15% of all cases
of cardiovascular disease can be attributed to overweight and
obesity (Wilson et al., 2002). The association with obesity is
slightly stronger, and the population-attributable fraction (PAF,
i.e., the fraction of cases within the population that can be
attributed to overweight and obesity) larger, for coronary heart
disease (relative risk about 1.5 to 2.0; PAF 15 to 20%) than for
cerebrovascular disease (RR 1.2 to 1.8; PAF 5 to 15%) (Field et
al., 2001; Wilson et al., 2002). Obesity is also associated with
an about two-fold higher risk of heart failure and a 50%
increased risk of atrial fibrillation (Kenchaiah et al., 2002).
The metabolic syndrome is a concept that encompasses
metabolic abnormalities that co-occur to a greater degree than
would be expected by chance alone, and which predispose
individuals for a high risk to develop cardiovascular disease
(Eckel et al., 2005). The World Health Organization (WHO),
the National Cholesterol Education Program (NCEP), and the
International Diabetes Federation (IDF) have proposed
algorithms to define the metabolic syndrome (WHO, 1999;
Executive Summary of The Third Report of The National
Cholesterol Education Program [NCEP] Expert Panel on

J Dent Res 86(5) 2007

Defining Level
Waist circumference
> 102 cm
> 88 cm
> 150 mg/dL
< 40 mg/dL
< 50 mg/dL
> 130/> 85 mm Hg
> 110 mg/dL

The presence of 3 of any of the above risk factors defines the


metabolic syndrome (Third Report of the National Cholesterol
Education Program [NCEP] Expert Panel on Detection, Evaluation,
and Treatment of High Blood Cholesterol in Adults [Adult Treatment
Panel III], final report, 2002).

Detection, Evaluation, and Treatment of High Blood


Cholesterol in Adults [Adult Treatment Panel III], 2001;
International Diabetes Federation, 2005). Although slightly
different in detail, these definitions agree on the essential
components, namely, glucose intolerance, obesity,
hypertension, and dyslipidemia (albeit the WHO also includes
microalbuminuria as a component) (WHO, 1999; International
Diabetes Federation, 2005). To date, most studies have used the
definition provided in the "Third Report of the National
Cholesterol Education Programm, Expert Panel on Detection,
Evaluation, and Treatment of High Blood Cholesterol in Adults
(Adult Treatment Panel III) (NCEP-ATPIII)", which requires
the presence of at least three of the following metabolic
abnormalities before the metabolic syndrome can be defined:
abdominal obesity, elevated triglycerides, reduced levels of
HDL cholesterol, high blood pressure, and high fasting glucose
(Table 3) (Executive Summary of The Third Report of The
National Cholesterol Education Program (NCEP) Expert Panel
on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults [Adult Treatment Panel III], 2001).
Based on this definition, the prevalence of the metabolic
syndrome was estimated to be around 23% in the United States
(Ford et al., 2002).
Although the exact underlying cause of the metabolic
syndrome is unknown, the more recent definitions emphasize
the focus on abdominal obesity as its core component
(International Diabetes Federation, 2005). This approach is
supported by a growing number of studies showing that the
adipose tissue itself is capable of producing several hormones
and proteins, which are involved in the development of obesityrelated diseases (see below).

Other Diseases and Mortality


Sufficient evidence exists that obesity also increases the risk of
respiratory disorders, reproductive abnormalities, non-alcoholic
steatohepatitis, gallbladder disease, osteoarthritis, and certain
types of cancer (see Table 1). Whether overweight and obesity
affect disease prognosis and total mortality is an ongoing area
of research, and recently published studies have found
contradictory results (Mokdad et al., 2004; Flegal et al., 2005).

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

J Dent Res 86(5) 2007

Obesity, Inflammation, and Periodontal Disease

403

Table 4. Epidemiological Studies Analyzing the Association between Obesity and Periodontal Disease*
Age Range
(yrs)

Assessment of
Periodontitis

241 apparently healthy dentulous


Japanese persons (69 men,
172 women) who attended a
health promotion program,
Fukuoka Health Promotion Center

20-59

CPITN code 3 or 4,
PPD > 4 mm

96

BMI
< 20.0,
20.0-24.9,
25.0-29.9,
> 30.0

OR
1 (reference),
1.7 (0.7-3.8),
3.4 (1.2-9.6),
8.6 (1.4-51.4)

Saito et al., 1998

643 apparently healthy dentulous


Japanese persons (131 men, 512
women) who attended a health
promotion program, Fukuoka
Health Promotion Center

19-79

At least one tooth per


sextant with PPD > 4 mm

334

WHR, men/women
< 0.9/< 0.8,
> 0.9/> 0.8

OR
1 (reference),
2.0 (1.4-2.9)

Saito et al., 2001

584 Japanese women with at least


10 teeth, Hisayama study

40-79

Mean PPD > 1.9 mm

114

BMI
15.5-20.8,
20.8-22.7,
22.7-24.9,
25.0-46.7

OR
1 (reference),
3.0 (1.4-6.3),
2.3 (1.1-5.0),
4.3 (2.1-8.9)

Saito et al., 2005

Presence of one or more sites


with CAL of > 3 mm and
PPD > 4 mm

2560

BMI,
< 18.5,
18.5-24.9,
25.0-29.9,
> 30

Study Population

> 18
US general population, Third
National Health and Nutrition
Examination Survey (NHANES III),
restricted to persons > 18 yrs with
periodontal examination; n = 13,665
(6466 men, 7199 women)

No. of Cases
with Periodontitis

Outcome

Waist circumference, men/women,

< 102/< 88,


> 102/> 88

Reference

OR
Al-Zahrani et al.,
0.79 (0.42-1.49),
2003; the relation1 (reference),
ship of parameters
1.06 (0.91-1.24),
of obesity and
1.37 (1.14-1.64),
insulin resistance
with periodontal
1 (reference),
disease within this
1.33 (1.11-1.60)
population is further
described by Genco
et al. (2005) and
Wood et al. (2003)

372 Japanese factory workers


(290 men, 82 women)

20-59

proportion of teeth with PPD >


3.5 mm being beyond the 20th
percentile within this population

74

BMI
< 25.0,
> 25.0

OR
1 (reference),
3.17 (1.79-5.61)

Nishida et al. (2005)

706 South Brazilian individuals


(329 men, 377 women) drawn
randomly from a larger representative sample of Porto Alegre

30-65

> 30% of teeth with CAL > 5 mm

298

BMI
men
18.5-24.9,
25.0-29.9,
> 30.0;
women
18.5-24.9,
25.0-29.9,
> 30.0

OR

Dalla Vecchia et al.


(2005)

1 (reference),
1.1 (0.4-3.3),
1.0 (0.5-1.7);
1 (reference),
1.3 (0.8-2.2),
2.1 (1.1-3.9)

All studies used a cross-sectional design. Studies were adjusted for age, gender, smoking history, socio-economic status, and oral hygiene. BMI,
body mass index; WHR, waist-hip ratio; CPITN, Community Periodontal Index of Treatment Needs; CAL, Clinical attachment loss; OR, odds ratio;
PPD, Periodontal pocket depth.

For example, although obesity increases the risk of heart


failure, the studies found that, among persons with prevalent
heart failure, obese individuals are likely to have a better
prognosis than non-obese individuals (Curtis et al., 2005). This
is likely due to the fact that lower BMI reflects wasting
processes in this patient group (as in other chronic diseases).
Further, several studies have found a U-shaped association
between BMI and total mortality, with a minimum at a BMI of
approximately 25.0 kg/m2 and increased mortality with higher
or lower BMI (Troiano et al., 1996; Calle et al., 1999; Flegal et
al., 2005). However, it has been argued that these analyses may

be confounded by smoking (smokers are usually leaner than


non-smokers but have a higher risk of mortality) or underlying
prevalent chronic diseases (individuals with chronic diseases
often have lower body weight) (Willett et al., 2005). Clearly,
further studies are needed to examine the effect of obesity on
morbidity, disease prognosis, and mortality.

ASSOCIATION BETWEEN OBESITY


AND PERIODONTAL DISEASE
It has been suggested that obesity is second only to smoking as
the strongest risk factor for inflammatory periodontal tissue

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

404

Pischon et al.

destruction (Nishida et al., 2005). The first report on the


relationship between obesity and periodontal disease appeared
in 1977, when Perlstein et al. observed histopathologic changes
in the periodontium in hereditary obese Zucker rats (Zucker
and Zucker, 1962; Perlstein and Bissada, 1977). Using ligatureinduced periodontitis, they found alveolar bone resorption to be
greater in obese animals compared with non-obese rats
(Perlstein and Bissada, 1977). Also, it seemed that, under
healthy oral conditions, obesity per se does not promote
pathologic periodontal alterations; however, in response to
bacterial plaque accumulation, periodontal inflammation and
destruction were more severe in obese animals. In obese and
hypertensive rats, plaque accumulation caused even more
pronounced periodontal destruction than in obese animals,
suggesting that a combination of risk factors, such as those
defined by the metabolic syndrome, elicit the most severe
periodontal effects (Koletsky, 1973; Perlstein and Bissada,
1977).
Later on, the hypothesis of obesity as a risk factor for
periodontal disease was supported by epidemiological studies
(Table 4). Besides one study performed in a Brazilian
population, the majority of reports of association between BMI
and periodontitis are primarily based on analyses of Japanese
populations and US data from the Third National Health and
Nutrition Examination Survey (NHANES III). Also, variability
exists in the definition of the periodontal disease reported.
In 1998, Saito et al. analyzed 241 healthy Japanese
individuals and showed, for the first time, an association
between obesity and periodontal disease in humans (Saito et
al., 1998). They applied the community periodontal index of
treatment needs (CPITN) and estimated, based on their crosssectional analysis, that the relative risk for periodontitis after
adjustment for confounders such as age, gender, oral-hygiene
status, and smoking was 3.4 in persons with BMI of 25 to 29.9
kg/m2, and 8.6 in those with BMI above 30 kg/m2.
In addition, studies have indicated that the fat distribution
pattern plays a crucial role in the association with periodontitis
(Saito et al., 2001; Al-Zahrani et al., 2003; Wood et al., 2003).
Saito et al. found, in 643 healthy Japanese adults, that high
upper body obesity and high total body fat were correlated with
a higher risk of periodontal disease, compared with normalweight persons (Saito et al., 2001). An examination of the
NHANES III data demonstrated that waist-to-hip ratio, BMI,
fat-free mass, and log sum of subcutaneous fat significantly
correlated with periodontal disease (Wood et al., 2003). Also,
high waist circumference was especially associated with
periodontal disease in 18- to 34-year-old persons, but not in
older adults, suggesting a closer correlation between high waist
circumference and periodontitis in young adults (Al-Zahrani et
al., 2003). In 706 South Brazilian individuals, no correlation
between BMI and periodontal disease was found in men, but a
strong correlation was found in obese females (Dalla Vecchia
et al., 2005).
Another recent study by Saito et al. concluded that obesity
is associated with deep periodontal pockets, independent of
glucose tolerance status (Saito et al., 2005). Genco et al.
analyzed NHANES III data and demonstrated that BMI was
positively correlated with the severity of periodontal
attachment loss; they found that this relationship is modulated
by insulin resistance (Genco et al., 2005).
Recent studies have indicated that maintaining a normal

J Dent Res 86(5) 2007

weight by regular physical activity is associated with a lower


periodontitis prevalence (Wakai et al., 1999; Karjalainen et al.,
2002; Merchant et al., 2003; Al-Zahrani et al., 2005a,b).
Individuals who pursued regular exercise have lower plasma
levels of inflammatory markers, such as IL-6 and C-reactive
protein (CRP), and show an increased insulin sensitivity that
may beneficially affect periodontal health (Merchant et al.,
2003; Pischon et al., 2003; Al-Zahrani et al., 2005a). A study
that analyzed the NHANES III study population demonstrated
that individuals who maintained a normal weight, pursued
regular exercise, and consumed a diet in conformity with the
Dietary Guidelines for Americans and the Food Guide Pyramid
recommendations were 40% less likely to have periodontitis
(Al-Zahrani et al., 2005a).
The results of the currently published cross-sectional
studies indicate an association between obesity and periodontal
disease. However, some limitations must be considered. First,
the design of these studies limits interpretability about temporal
relationships. Because anthropometry and dental status were
assessed simultaneously, it is unclear whether obesity truly
precedes periodontitis. Prospective cohort studies may
circumvent this problem. For example, by enrolling individuals
without periodontitis into a cohort, one could assess whether
obese participants are more likely to develop periodontitis over
time than non-obese participants. Second, observational studies
can show only associations, but not causal effects. Although
adjustment for factors related to obesity and known to affect
the risk of periodontitis (e.g., socio-economic status) may
reduce confounding in these observational studies (listed in
Table 4), the observed association may be caused by
unidentified underlying factors. Interventional studies
(Randomized Controlled Trials) may be the gold standard for
Evidence-based Dental Medicine; however, such studies may
be difficult to conduct, given that obesity is the exposure
variable of interest. One alternative approach would be to
examine whether a weight-loss intervention in obese
individuals may beneficially affect periodontal disease.
However, the long-term success of weight loss achieved by
caloric restriction or increased physical activity is questionable,
and additional anti-obesity drug therapy or anti-obesity surgery
may be necessary (Expert Panel, 1998).
The underlying biological mechanisms for the association
of obesity with periodontitis are not well-known; however,
adipose-tissue-derived cytokines and hormones may play a key
role. Fat tissue is not merely a passive triglyceride reservoir of
the body, but also produces a vast amount of cytokines and
hormones, collectively called adipokines or adipocytokines
(Kershaw and Flier, 2004), which in turn may modulate
periodontitis.

ADIPOSE-TISSUE-DERIVED HORMONES
AND CYTOKINES (ADIPOKINES)
Inflammatory Markers
Adipose tissue secretes pro-inflammatory cytokines such as
tumor necrosis factor-alpha (TNF-) and interleukin-6 (IL-6).
TNF- and IL-6 are the main inducers of acute-phase hepatic
protein production, including C-reactive protein (CRP) (Yudkin
et al., 2000). Both TNF- and IL-6 have been shown to impair
intracellular insulin signaling, which may lead to insulin
resistance (Hotamisligil, 2000; Rotter et al., 2003). In humans,

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

J Dent Res 86(5) 2007

Obesity, Inflammation, and Periodontal Disease

plasma levels of TNF-, IL-6, and CRP are closely related to


obesity and insulin resistance (Hotamisligil, 1999; Kern et al.,
2001). There is compelling evidence that inflammation plays an
essential role in the development of type 2 diabetes mellitus
and atherosclerosis, and studies in humans suggest that
circulating inflammatory marker levels may predict type 2
diabetes and cardiovascular events years in advance of the
onset of these diseases (Pradhan et al., 2001; Libby, 2002;
Pradhan and Ridker, 2002; Ridker, 2002; Danesh et al., 2004;
Pai et al., 2004).
Periodontitis is a chronic inflammatory disease of
periodontal tissues (Offenbacher, 1996). Some individuals are
more susceptible and exhibit a greater degree of periodontal
infection and inflammation (Beck et al., 1996, 1998). An up to
10-fold increase in local and systemic expression of
inflammatory cytokines, such as TNF- and IL-6, by
monocytes and macrophages has been reported in some
individuals with periodontitis (Beck et al., 1996). In persons
with periodontitis, bacterial pathogens, endotoxins, and
inflammatory cytokines may systemically trigger an upregulated leukocytosis, synthesis of acute-phase proteins (CRP,
Amyloid A), and enhanced lipid metabolism, along with
increased serum cholesterol and triglyceride levels, which may
contribute to the risk of systemic diseases such as
cardiovascular diseases (Beck et al., 1998; Loos et al., 1998;
Nishimura et al., 2003; Beck and Offenbacher, 2005; Loos,
2005; Mattila et al., 2005).

Leptin
Leptin is a pleiotropic cytokine, secreted by adipocytes, which
is involved in a variety of biological processes, including
energy metabolism, endocrine functions, reproduction, and
immunity (Zhang et al., 1994). Leptin is thought to act as a
"lipostat" that regulates adipose tissue mass. As a negative
feedback mechanism, elevated leptin concentrations result in
increased energy expenditure, decreased food intake, and a
negative energy balance (Kennedy, 1953; Friedman, 1998).
Leptin deficiency caused by mutations in the ob gene encoding
leptin (which are only rarely observed in humans) results in
hyperphagia and severe obesity, while substitution of leptin in
leptin-deficient mice and humans is able, at least partially, to
normalize food intake and body weight (Farooqi et al., 1999;
Margetic et al., 2002). In contrast, most overweight and obese
persons show resistance to leptin at the receptor level, and,
therefore, have higher leptin levels than non-overweight
individuals (Margetic et al., 2002).
In addition, leptin has been shown to be involved in bone
metabolism. Although reported data appear somewhat
conflicting, evidence exists that leptin may decrease bone
formation via central nervous pathways, and may stimulate
bone formation via direct peripheral effects on bone cells
(Thomas et al., 1999; Ducy et al., 2000; Cornish et al., 2002;
Reseland et al., 2001; Thomas, 2003). The net result on bone
formation may depend on various general and bone-specific
factors, such as species, age, gender, serum leptin levels, bloodbrain barrier permeability, bone tissue, skeletal maturity, and
signaling pathways (Thomas and Burguera, 2002; Thomas,
2003).
In addition, several studies have suggested that elevated
levels of leptin can be found during infection and inflammation
(Otero et al., 2005). In animal experiments, leptin levels are
acutely increased by endotoxins (lipopolysaccarides [LPS]) and

405

administration of pro-inflammatory cytokines (TNF-, Il-1)


(Grunfeld et al., 1996; Faggioni et al., 1998). In humans, leptin
production can be increased in inflammatory bowel disease and
rheumatoid arthritis (Otero et al., 2005). In inflammatory
periodontal disease, leptin regulation has still to be examined,
especially with respect to the epidemiological association
between obesity and periodontitis. One study implied
decreasing leptin levels in gingival biopsies with increasing
pocket probing depths, which would be contrary to the cited
data on other inflammatory diseases (Johnson and Serio, 2001).

Adiponectin, Resistin, and


Other Adipose-tissue-derived Cytokines
Adiponectin is a circulating hormone secreted by adipose tissue
that is involved in glucose and lipid metabolism, and which
accounts for about 0.05% of total serum proteins (Berg et al.,
2002; Chandran et al., 2003). Contrary to other adipose-derived
hormones, adiponectin levels are reduced in persons with
obesity, insulin resistance, or type 2 diabetes (Berg et al., 2002;
Chandran et al., 2003). Adiponectin improves insulin
sensitivity and may have anti-atherogenic and antiinflammatory properties (Ouchi et al., 2000, 2001; Arita et al.,
2002; Kubota et al., 2002), and low plasma adiponectin levels
have been shown to predict type 2 diabetes and coronary heart
disease in humans (Berg et al., 2001; Yamauchi et al., 2001;
Lindsay et al., 2002; Maeda et al., 2002; Spranger et al., 2003;
Pischon et al., 2004). Experimental models suggest that
adiponectin could play a role as a mediator of inflammation;
however, the exact role of adiponectin in inflammatory diseases
remains to be elucidated (Ouchi et al., 2000; Maeda et al.,
2002).
Resistin belongs to a family of resistin-like molecules
(RELM) and has been reported to be secreted by adipocytes
and to cause insulin resistance in animal models (Steppan et al.,
2001a,b; Rajala et al., 2002). However, studies have shown that
the biology of resistin differs substantially between species, and
many aspects, specifically its association with obesity and its
effects on insulin sensitivity in humans, remain controversial.
Thus, in contrast to mice, human resistin is expressed at lower
levels in adipocytes, but at higher levels in circulating blood
monocytes (Nagaev and Smith, 2001; Savage et al., 2001), and
current evidence suggests that, in humans, resistin is more
closely related to inflammatory processes than to insulin
resistance (Verma et al., 2003; Kawanami et al., 2004).
Interestingly, the amino acid sequences of resistin and of
RELM and RELM are identical to the previously discovered
proteins FIZZ3, FIZZ1, and FIZZ2, respectively, which are
involved in inflammatory processes (Holcomb et al., 2000;
Gomez-Ambrosi and Fruhbeck, 2001), and elevated resistin
levels were found in persons with coronary heart disease
(Pischon et al., 2005; Burnett et al., 2006). Whether or not
resistin plays a role in inflammatory periodontal disease
remains to be defined.
As more and more adipose-tissue-derived cytokines and
hormones are being discovered, the complexity of the
endocrine network of which these mediators are a part becomes
more and more apparent. Recent additions to this list of
adipokines include visfatin, which elicits insulin-like effects,
and serum-retinol-binding protein 4 (RBP4) (Fukuhara et al.,
2005; Yang et al., 2005). Regarded initially as markers mainly
related to weight regulation and insulin resistance, it has
become clear that hormones like leptin, resistin, or adiponectin

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

Pischon et al.

406

J Dent Res 86(5) 2007

disease (Beck and Offenbacher, 2005; Loos, 2005). In this


context, it is interesting to note that periodontal treatment has
been shown to reduce circulating TNF- and serum levels of
glycosylated hemoglobin, and has beneficial effects on the
control of type 2 diabetes (Grossi and Genco, 1998).

RISK AND RISK ASSESSMENT


IN THE PERIODONTAL OFFICE

Figure 2. Model linking periodontitis and obesity with inflammatory


related chronic diseases.

are involved in a variety of functions and diseases (see above),


including cardiovascular disease, diabetes, and inflammatory
diseases (Otero et al., 2005).

ASSOCIATION OF PERIODONTITIS WITH


OBESITY-RELATED CHRONIC DISEASES
Pro-inflammatory cytokines may play a crucial role in the close
relationship among periodontitis, obesity, and chronic diseases
(Beck and Offenbacher, 2005; Genco et al., 2005). In fact, this
association may be multidirectional (Fig. 2). For example, it
has been well-established that inflammation is an essential
component in the development of atherosclerosis, and
observational studies showed that periodontitis is associated
with a moderately, but significantly, higher risk of coronary
heart disease (Beck and Offenbacher, 2005; Dietrich and
Garcia, 2005; Mattila et al., 2005). Interventional studies that
examined the effects of antibiotic treatment on cardiovascular
risk have generally failed to show any beneficial effect;
however, these studies have mostly been of short duration (less
than 1 year of treatment) and have investigated the effects on
secondary prevention only. Inflammatory diseases like
periodontitis induce the production of pro-inflammatory
cytokines such as TNF-, IL-1, and IL-6 (Beck et al., 1996;
Loos, 2005). It has been suggested that the secretion of TNF-
by adipose tissue triggered by LPS from periodontal Gramnegative bacteria promotes hepatic dyslipidemia and decreases
insulin sensitivity (Saito et al., 2001; Nishimura et al., 2003).
Type 2 diabetes and decreased insulin sensitivity are associated
with the production of advanced glycation end-products
(AGE), which trigger inflammatory cytokine production, thus
predisposing for inflammatory diseases such as periodontitis
(Grossi and Genco, 1998; Genco et al., 2005). These
observations suggest a potential interaction among obesity,
periodontitis, and chronic disease incidence, although present
studies are insufficient to conclude whether such associations
are causal. Thus, in addition to being a risk factor for type 2
diabetes and coronary heart disease, obesity-related
inflammation may also promote periodontitis. Conversely,
periodontitis, once it exists, may promote systemic
inflammation and thereby increase the risk of coronary heart

When one considers that more than 60% of the US population


is overweight or obese (and the numbers are rising), treating
overweight persons in the dental office will become more and
more common.
Until recently, a definite diagnosis of obesity was only
rarely made by physicians, and body weight or body height was
rarely measured in clinical practice (Linne and Rossner, 1998;
Cleator et al., 2002). Further, it has been shown that about 25%
of obese persons have been misclassified, by subjective
estimation of the physician, as having normal weight
(Caccamese et al., 2002). In the future, if obesity is to be
acknowledged as a multiple-risk-factor syndrome for overall
and oral health, general and oral risk assessment in the dental
office should include the evaluation of body mass index on a
regular basis. Although there is still research ongoing as to
whether BMI or waist circumference, or both, is a better
disease risk predictor, the assessment of waist circumference in
addition to BMI seems advisable, based on current obesity
guidelines. Besides the suggested association between
periodontal disease and obesity, periodontists need to be aware
of the potential health problems related to obesity, and should
take them into account during treatment. For example, pain and
anxiety trigger the release of catecholamines, resulting in
peripheral vasoconstriction and further diminished tissue
oxygenation (Wilson and Clark, 2004). Co-existent coronary
heart disease or type 2 diabetes in obese individuals may lead
to acute angina or to hyper- or hypoglycemia during dental
treatment. Due to the person's overweight, which prevents full
expansion of the lungs, an obesity-hypoventilation syndrome
can develop and cause hypercapnia, hypoxia, somnolence,
hypoxic pulmonary vasoconstriction, pulmonary hypertension,
and right-sided heart failure (Kempers et al., 2000). Therefore,
it has been suggested that supine patient positioning should be
avoided, to maximize the pulmonary mechanics (Kempers et
al., 2000). Impaired chest expansion decreases vital capacity
and tidal function, which compromise tissue oxygenation
(Wilson and Clark, 2004). These conditions put the obese
person at high anesthetic and surgical risk (Kempers et al.,
2000). Wound-healing processes are dependent on sufficient
tissue oxygenation (Armstrong, 1998). Also, higher incidences
of infections and post-surgical hematoma formation have been
reported among obese persons (Wilson and Clark, 2004). The
vulnerability to wound complications increases not only
morbidity and mortality of obese persons, but also the length of
individual treatment sessions, the overall length of the
treatment, and, consequently, the economic costs of treatment
(Wilson and Clark, 2004). Pharmacological aspects, such as
altered pharmacokinetics due to the person's increased blood
volume or fat mass, and technical incompatibilities, such as
small dental chairs or tight blood pressure cuffs, should be
considered (Kempers et al., 2000). Kempers et al. have
emphasized the importance of details in the individual's
medical and dental history when overweight persons present to

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

J Dent Res 86(5) 2007

Obesity, Inflammation, and Periodontal Disease

the office, to keep complications during and after the dental


treatment to a minimum (Kempers et al., 2000). They proposed
to ascertain, in individuals, symptoms of general fatigue,
weakness, and sleep disturbances, which may be signs of
obstructive sleep apnea. Also, chest pain, shortness of breath,
dyspnea on exercise, and peripheral edema could indicate
compromised cardiac function. Persons should be questioned
about symptoms of diabetes, such as polyuria, polydipsia, or
polyphagia. Also, a close collaboration with the general
physician and the dietician may be beneficial to ensure
effective periodontal treatment.

SUMMARY
Periodontists must be aware of the increasing numbers of obese
persons and of the significance of obesity as a multiple-riskfactor syndrome for overall and oral health. Recent crosssectional and prospective studies have indicated a close
correlation of obesity with periodontal disease and with other
chronic inflammatory diseases, including type 2 diabetes and
cardiovascular disease. Whether the relationship between
obesity and periodontitis is causal needs to be assessed in
future studies. Pro-inflammatory cytokines may be a
multidirectional link among periodontitis, obesity, and other
chronic diseases. The adipose tissue is a large reservoir of
biologically active mediators, such as TNF- and other
adipokines. Studies have demonstrated a close involvement of
the adipokinessuch as leptin, resistin, and adiponectinin
inflammatory processes. However, their role in periodontal
inflammation has yet to be defined.
Obesity is a complex disease, and its relationship to oral
status has been realized by the scientific community in recent
years. Although this relationship needs further investigation,
periodontists should counsel obese persons regarding the
possible oral complications of obesity, to diminish morbidity
for these individuals. This includes the measurement of body
mass index and waist circumference for periodontal risk
assessment on a regular basis.

REFERENCES
Al-Zahrani MS, Bissada NF, Borawskit EA (2003). Obesity and periodontal
disease in young, middle-aged, and older adults. J Periodontol 74:610615.
Al-Zahrani MS, Borawski EA, Bissada NF (2005a). Periodontitis and three
health-enhancing behaviors: maintaining normal weight, engaging in
recommended level of exercise, and consuming a high-quality diet. J
Periodontol 76:1362-1366.
Al-Zahrani MS, Borawski EA, Bissada NF (2005b). Increased physical
activity reduces prevalence of periodontitis. J Dent 33:703-710.
Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, et al.
(2002). Adipocyte-derived plasma protein adiponectin acts as a plateletderived growth factor-BB-binding protein and regulates growth factorinduced common postreceptor signal in vascular smooth muscle cell.
Circulation 105:2893-2898.
Armstrong M (1998). Obesity as an intrinsic factor affecting wound healing.
J Wound Care 7:220-221.
Beck JD, Offenbacher S (2005). Systemic effects of periodontitis:
epidemiology of periodontal disease and cardiovascular disease. J
Periodontol 76(11 Suppl):2089-2100.
Beck J, Garcia R, Heiss G, Vokonas P, Offenbacher S (1996). Periodontal
disease and cardiovascular disease. J Periodontol 67(10 Suppl):11231137.
Beck JD, Offenbacher S, Williams R, Gibbs P, Garcia R (1998).
Periodontitis: a risk for coronary heart disease? Ann Periodontol 3:127141.

407

Berg AH, Scherer PE (2005). Adipose tissue, inflammation, and


cardiovascular disease. Circ Res 96:939-949.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001). The
adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat
Med 7:947-953.
Berg AH, Combs TP, Scherer PE (2002). ACRP30/adiponectin: an
adipokine regulating glucose and lipid metabolism. Trends Endocrinol
Metab 13:84-89.
Burnett MS, Devaney JM, Adenika RJ, Lindsay R, Howard BV (2006).
Cross-sectional associations of resistin, coronary heart disease and
insulin resistance. J Clin Endocrinol Metab 91:64-68.
Caccamese SM, Kolodner K, Wright SM (2002). Comparing patient and
physician perception of weight status with body mass index. Am J Med
112:662-666.
Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr (1999). Bodymass index and mortality in a prospective cohort of U.S. adults. N Engl
J Med 341:1097-1105.
Chandran M, Phillips SA, Ciaraldi T, Henry RR (2003). Adiponectin: more
than just another fat cell hormone? Diabetes Care 26:2442-2450.
Choo V (2002). WHO reassesses appropriate body-mass index for Asian
populations. Lancet 360(9328):235.
Cleator J, Richman E, Leong KS, Mawdsley L, White S, Wilding J (2002).
Obesity: under-diagnosed and under-treated in hospital outpatient
departments. Int J Obes Relat Metab Disord 26:581-584.
Clinical guidelines on the identification, evaluation, and treatment of
overweight and obesity in adultsThe evidence report (1998). NIH
Publication No. 98-4083, September. National Institutes of Health.
http://www.nhlbi.gov/guidelines/obesity/ob_gdlns.pdf
Cornish J, Callon KE, Bava U, Lin C, Naot D, Hill BL, et al. (2002). Leptin
directly regulates bone cell function in vitro and reduces bone fragility
in vivo. J Endocrinol 175:405-415.
Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F, et al.
(2005). The obesity paradox: body mass index and outcomes in patients
with heart failure. Arch Intern Med 165:55-61.
Dalla Vecchia CF, Susin C, Rsing CK, Oppermann RV, Albandar JM
(2005). Overweight and obesity as risk indicators for periodontitis in
adults. J Periodontol 76:1721-1728.
Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et
al. (2004). C-reactive protein and other circulating markers of
inflammation in the prediction of coronary heart disease. N Engl J Med
350:1387-1397.
Dietrich T, Garcia RI (2005). Associations between periodontal disease and
systemic disease: evaluating the strength of the evidence. J Periodontol
76(11 Suppl):2175-2184.
Ducy P, Schinke T, Karsenty G (2000). The osteoblast: a sophisticated
fibroblast under central surveillance. Science 289:1501-1504.
Eckel RH, Grundy SM, Zimmet PZ (2005). The metabolic syndrome.
Lancet 365(9468):1415-1428.
Executive Summary of The Third Report of The National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High Blood Cholesterol In Adults (Adult Treatment
Panel III) (2001). J Am Med Assoc 285:2486-2497.
Expert Panel (1998). Executive summary of the clinical guidelines on the
identification, evaluation, and treatment of overweight and obesity in
adults. Arch Intern Med 158:1855-1867.
Faggioni R, Fantuzzi G, Fuller J, Dinarello CA, Feingold K, Grunfeld C
(1998). Il-1 beta mediates leptin induction during inflammation. Am J
Physiol 274:204-208.
Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice
AM, et al. (1999). Effects of recombinant leptin therapy in a child with
congenital leptin deficiency. N Engl J Med 341:879-884.
Field AE, Coakley EH, Must A, Spadano JL, Laird N, Dietz WH, et al.
(2001). Impact of overweight on the risk of developing common
chronic diseases during a 10-year period. Arch Intern Med 161:15811586.
Flegal KM (2006). Excess deaths associated with obesity: cause and effect.
Int J Obes (Lond) 30:1171-1172.
Flegal KM, Graubard BI, Williamson DF, Gail MH (2005). Excess deaths
associated with underweight, overweight and obesity. J Am Med Assoc
293:1861-1867.
Ford ES, Giles WH, Dietz WH (2002). Prevalence of the metabolic

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

408

Pischon et al.

syndrome among US adults: findings from the third National Health


and Nutrition Examination Survey. J Am Med Assoc 287:356-359.
Friedman JM (1998). Leptin, leptin receptors, and the control of body
weight. Nutr Rev 56(2 Pt 2):s38-s46; discussion s54-s75.
Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto
K, et al. (2005). Visfatin: a protein secreted by visceral fat that mimics
the effects of insulin. Science 307(5708):426-430.
Genco RJ, Grossi SG, Ho A, Nishimura F, Murayama Y (2005). A proposed
model linking inflammation to obesity, diabetes, and periodontal
infections. J Periodontol 76(11 Suppl):2075-2084.
Gomez-Ambrosi J, Fruhbeck G (2001). Do resistin and resistin-like
molecules also link obesity to inflammatory diseases? Ann Intern Med
135:306-307.
Gregg EW, Cheng YJ, Cadwell BL, Imperatore G, Williams DE, Flegal
KM, et al. (2005). Secular trends in cardiovascular disease risk factors
according to body mass index in US adults. J Am Med Assoc 293:18681874.
Grossi SG, Genco RJ (1998). Periodontal disease and diabetes mellitus: a
two-way relationship. Ann Periodontol 3:51-61.
Grunfeld C, Zhao C, Fuller J, Pollack A, Moser A, Friedman J, et al. (1996).
Endotoxin and cytokines induce expression of leptin, the ob gene
product, in hamsters. J Clin Invest 97:2152-2157.
Haslam DW, James WP (2005). Obesity. Lancet 366(9492):1197-1209.
Heymsfield SB, Allison DB, Wang Z, Baumgartner RN, Ross R (1998).
Evaluation of total and regional body composition. In: Handbook of
obesity. Bray GA, Bouchard C, James WPT, editors. New York:
Marcel Dekker, pp. 41-77.
Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, et al.
(2000). FIZZ1, a novel cysteine-rich secreted protein associated with
pulmonary inflammation, defines a new gene family. EMBO J 19:40464055.
Hotamisligil GS (1999). The role of TNFalpha and TNF receptors in obesity
and insulin resistance. J Intern Med 245:621-625.
Hotamisligil GS (2000). Molecular mechanisms of insulin resistance and the
role of the adipocyte. Int J Obes Relat Metab Disord 24(Suppl 4):S23-S27.
International Diabetes Federation (2005). The IDF consensus worldwide
definition of the metabolic syndrome. 1st International Congress on
"Prediabetes" & the Metabolic Syndrome, Berlin.
Johnson RB, Serio FG (2001). Leptin within healthy and diseased human
gingiva. J Periodontol 72:1254-1257.
Karjalainen S, Vanhamaki M, Kanto D, Kossi L, Sewon L, Salo M (2002).
Long-term physical inactivity and oral health in Finnish adults with
intellectual disability. Acta Odontol Scand 60:50-55.
Kawanami D, Maemura K, Takeda N, Harada T, Nojiri T, Imai Y, et al.
(2004). Direct reciprocal effects of resistin and adiponectin on vascular
endothelial cells: a new insight into adipocytokine-endothelial cell
interactions. Biochem Biophys Res Commun 314:415-419.
Kempers KG, Foote JW, DiFlorio-Brennan T (2000). Obesity: prevalence
and considerations in oral and maxillofacial surgery. J Oral Maxillofac
Surg 58:137-143.
Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, et
al. (2002). Obesity and the risk of heart failure. N Engl J Med 347:305313.
Kennedy GC (1953). The role of depot fat in the hypothalamic control of
food intake in the rat. Proc R Soc Lond B Biol Sci 140:578-596.
Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001). Adipose
tissue tumor necrosis factor and interleukin-6 expression in human
obesity and insulin resistance. Am J Physiol Endocrinol Metab
280:E745-E751.
Kershaw EE, Flier JS (2004). Adipose tissue as an endocrine organ. J Clin
Endocrinol Metab 89:2548-2556.
Kolanowski J (1999). Obesity and hypertension: from pathophysiology to
treatment. Int J Obes Relat Metab Disord 23(Suppl 1):42-46.
Koletsky S (1973). Obese spontaneously hypertensive ratsa model for
study of atherosclerosis. Exp Mol Pathol 19:53-60.
Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, et al.
(2002). Disruption of adiponectin causes insulin resistance and
neointimal formation. J Biol Chem 277:25863-25866.
Libby P (2002). Inflammation in atherosclerosis. Nature 420:868-874.
Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni
PA, et al. (2002). Adiponectin and development of type 2 diabetes in

J Dent Res 86(5) 2007

the Pima Indian population. Lancet 360:57-58.


Linne Y, Rossner S (1998). What is "obesity"an analysis of referral letters
to an obesity unit. Int J Obes Relat Metab Disord 22:1231-1233.
Loos BG (2005). Systemic markers of inflammation in periodontitis. J
Periodontol 76(11 Suppl):2106-2115.
Loos BG, Hutter J, Varoufaki A, Bulthuis H, Craandijk J, Huffels RAM, et
al. (1998). Levels of C-reactive protein in periodontitis patients and
healthy controls (abstract). J Dent Res 77(Spec Iss B):666.
Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani
H, et al. (2002). Diet-induced insulin resistance in mice lacking
adiponectin/ACRP30. Nat Med 8:731-737.
Margetic S, Gazzola C, Pegg GG, Hill RA (2002). Leptin: a review of its
peripheral actions and interactions. Int J Obes Relat Metab Disord
26:1407-1433.
Mattila KJ, Pussinen PJ, Paju S (2005). Dental infections and cardiovascular
diseases: a review. J Periodontol 76(11 Suppl):2085-2088.
Merchant AT, Pitiphat W, Rimm EB, Joshipura K (2003). Increased
physical activity decreases periodontitis risk in men. Eur J Epidemiol
18:891-898.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al.
(2003). Prevalence of obesity, diabetes, and obesity-related health risk
factors, 2001. J Am Med Assoc 289:76-79.
Mokdad AH, Marks JS, Stroup DF, Gerberding JL (2004). Actual causes of
death in the United States, 2000. J Am Med Assoc 291:1238-1245.
Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH (1999).
The disease burden associated with overweight and obesity. J Am Med
Assoc 282:1523-1529.
Nagaev I, Smith U (2001). Insulin resistance and type 2 diabetes are not
related to resistin expression in human fat cells or skeletal muscle.
Biochem Biophys Res Commun 285:561-564.
Nishida N, Tanaka M, Hayashi N, Nagata H, Takeshita T, Nakayama K, et
al. (2005). Determination of smoking and obesity as periodontitis risks
using the classification and regression tree method. J Periodontol
76:923-928.
Nishimura F, Iwamoto Y, Mineshiba J, Shimizu A, Soga Y, Murayama Y
(2003). Periodontal disease and diabetes mellitus: the role of tumor
necrosis factor-alpha in a 2-way relationship. J Periodontol 74:97-102.
Offenbacher S (1996). Periodontal diseases: pathogenesis. Ann Periodontol
1:821-878.
Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM
(2006). Prevalence of overweight and obesity in the United States,
1999-2004. J Am Med Assoc 295:1549-1555.
Otero M, Lago R, Lago F, Casanueva FF, Dieguez C, Gomez-Reino JJ, et
al. (2005). Leptin, from fat to inflammation: old questions and new
insights. FEBS Lett 579:295-301.
Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, et al.
(2000). Adiponectin, an adipocyte-derived plasma protein, inhibits
endothelial NF-kappaB signaling through a cAMP-dependent pathway.
Circulation 102:1296-1301.
Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y, et al.
(2001). Adipocyte-derived plasma protein, adiponectin, suppresses lipid
accumulation and class A scavenger receptor expression in human
monocyte-derived macrophages. Circulation 103:1057-1063.
Overweight, obesity, and health risk. National Task Force on the Prevention
and Treatment of Obesity (2000). Arch Intern Med 160:898-904.
Pai JK, Pischon T, Ma J, Manson JE, Hankinson SE, Joshipura K, et al.
(2004). Inflammatory markers and the risk of coronary heart disease in
men and women. N Engl J Med 351:2599-2610.
Perlstein MI, Bissada NF (1977). Influence of obesity and hypertension on
the severity of periodontitis in rats. Oral Surg Oral Med Oral Pathol
43:707-719.
Pischon T, Hankinson SE, Hotamisligil GS, Rifai N, Rimm EB (2003).
Leisure-time physical activity and reduced plasma levels of obesityrelated inflammatory markers. Obes Res 11:1055-1064.
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB (2004).
Plasma adiponectin levels and risk of myocardial infarction in men. J
Am Med Assoc 291:1730-1737.
Pischon T, Bamberger CM, Kratzsch J, Zyriax BC, Algenstaedt P, Boeing
H, et al. (2005). Association of plasma resistin levels with coronary
heart disease in women. Obes Res 13:1764-1771.
Pouliot MC, Despres JP, Lemieux S, Moorjani S, Bouchard C, Tremblay A,

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research

J Dent Res 86(5) 2007

Obesity, Inflammation, and Periodontal Disease

et al. (1994). Waist circumference and abdominal sagittal diameter:


best simple anthropometric indexes of abdominal visceral adipose
tissue accumulation and related cardiovascular risk in men and women.
Am J Cardiol 73:460-468.
Pradhan AD, Ridker PM (2002). Do atherosclerosis and type 2 diabetes
share a common inflammatory basis? Eur Heart J 23:831-834.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001). C-reactive
protein, interleukin 6, and risk of developing type 2 diabetes mellitus. J
Am Med Assoc 286:327-334.
Rajala MW, Lin Y, Ranalletta M, Yang XM, Qian H, Gingerich R, et al.
(2002). Cell type-specific expression and coregulation of murine
resistin and resistin-like molecule-alpha in adipose tissue. Mol
Endocrinol 16:1920-1930.
Reseland JE, Syversen U, Bakke I, Qvigstad G, Eide LG, Hjertner O, et al.
(2001). Leptin is expressed in and secreted from primary cultures of
human osteoblasts and promotes bone mineralization. J Bone Miner
Res 16:1426-1433.
Ridker PM (2002). On evolutionary biology, inflammation, infection, and
the causes of atherosclerosis. Circulation 105:2-4.
Rotter V, Nagaev I, Smith U (2003). Interleukin-6 (IL-6) induces insulin
resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis
factor-alpha, overexpressed in human fat cells from insulin-resistant
subjects. J Biol Chem 278:45777-45784.
Saito T, Shimazaki Y, Sakamoto M (1998). Obesity and periodontitis. N
Engl J Med 339:482-483.
Saito T, Shimazaki Y, Koga T, Tsuzuki M, Oshima A (2001). Relationship
between upper body obesity and periodontitis. J Dent Res 80:1631-1636.
Saito T, Shimazaki Y, Kiyohara Y, Kato I, Kubo M, Iida M, et al. (2005).
Relationship between obesity, glucose tolerance, and periodontal
disease in Japanese women: the Hisayama study. J Periodontal Res
40:346-353.
Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV,
et al. (2001). Resistin/Fizz3 expression in relation to obesity and
peroxisome proliferator-activated receptor-gamma action in humans.
Diabetes 50:2199-2202.
Seidell JC (2000). Obesity, insulin resistance and diabetesa worldwide
epidemic. Br J Nutr 83(Suppl 1):5-8.
Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, et
al. (2003). Adiponectin and protection against type 2 diabetes mellitus.
Lancet 361(9353):226-228.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al.
(2001a). The hormone resistin links obesity to diabetes. Nature
409(6818):307-312.
Steppan CM, Brown EJ, Wright CM, Bhat S, Banerjee RR, Dai CY, et al.
(2001b). A family of tissue-specific resistin-like molecules. Proc Natl
Acad Sci USA 98:502-506.
Stumvoll M, Goldstein BJ, van Haeften TW (2005). Type 2 diabetes:
principles of pathogenesis and therapy. Lancet 365(9467):1333-1346.
Third Report of the National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults (Adult Treatment Panel III) final report (2002).
Circulation 106:3143-3421.
Thomas T (2003). Leptin: a potential mediator for protective effects of fat
mass on bone tissue. Joint Bone Spine 70:18-21.
Thomas T, Burguera B (2002). Is leptin the link between fat and bone mass?
J Bone Miner Res 17:1563-1569.
Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL (1999).
Leptin acts on human marrow stromal cells to enhance differentiation

409

to osteoblasts and to inhibit differentiation of adipocytes.


Endocrinology 140:1630-1638.
Thompson D, Wolf AM (2001). The medical-care cost burden of obesity.
Obes Rev 2:189-197.
Troiano RP, Frongillo EA Jr, Sobal J, Levitsky DA (1996). The relationship
between body weight and mortality: a quantitative analysis of combined
information from existing studies. Int J Obes Relat Metab Disord
20:63-75.
Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, et al. (2003).
Resistin promotes endothelial cell activation: further evidence of
adipokine-endothelial interaction. Circulation 108:736-740.
Wajchenberg BL (2000). Subcutaneous and visceral adipose tissue: their
relation to the metabolic syndrome. Endocr Rev 21:697-738.
Wakai K, Kawamura T, Umemura O, Hara Y, Machida J, Anno T, et al.
(1999). Associations of medical status and physical fitness with
periodontal disease. J Clin Periodontol 26:664-672.
Wang Y, Rimm EB, Stampfer MJ, Willett WC, Hu FB (2005). Comparison
of abdominal adiposity and overall obesity in predicting risk of type 2
diabetes among men. Am J Clin Nutr 81:555-563.
WHO (1999). Definition, diagnosis and classification of diabetes mellitus
and its complications. Part 1: diagnosis and classification of diabetes
mellitus provisional report of a WHO consultation. Geneva: World
Health Organization.
WHO/IASO/IOTF (2000). The Asia-Pacific perspective: redefining obesity and
its treatment. Melbourne: Health Communications Australia Pty Limited.
Willett WC, Hu FB, Colditz GA, Manson JE (2005). Underweight,
overweight, obesity, and excess deaths. J Am Med Assoc 294:551;
author reply, J Am Med Assoc 294:552-553.
Wilson JA, Clark JJ (2004). Obesity: impediment to postsurgical wound
healing. Adv skin wound care 17:426-435.
Wilson PW, D'Agostino RB, Sullivan L, Parise H, Kannel WB (2002).
Overweight and obesity as determinants of cardiovascular risk: the
Framingham experience. Arch Intern Med 162:1867-1872.
Wolf HK, Tuomilehto J, Kuulasmaa K, Domarkiene S, Cepaitis Z, Molarius
A, et al. (1997). Blood pressure levels in the 41 populations of the
WHO MONICA Project. J Hum Hypertens 11:733-742.
Wood N, Johnson RB, Streckfus CF (2003). Comparison of body
composition and periodontal disease using nutritional assessment
techniques. Third National Health and Nutrition Examination Survey
(NHANES III). J Clin Periodontol 30:321-327.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al.
(2001). The fat-derived hormone adiponectin reverses insulin resistance
associated with both lipoatrophy and obesity. Nat Med 7:941-946.
Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al.
(2005). Serum retinol binding protein 4 contributes to insulin resistance
in obesity and type 2 diabetes. Nature 436:356-362.
Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V (2000).
Inflammation, obesity, stress and coronary heart disease: is interleukin6 the link? Atherosclerosis 148:209-214.
Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, et
al. (2005). Obesity and the risk of myocardial infarction in 27,000
participants from 52 countries: a case-control study. Lancet 366:16401649.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM
(1994). Positional cloning of the mouse obese gene and its human
homologue. Nature 372:425-432.
Zucker TF, Zucker LM (1962). Hereditary obesity in the rat associated with
high serum fat and cholesterol. Proc Soc Exp Biol Med 110:165-171.

Downloaded from jdr.sagepub.com at Universitas Gadjah Mada on May 13, 2014 For personal use only. No other uses without permission.
International and American Associations for Dental Research