Special Article

Normal-weight obesity syndrome: diagnosis, prevalence, and

clinical implications
Lana P. Franco, Carla C. Morais, and Cristiane Cominetti

The growing concern about the impact of overweight on health has led to studies
that shed light on types of obesity other than the classic model based on body
mass index. Normal-weight obesity syndrome is characterized by excess body fat in

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individuals with adequate body mass index (18.5–24.9 kg/m2). This condition
increases the risk of cardiovascular morbidity and mortality and other conditions
associated with chronic diseases, such as insulin resistance, hypertension, and dysli-
pidemia. The aims of this review are to define the diagnostic criteria for normal-
weight obesity syndrome and to examine the risks associated with this condition in
order to promote preventive measures and early treatment for affected individuals.

INTRODUCTION have either an appropriate body fat percentage or an ex-

Excessive body fat is responsible for at least 2.8 million
deaths per year worldwide. Overweight and obesity in-
crease the risk of other noncommunicable diseases,
such as cardiovascular disease, diabetes mellitus, and
certain types of cancer.1 The metabolic effects of body
fat accumulation on blood pressure, lipid profile, insu-
lin sensitivity, inflammatory and oxidative states, and
on gene expression patterns have been a frequent target
of scientific research.
The World Health Organization (WHO) defines
obesity as excessive body fat accumulation, which is as-
sociated with clear risks to health. To overcome the dif-
ficulties associated with measuring and classifying the
percentage of body fat, the WHO established the body
mass index (BMI) as the parameter for identifying over-
weight and obesity.2
Body mass index, however, does not allow the as-
sessment of body composition, as it does not differenti-
ate fat-free mass from adipose tissue. Thus, an
individual with normal BMI (18.5–24.9 kg/m2) may
cess of fat that might be masked by the normal BMI.3
Excessive body fat despite normal body weight has
been described as normal-weight obesity syndrome
(NWO).4 Normal-weight obesity is a condition in which
a person has an adequate BMI but an increased body fat
percentage and a greater risk of developing noncommu-
nicable chronic diseases. Although investigations are re-
cent, estimates show that about 30 million Americans
are affected by NWO.5,6 This prevalence is not well es-
tablished, however, and there is wide variation between
the studies carried out thus far. This variation is attrib-
uted to aspects such as ethnic differences, diverse meth-
odologies used to assess body composition, and different
cutoff points established for the diagnosis of NWO.
Individuals with NWO tend to develop certain char-
acteristic health conditions, such as low-grade proinflam-
matory status, increased oxidative stress, insulin
resistance, and dyslipidemia, which lead to a higher risk
of cardiovascular disease, metabolic syndrome, and
cardiovascular-related death.3,4,6–10 Furthermore, nutri-
genetic studies suggest that NWO may interfere with the

Affiliation: L.P. Franco and C. Cominetti are with the Postgraduate Program in Nutrition and Health, Faculty of Nutrition, Federal University
of Goias, Goi^ania, Goias, Brazil. C.C. Morais is with the Postgraduate Program in Health Sciences, Faculty of Medicine, Federal University of
Goias, Goi^ania, Goias, Brazil.
Correspondence: C. Cominetti, Faculty of Nutrition, Federal University of Goias, Rua 227, Quadra 68 s/n, Setor Leste Universitario, Goi^ania,
Goias, Brazil CEP 74.605-080. Email: ccominetti@ufg.br. Phone: þ55-(62)-3209-6270, ext 210.
Key words: body composition, inflammation, insulin resistance, obesity, oxidative stress.
C The Author(s) 2016. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For
V
Permissions, please e-mail: journals.permissions@oup.com.

doi: 10.1093/nutrit/nuw019
558 Nutrition ReviewsV Vol. 74(9):558–570
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relationship between genetic polymorphisms and an in-
dividual’s health.7,11–13 Considering that body composi-
tion is not routinely assessed in outpatient care, it is
important to characterize NWO syndrome and to iden-
tify the health risks associated with this condition. Clarity
about the diagnosis, prevalence, and clinical implications
of NWO syndrome will help healthcare providers incor-
porate specific actions into healthcare plans – including
the periodic assessment of adiposity, even in people with
adequate BMI – in order to maintain health and reduce
the risk of disease in NWO populations.
Therefore, the aims of this review are to character-
ize NWO syndrome, to examine the diagnostic criteria,
and to highlight factors associated with the risk of dis-
ease development in affected individuals.
DEFINITIONS AND RELATED CONCEPTS
Overweight and obesity are defined as the excessive ac-
cumulation of body fat, which represents a risk to
health, according to the WHO.2 The most commonly
used parameter for classifying overweight and obesity
in a population is BMI. The WHO also recommends
the use of this index in association with measurement
of waist circumference and calculation of waist-to-hip
ratio.1
Although BMI has high specificity to detect exces-
sive body adiposity, its sensitivity is low. An important
limitation is that BMI has no ability to distinguish fat-
free mass from fat mass; consequently, it cannot be used
to assess the distribution of body fat. Sex, age, genetic
and environmental factors all influence body fat distribu-
tion, and visceral (intra-abdominal or android) fat is a
risk factor for the development of noncommunicable
diseases, regardless of the total body fat content. In addi-
tion, BMI cutoff points do not consider differences in
the body proportions of different populations.5,14
The need to properly diagnose individuals with ex-
cessive body fat prompted De Lorenzo et al.4 to define
NWO, a condition characterized by weight within nor-
mal limits according to BMI, but with a high percentage
of body fat.
It is important to differentiate individuals with
NWO from those who are metabolically obese but of
normal weight, a condition that has been studied for
some decades. Individuals who are metabolically obese
but of normal weight have an appropriate weight ac-
cording to BMI but have changes related to metabolic
syndrome. These individuals usually have excessive vis-
ceral fat, hyperinsulinemia, insulin resistance, dyslipide-
mia, high blood pressure, and an increased risk for type
2 diabetes, cardiovascular events, and cardiovascular
death. Normal-weight obesity differs from metabolic
obesity with normal weight in that it is associated with
Nutrition ReviewsV Vol. 74(9):558–570
R
metabolic disorders of lesser magnitude, which are usu-
ally undiagnosed. Moreover, an increase in visceral fat
is not always present.3 As a result, individuals with
NWO are unaware of the risks to which they are ex-
posed, in contrast to metabolically obese but normal-
weight subjects, who present major metabolic changes
that result in signs and symptoms as well as subsequent
diagnosis. Indeed, individuals with NWO might eventu-
ally present as being metabolically obese but of normal
weight if they are not correctly diagnosed.
PREVALENCE AND CRITERIA FOR DIAGNOSIS
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As noted previously, NWO prevalence data differ be-
tween studies because of ethnic differences in popula-
tions and the lack of consensus on diagnostic criteria.
Normal-weight obesity has been studied more com-
monly among women, in whom it is highly prevalent,
suggesting that sex hormones may play a role in the de-
velopment of this condition.10
The study that first described NWO established
normal BMI and a high percentage of body fat as the di-
agnostic criteria.4 The authors used dual-energy X-ray
absorptiometry to measure body fat percentage, and the
cutoff point for diagnosis was 30%. The study only in-
cluded females in whom no metabolic changes or non-
communicable diseases had been previously detected,
and NWO prevalence was not evaluated.
Studies have shown that individuals with NWO
may or may not present with changes in other anthro-
pometric parameters, such as waist circumference,
waist-to-hip ratio, waist-to-height ratio, and percentage
of android or gynoid fat. Therefore, these parameters
are typically used to provide complementary informa-
tion when evaluating individuals clinically, but they are
not suitable for diagnosing NWO.3,4,6,9,10,15
Another consideration is that variation in the body
composition pattern may depend on ethnicity.5,14 For
example, adjustment of the BMI reference value for the
Asian population may help prevent overestimation of
the prevalence of overweight and obesity. On the other
hand, the use of the universal BMI cutoff point set by
the WHO has allowed the comparison of data from dif-
ferent epidemiological studies in order to establish the
relation between BMI and the risk of noncommunicable
diseases.1,14
Kim et al.15 found an NWO prevalence of 36%
(men) and 29% (women) in Koreans with normal
weight (BMI, 18.5–22.9 kg/m2 for Asians16). This study
in Koreans included 5313 men and 6904 women older
than 20 years, and dual-energy X-ray absorptiometry
was used to measure the percentage of body fat. The au-
thors established the lowest percentage of body fat pre-
sented by overweight individuals (BMI, 22.9 kg/m2) as
559
the cutoff point for NWO. Thus, men with a body fat
percentage 20.6% and women with a body fat percent-
age 33.4% were included in the NWO group.15
Thus far, only one study about NWO in Latin
America has been published.9 It included 1222 young
adults aged 23 to 25 years with normal BMI, 55.3% of
whom were women. The prevalence of NWO among
the total sample was 9.1% (9.2% for men and 9.0% for
women). Body fat was estimated by measurement of
skinfold thickness, and the cutoff point for NWO was
the 90th percentile of the sum of the subscapular and
triceps skinfolds, applying Slaughter’s equation.17
Some studies have used the quartiles method to di-
agnose NWO. In these investigations, volunteers were
separated into tertiles of body fat percentage according
to sex, and diagnosis of NWO was based on the upper
tertile cutoff point.6,8,10 Using the tertile criterion for di-
agnosis, Romero-Corral et al.6 evaluated 6171
Americans (3129 women) older than 20 years and
found an overall NWO prevalence of 33.4%. Body fat
percentage was evaluated by bioelectrical impedance,
and the cutoff point (upper tertile) used for classifica-
tion of NWO was 23.1% for men and 33.3% for women.
From the results, the authors estimate that 30 million
Americans have NWO.
Using the highest tertile of body fat percentage
(26% for men and 38% for women) as the cutoff
value, Marques-Vidal et al.10 found an NWO prevalence
of 2.8% in men and 5.4% in women. The study popula-
tion consisted of 6188 Caucasians aged 35 to 75 years
and classified into various BMI ranges. Kang et al.8 also
used the upper tertile of body fat percentage for NWO
classification (23.5% for men and 29.2% for
women), but they did not evaluate the prevalence of
NWO syndrome.
Marques-Vidal et al.18 used bioelectrical impedance
and various diagnostic cutoff points to calculate body fat
percentage and to assess the prevalence of NWO, which
ranged from 0.1% to 41.1% in women and from 0.1% to
3.6% in men. This study and the others mentioned above
confirm the lack of consensus regarding NWO diagnos-
tic criteria and, hence, the discrepancies in the reported
data. Table 13,4,6,8–11,15,18–25 shows the differences be-
tween studies. In light of this lack of consensus, there is a
need to establish cutoff points for body fat percentages to
define obesity. Moreover, it is urgent that appropriate di-
agnostic criteria for NWO are established, given that ex-
cessive body fat is associated with the development of
disease, especially cardiovascular disease.
CONDITIONS ASSOCIATED WITH EXCESSIVE BODY FAT
Excessive body fat is a major risk factor for the de-
velopment of noncommunicable diseases such as
560
cardiovascular conditions, as it is associated with the
development of dyslipidemia, insulin resistance, and
changes in blood pressure as well as pro-oxidative ef-
fects and the exacerbation of low-grade chronic proin-
flammatory status. An increase in body fat percentage is
usually linked to sedentary behavior and poor eating
habits, which further aggravate the problem.1
Cardiovascular disease is the leading cause of death
worldwide, accounting for more than 17.5 million
deaths in 2012 and estimated to cause approximately
22.2 million deaths in 2030.26 Recent studies have de-
scribed increased cardiovascular risk in subjects with
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NWO, emphasizing the importance of characterizing
NWO syndrome and the metabolic changes associated
with it.5,8,21,27
Blood pressure, lipid profile, and homocysteine
concentrations
In an attempt to establish the relationship between
NWO and cardiovascular risk, some authors have in-
vestigated lipid profile, blood pressure, apolipoproteins,
and homocysteine concentrations in subjects with
NWO. Some found an increased risk of cardiovascular
disease and mortality in this population. This relation-
ship was observed only in women, suggesting a specific
association with sex and a possible involvement of hor-
monal metabolism.6,10
Shea et al.25 and Kim et al.21 evaluated the presence
of cardiovascular risk factors in subjects with NWO. In
the first study, Canadian individuals were evaluated for
the presence of hypertension, dyslipidemia, increased
homeostasis model assessment of insulin resistance
(HOMA-IR), and ultrasensitive C-reactive protein.
Those who presented two or more changes were con-
sidered to be at high risk. Classifying individuals into
tertiles of body fat percentage resulted in a greater prev-
alence of risk among those in the middle and upper ter-
tiles (12.0% and 19.5%, respectively) when compared
with those in the lowest tertile (7.4%).25 In the second
study, Korean individuals with NWO had a higher risk
of developing one or more cardiovascular risk factors
(hypertension, dyslipidemia, and/or hyperglycemia)
than individuals with an appropriate body fat percent-
age (odds ratio [OR] ¼ 1.63, 95%CI 1.21–2.19 in men;
and OR ¼ 1.56, 95%CI 1.36–1.8 in women).21
Among individuals with NWO syndrome, both
mean blood pressure and prevalence of hypertension
seem to be higher.6,8,10,20 Blood pressure above 115/
75 mmHg has been linearly associated with increased
mortality from cardiovascular disease in the general
population. Indeed, hypertension is a major risk factor
for the development of heart failure and coronary artery
disease.28 Small increases in blood pressure are related
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 Table 1 Diagnostic criteria for normal-weight obesity (NWO), prevalence of NWO, and observations in subjects with NWO in 16 studies
Reference Sample Evaluation Diagnostic criterion Prevalence of NWO Observations in NWO subjects
method
BMI (kg/m2) Percent body fat
4
De Lorenzo et al. (2006) 74 Italian women DXA 18.5–24.9 >30% in women Not evaluated "LDL-C to HDL-C ratio

R
16–74 y "HDL-C
De Lorenzo et al. (2007)3 60 Italian women DXA 18.5–24.9 >30% in women Not evaluated "TNF-a, "IL-1a
20–68 y "IL-1b, "IL-6
"IL-8
Di Renzo et al. (2006)11 75 Italian women DXA 18.5–24.9 >30% in women Not evaluated #BMR
20–45 y

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Di Renzo et al. (2010)19 60 Italian women DXA 18.5–24.9 >30% in women Not evaluated #NO2/NO3
20–35 y #Glutathione
"Lipid peroxides
#Nonprotein antioxidant capacity
Kang et al. (2014)8 82 NWO Koreans Bioelectrical 18.5–24.9 Upper tertile: Not evaluated "Visceral fat
33 men impedance 23.5% in men; "Systolic BP
49 women 29.2% in women "Fasting glucose
82 controls "Triacylglycerols
#HDL-C
"Subclinical vascular inflammation
Kim et al. (2014)15 12 217 adult Koreans: DXA 18.5–22.9 20.6% in men; Among normal-BMI "WC, "TC
5313 men 33.4% in women subjects: #HDL-C, "triacylglycerols
6904 women 32% total "Systolic BP (men)
Mean age, 44.6 y 36% in men; 29% in "Fasting glucose
women "HOMA-IR
"Diabetes (men)
"CVRF, "SAH
"Dyslipidemia
"Metabolic syndrome
Kim et al. (2015)20 2078 adult Koreans Bioelectrical 18.5–24.9 Upper tertile: 8.3% "PWV
1141 men impedance 25.4% in men; "Risk for soft coronary plaques
1026 women 31.4% in women
Mean age 6 SD, 53 6 9 y
Kim et al. (2013)21 12 386 Koreans Bioelectrical 18.5–24.9 25% in men; 30% in 12.9% total "Systolic BP, "WC
6534 men impedance women 4.5% in men; 21.9% in "TC, "triacylglycerols
5852 women women "LDL-C, "CVRF
30–49 y "Fasting glucose
"Fasting insulin
"HOMA-IR
"SAH (men)
"Hyperglycemia
"Dyslipidemia
Kosmala et al. (2012)22 73 NWO Polish adults DXA 18.5–24.9 20–39 y: Not evaluated "Fasting insulin
95 controls 19% in men; 32% in "HOMA-IR, "LDL-C, #HDL-C,
Mean age 6 SD, 38 6 7 y women "triacylglycerols

561
(continued)

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 Table 1 Continued

562
Reference Sample Evaluation Diagnostic criterion Prevalence of NWO Observations in NWO subjects
method 2
BMI (kg/m ) Percent body fat
40–59 y: "CRP > WC
21% for men; 33% in "Abdominal fat
women "Android/gynoid fat rate
60–79 y: Myocardial dysfunction
24% for men; 35% in
women
Madeira et al. (2013)9 1222 adult Brazilians Skinfold 18.5–24.9 TSF þ SSF  P90, corre- Among normal-BMI "Prevalence of metabolic syn-
546 men thickness sponding to 23.1% in subjects: drome, insulin resistance, and
676 women men; 33.3% in 9.1% total hyperinsulinemia
23–25 y women 9.2% in men; 9.0% in "WC, #HDL-C
women "Hypertriglyceridemia
Marques-Vidal 1523 Caucasians Bioelectrical 18.5–24.9 1) 30% overall 1) 3.2% in men; 10.1% in Not evaluated
et al. (2008)23,a 648 men impedance 2) 29.1% in men; 37.2% women
875 women in women 2) 3.4% in men; 2.5% in
Mean age 6 SD, 38 6 17 y 3) 26%–31% in men; women
39%–43% in women 3) 3.9% in men; 0.6% in
(according to age) women
4) 26.8%–32.6% in men, 4) 2.6% in men; 0.5% in
35.4%–44.4% in women
women (according to Among normal-BMI
age) subjects:
1) 6.9% in men; 15.0% in
women
2) 7.2% in men; 3.7% in
women
3) 5.6% in men; 0.9% in
women
4) 3.9% in men; 0.7% in
women
Marques-Vidal 6188 Caucasians Bioelectrical 18.5–24.9 1) 30% overall Among normal-BMI Not evaluated
et al. (2008)18,b 3213 women impedance 2) 29.1% for men; subjects:
2912 men 37.2% in women 1) 0.7% in men; 27.8% in
35–75 y 3) 26%–31% in men; women
39%–43% in women 2) 1.0% in men; 6.9% in
(according to age) women
4) 28.1%–32.6% in men; 3) 0.8% in men; 1.4% in
35.9%–44.4% in women

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women (according to 4) 0.6% in men; 2.5% in
age) women
5) Fat mass index: 5) 0.1% in men; 0.1% in
women
(continued)

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 Table 1 Continued
Reference Sample Evaluation Diagnostic criterion Prevalence of NWO Observations in NWO subjects
method
BMI (kg/m2) Percent body fat
8.3 kg/m2 in men;

R
11.8 kg/m2 in
women
1) De Lorenzo et al.
(2006)
2) Zhu et al. (2003)
3) Gallager et al. (2000)

Nutrition ReviewsV Vol. 74(9):558–570

4) Kyle et al. (2001)
5) Kyle et al. (2003)
Marques-Vidal et al. (2010)10 6188 Caucasians Bioelectrical 18.5–24.9 Upper tertile: 2.8% in men; 5.4% in "Cardiovascular risk (women)
3213 women impedance 26% in men; 38% in women "Systolic BP
2912 men women Dyslipidemia
35–75 y "Hyperhomocysteinemia
"Leptin (women)
Miazgowski and 145 Polish women DXA 18.5–24.9 2 analyses: Not evaluated "Diastolic BP
Safranow (2013)24 20–40 y 30% (De Lorenzo "Triacylglycerols
et al., 2006) "LDL-C
Upper tertile: 35% #HDL-C
"Android and gynoid fat
Romero-Corral et al. (2010)6 6171 North Americans Bioelectrical 18.5–24.9 Upper tertile: Among normal-BMI sub- Not evaluated
3129 women impedance 23.1% in men; jects: 33.4%
3042 men 33.3% in women
Mean age 6 SD, 41.3 6 0.31 y
Shea et al. (2012)25 977 Canadians DXA 18.5–24.9 Upper tertile: Among normal-BMI sub- "Systolic BP
785 women 20.8% in men; jects: 33.7% "Triacylglycerols
192 men 35.0% in women "HOMA-IR
20–79 y "CRP
"Prevalence of cardiometabolic
changes

Abbreviations: BMI, body mass index; BMR, basal metabolic rate; BP, blood pressure; CRP, C-reactive protein; CVRF, cardiovascular risk factors; DXA, dual-energy X-ray absorptiometry; HDL-C,
high-density lipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; IL-1a, interleukin 1a; IL-1b, interleukin 1b; IL-6, interleukin 6; IL-8, interleukin 8; LDL-C, low-density li-
poprotein cholesterol; NO2/NO3, nitrite to nitrate ratio; NWO, normal-weight obesity; PWV, pulse wave velocity; SAH, systemic arterial hypertension; TC, total cholesterol; TNF-a, tumor ne-
crosis
a
factor a; TSF, triceps skinfold; SSF, subscapularis skinfold; WC, waist circumference.
Indicates study evaluated NWO prevalence according to several cutoff points established by different authors. Numbered percentages listed in the Percent body fat column correspond to
numbered prevalences in the Prevalence of NWO column.
b
Indicates study evaluated NWO prevalence according to several cutoff points established by different authors. These cutoff points, as well as the prevalence found by each author, are num-
bered according to the studies listed in the Percent body fat column. These studies are cited in the reviews by Marques-Vidal (2008).18

563
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to the pathophysiological mechanisms of endothelial
dysfunction, which can progress to the development of
atherosclerosis.29
Normal-weight obesity has been associated with an
increased risk of subclinical atherosclerosis in a study
that evaluated 2078 Koreans with normal BMI and no
history of coronary artery disease. The cutoff points of
body fat percentage used for NWO diagnosis were
25.4% for men and 31.4% for women (upper tertile).
After adjustments for age, sex, and smoking habits, in-
dividuals with NWO showed higher values of pulse
wave velocity and a higher prevalence of soft coronary
plaques compared with those with an adequate body fat
percentage (1474.0 6 275.4 cm/s vs 1380.7 6 234.3 cm/s
and 21.6% vs 14.5%, respectively). Furthermore, the
presence of NWO was considered an independent risk
factor for the development of soft coronary plaques
(OR ¼ 1.46; 95%CI, 1.03–2.07).20
The atherogenesis process contributes to higher car-
diovascular risk. Dyslipidemia, evidenced by increased
levels of total cholesterol, low-density lipoprotein choles-
terol (LDL-C), and triacylglycerols or by reduced
concentrations of high-density lipoprotein cholesterol
(HDL-C) as well as by the accumulation of oxidized
low-density lipoprotein particles in the endothelium, is
among the factors that favor this process.30
Some studies have linked NWO with greater risk of
dyslipidemia.6,8,10 In a study of 164 Koreans, Kang
et al.8 reported that individuals with NWO had higher
triacylglycerol levels and lower HDL-C concentrations
compared with individuals with normal BMI and body
fat percentage. In Brazil, Madeira et al.9 observed an as-
sociation between now, low HDL-C levels (OR ¼ 1.65;
95%CI, 1.11–2.47) and hypertriglyceridemia
(OR ¼ 1.93; 95%CI, 1.02–3.64). In a study of 6171
American adults of both sexes, Romero-Corral et al.6
reported that individuals with NWO had lower serum
HDL-C concentrations, higher LDL-C and triacylgly-
cerol levels, and altered ratios of apolipoprotein B to
apolipoprotein A1 when compared with subjects with
normal BMI and adequate body fat percentage. They
also observed a proportional relationship between in-
creased body fat percentage and the highest risk of dys-
lipidemia and cardiovascular disease mortality in
women with NWO (HR ¼ 1.06 for each point increase
in body fat percentage; 95%CI, 1.01–1.12).6
On the other hand, De Lorenzo et al.4 did not find
differences between lipid profiles of adult Italians with
NWO and those of the control group, although they
found a higher ratio of LDL-C to HDL-C, a marker of
cardiovascular risk, in individuals with NWO
(2.14 6 1.19 vs 1.29 6 0.37). In this study, however, the
NWO group presented higher HDL-C levels
(1.92 6 0.36 mmol/L vs 1.57 6 0.33 mmol/L).4
564
Excessive body fat is usually related to lower HDL-
C concentrations, higher triacylglycerol levels, and
changes in LDL-C particles. In obesity, the lipolysis pro-
cess is altered: there is greater lysis of triacylglycerols
and a higher release of free fatty acids in the blood-
stream, which inhibits the action of lipoprotein lipase
and increases the hepatic synthesis of very low-density
lipoprotein, with a consequent increase in plasma tria-
cylglycerols. In this situation, there is increased produc-
tion of cholesteryl ester transfer protein, which
promotes the exchange between triacylglycerol from
very low-density. and cholesterol from high-density li-
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poproteins. Triacylglycerol-rich high-density lipopro-
tein is degraded and, in turn, there is a decrease in
blood levels of high-density lipoprotein. This results in
hypertriglyceridemia, in which low-density lipoprotein
becomes richer in triacylglycerol and contains a lower
amount of cholesterol. However, the triacylglycerol of
these particles is hydrolyzed by hepatic lipase, which re-
sults in smaller and denser low-density lipoprotein par-
ticles with a greater potential to cause
atherogenesis.31,32
Hyperhomocysteinemia has also been linked to in-
creased cardiovascular risk.33 Homocysteine is a sulfhy-
dryl substance produced from methionine conversion
in the crosstalk with folate metabolism. When concen-
trations of homocysteine in the blood are high, homo-
cysteine is oxidized and there is an increase in pro-
oxidant substances that favor modification of low-
density lipoprotein particles; activation of nuclear factor
jB; reduction in vascular endothelium antioxidant ac-
tivity; bioavailability of nitric oxide, endothelin-1, and
prostaglandin I2; and inhibition of C-reactive pro-
tein.34,35 Furthermore, hyperhomocysteinemia has been
associated with accumulation of body fat. In vitro and
in vivo experimental studies suggest that lipolysis is in-
hibited at high levels of homocysteine, which stimulates
the protein kinase activated by adenosine monophos-
phate, resulting in further accumulation of fat in
adipocytes.36
To date, only one study has evaluated homocysteine
levels in subjects with NWO. Marques-Vidal et al.10 eval-
uated 6125 Swiss adults of both sexes and reported
higher mean plasma homocysteine levels in subjects with
NWO than in those with normal BMI and body fat per-
centage (9.52 6 0.24 mmol/L vs 9.33 6 0.08 mmol/L).
In addition to differences in blood pressure, lipid
profile, and cardiovascular risk, the relationship be-
tween NWO and increased risk of inflammation has
been studied. Higher plasma concentrations of inflam-
matory biomarkers (interleukins, C-reactive protein,
and tumor necrosis factor a [TNF-a]) are related to the
development of atherosclerosis and, consequently, to
increased cardiovascular risk.3,6,8
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Proinflammatory state
White adipose tissue has been functionally classified as
an endocrine organ on the basis of its production and
secretion of proatherogenic adipocytokines (eg, resis-
tin), antiatherogenic adipocytokines (eg, adiponectin),
prothrombotic factors (eg, inhibitor of plasminogen ac-
tivator type 1), and proinflammatory factors (eg, leptin,
TNF-a, interleukin [IL]-1, IL-6).3,37
Some researchers have reported associations be-
tween NWO and concentrations of adipocytokines. In a
study of Swiss men and women between 35 and 75 years
of age, Marques-Vidal et al.10 verified higher leptin con-
centrations in women with NWO than in those with an
adequate body fat percentage. No significant differences
in adiponectin concentrations or in the leptin to adipo-
nectin ratio between groups were observed. Increased
leptin levels in American individuals with NWO were
also reported by Romero-Corral et al.6
Leptin is a hormone that acts as a metabolic marker
of energy storage. Consequently, it decreases appetite
while increasing thermogenesis, hepatic lipid oxidation,
and lipolysis in adipocytes and skeletal muscle. Obese
individuals typically have high levels of leptin; however,
they seem to be resistant to this hormone’s action.37,38
Adiponectin, in turn, is an antiatherosclerotic and
insulin-sensitizing protein. It inhibits hepatic glucose
production, increases the uptake of glucose by muscle
and the oxidation of fatty acids by muscle and liver
cells, and increases energy expenditure. Adiponectin
also seems to have a protective effect against insulin re-
sistance, atherogenesis, and proinflammatory status.37,38
However, to date, no study has found a relationship be-
tween adiponectin levels and NWO.
On the other hand, some authors have reported an
association between NWO and a proinflammatory
state.3,6–8 Indeed, since adipocytes produce several
proinflammatory cytokines, subjects with a high body
fat percentage, such as those with NWO, would be ex-
pected to show increased levels of these cytokines when
compared with individuals with an adequate body fat
percentage. Therefore, the risk of developing cardiovas-
cular disease and metabolic syndrome would be greater
in those individuals.31
In a study of 60 Italian women aged 20 to 35 years,
De Lorenzo et al.3 identified a proinflammatory state in
those diagnosed with NWO, but not in the control
group. This state was characterized by increased plasma
levels of TNF-a, IL-1a, IL-1b, IL-6, and IL-8. The au-
thors also observed a correlation between TNF-a and
IL-6 levels and body fat percentage (r ¼ 0.55, P < 0.005).
Other cytokines were evaluated, and there were no sig-
nificant differences between groups for levels of C-reac-
tive protein, IL-10, IL-2, IL-12p70, or interferon
Nutrition ReviewsV Vol. 74(9):558–570
R
gamma. Similarly, Di Renzo et al.19 also found higher
concentrations of cytokines (TNF-a, IL-1a, IL-2b, IL-6,
and IL-15) in Italian women with NWO than in those
with normal weight and body fat percentage. No differ-
ence in mean IL-10 levels between groups was observed.
Marques-Vidal et al.10 and Kang et al.8 evaluated C-re-
active protein levels in subjects with NWO and also
found no significant differences between groups. In
contrast, in a study of American individuals, NWO was
associated with higher C-reactive protein levels.6
Interleukins and TNF-a regulate several processes
in the body, including lipid and glucose metabolism as
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well as immune functions related to the body’s inflam-
matory response. Therefore, these cytokines may be in-
volved in the development of insulin resistance and
dyslipidemia when their metabolism is altered.
Interleukin 1, IL-18, IL-8, and TNF-a act as proinflam-
matory cytokines, while IL-10 is an anti-inflammatory
cytokine that acts by controlling the immune response.
Interleukin 6 appears to have different functions, having
either a proinflammatory or an anti-inflammatory role,
depending on the tissue in which it is expressed.31
In addition to cytokines, C-reactive protein is also
involved in atherosclerosis, apparently by facilitating
monocyte adhesion to vascular endothelium and mono-
cyte migration into the vessel wall. Moreover, C-reac-
tive protein is associated with reduced activity of
endothelial nitric oxide synthase and increased migra-
tion of macrophages to atherosclerotic lesions. Thus, C-
reactive protein is classified as a biomarker of inflam-
mation and may indicate increased cardiovascular
risk.39
On the basis of the studies presented here, it is
speculated that subjects with NWO show altered levels
of proinflammatory cytokines, which may contribute to
an increased risk of developing noncommunicable dis-
eases. Adding support to this, Kang et al.8 reported the
risk of vascular inflammation to be about 3 times higher
in subjects with NWO than in control subjects
(OR ¼ 3.07; 95%CI, 1.29–7.30; P ¼ 0.01).
Another study revealed that individuals with NWO
present intermediate levels of proinflammatory cyto-
kines in comparison with levels observed in normal and
obese individuals. The authors suggested this finding
might be related to the increased percentage of body fat
in individuals with NWO. They also suggest that indi-
viduals with NWO present a proinflammatory state that
is “under development”, as the cytokines found (TNF-a,
IL-1a, IL-1b, and IL1-IL8) are characteristic of an acute
inflammatory response. This condition, however, can
progress to chronic inflammation, a feature of obesity
and a strong indicator of cardiovascular risk.3
Researchers are investigating the effectiveness of
measures to reduce cardiovascular risk in individuals
565
with NWO. Di Renzo et al.40 evaluated the effects of the
consumption of dark chocolate (70% cocoa), which has
known antioxidant and anti-inflammatory properties,
in 15 adult women with NWO (aged 20–40 years).
After a washout period, patients were given chocolate,
100 g/d for 1 week. At the end of the study, the authors
verified a significant increase in HDL-C levels (D%,
10.41 6 13.53) as well as a reduction in the total choles-
terol to HDL-C ratio (D%, 11.45 6 7.03), in the LDL-
C to HDL-C ratio (D%, 11.70 6 8.91), and in levels of
IL-1 receptor antagonist (D%, 32.99 6 3.84), suggest-
ing that the consumption of concentrated cocoa may
have cardioprotective effects in this population.40
Despite the findings of the above studies, Marques-
Vidal et al.10 questioned the relationship between NWO
and a proinflammatory state because of differences in
the studies’ data. However, Kang et al.8 emphasize that
body fat percentage may be even more important than
BMI in identifying the risk of developing a chronic low-
grade proinflammatory state and, consequently, cardio-
vascular disease.
Insulin resistance
The relationship between excessive body fat, insulin re-
sistance, and type 2 diabetes has already been widely de-
scribed. Both a very low body fat percentage and an
excessive body fat percentage are associated with insulin
resistance. This paradox highlights the complexity of
the mechanisms involved in insulin resistance. Adipose
tissue has long been recognized as an endocrine gland,
having several functions in the body, including glucose
metabolism and regulation of inflammatory status. As
already described, adipocytes secrete a large variety of
molecules, including hormones such as leptin, cytokines
such as TNF-a, and fatty acids. Thus, adipose tissue
plays an essential role in energy balance and glucose
homeostasis.41
Madeira et al.9 reported that individuals with
NWO are at increased risk of developing early met-
abolic syndrome, especially insulin resistance, indicat-
ing a need for careful clinical evaluation of these
individuals. In a study conducted in Brazil, logistic
regression models were adjusted for age, sex, and
skin color. Normal-weight obesity was associated with
metabolic syndrome (OR ¼ 6.83; 95%CI, 2.84–16.47),
insulin resistance (OR ¼ 3.89; 95%CI, 2.39–6.33),
hyperinsulinemia (OR ¼ 2.17; 95%CI, 1.24–3.80), and
increased waist circumference (OR ¼ 8.46; 95%CI,
5.09–14.04), and it was related to low HDL-C levels and
hypertriglyceridemia.
In a study of 6125 Swiss individuals (3213 women),
women with NWO showed a 1.63-times higher risk of
developing hyperglycemia (95%CI, 1.10–2.42)
566
compared with those with adequate body fat percent-
age. However, there were no differences in the other pa-
rameters measured (C-reactive protein, adiponectin,
and markers of liver function).10
Another study conducted in the province of
Navarra, Spain, investigated the relationship between
body fat percentage, insulin resistance, and prevalence of
diabetes in 4828 Spanish adults (3186 women) aged 18–
80 years.42 The sample comprised 587 individuals with
normal BMI, 1320 who were overweight, and 2921 who
were obese. The group with normal BMI and prediabetes
or type 2 diabetes had a higher percentage of body fat
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compared with normoglycemic individuals, a finding
consistent for both sexes (35.5 6 7.0% vs 30.3 6 7.7%
and 25.2 6 9.0% vs 19.9 6 8.0% for women and men, re-
spectively). It was noted that a high percentage of body
fat was also associated with inflammation and markers of
oxidative stress. The high levels of insulin secretion
found in individuals with NWO is probably a compensa-
tory response to reduced insulin sensitivity.42
Furthermore, it seems that hypoxia in adipose tis-
sue, found in individuals with excessive body fat, results
in increased production of reactive oxygen species and
activation of kinases. This induces the expression of
proinflammatory cytokines and insulin resistance. The
overproduction of reactive oxygen species can also re-
sult in mitochondrial dysfunction in liver and skeletal
muscle, which can cause lipid accumulation in these tis-
sues and contribute to the maintenance of insulin
resistance.19
Oxidative stress
Oxidative stress is characterized as an imbalance between
the production of reactive oxygen species and an organ-
ism’s antioxidant status and DNA damage repair capacity.
In addition to reactive oxygen species, reactive nitrogen
species and free radicals can also cause cell damage.43
Oxidative stress interferes with both pancreatic secretion
of insulin and glucose uptake by muscle and adipose tis-
sues. It also promotes damage to cell membranes, pro-
teins, and DNA. Thus, it is directly involved in increasing
the risk of developing noncommunicable diseases such as
cardiovascular disease and diabetes.44
Excessive body fat is usually associated with in-
creased secretion of cytokines by adipose tissue, which
may result in the production of reactive oxygen species.
Additionally, the excess of free fatty acids promotes a
greater accumulation of energy (as glucose and lipids),
with consequent increases in the oxidation of these sub-
strates and in the formation of free radicals. This entire
process, if not controlled, generates inflammatory and ox-
idative stress in the body.44 As a result, individuals with
NWO are likely to have higher levels of oxidative stress.
Nutrition ReviewsV Vol. 74(9):558–570
R
 Di Renzo et al.19 evaluated oxidative stress status in
60 Italian women classified into 3 groups: normal BMI,
NWO, and overweight/obesity. They reported that indi-
viduals with NWO, in addition to presenting a proin-
flammatory state, are exposed to higher oxidative stress
than those with an adequate body fat percentage. In this
study, body fat percentage was correlated with the for-
mation of lipid peroxides and lower glutathione levels.
The authors highlight lipid peroxidation as an indicator
of initial oxidative damage to cell membranes, lipopro-
teins, and other structures formed by lipids.
Additionally, individuals with NWO showed lower ni-
tric oxide concentrations and a reduced nonprotein an-
tioxidant capacity. These results were attributed to the
beginning of systemic oxidative stress.19 The authors
also suggest that inflammation and oxidative stress sta-
tus develop long before the symptoms of metabolic syn-
drome appear. Indeed, individuals with NWO are
usually not diagnosed with metabolic syndrome; how-
ever, as reported in the literature, the metabolic changes
observed in this population are important and should
be investigated. Finally, the authors highlight the need
to explore the genetic profile of individuals with NWO
in order to elucidate the mechanisms involved in the re-
lationship between body composition, inflammation,
oxidative stress, and other NWO-associated changes.19
NUTRIGENETICS AND NORMAL-WEIGHT
OBESITY SYNDROME
Nutritional genomics is the study of interactions be-
tween food components and the human genome, on
molecular, cellular, and systemic levels. It comprises
nutrigenomics, nutrigenetics, and nutritional epige-
nomics. Nutrigenomics investigates the effects of food
intake on the gene expression pattern. Nutritional epi-
genomics is the study of epigenetic mechanisms that
Table 2 Genetic polymorphisms associated with normal-weight obesity (NWO) syndrome
Reference SNP gene Genotype/
risk allele
Di Renzo et al. (2007)7 IL-1 receptor A2
antagonist
Di Renzo et al. (2006)11 MTHFR TT
IL-15Ra GG
Di Renzo et al. (2008)12 IL-6 GG
Di Renzo et al. (2013)13 TNF-a GG
Abbreviations: HOMA-IR, homeostasis model assessment of insulin resistance; IL-1, interleukin 1; IL-1b, interleukin 1b; IL-6, interleukin
6; IL-15Ra, interleukin 15 receptor a; MTHFR, methylenetetrahydrofolate reductase; SNP, single nucleotide polymorphism; TNF-a, tumor
necrosis factor a.
Nutrition ReviewsV Vol. 74(9):558–570
R
influence gene expression without promoting changes
in the DNA sequence. Nutrigenetics is the study of how
genetic variations may interfere with the interaction be-
tween diet and the development of diseases. Therefore,
studies of nutritional genomics aim to support the es-
tablishment of individualized nutritional recommenda-
tions and genetically personalized nutrition.45,46
The human genome presents highly complex varia-
tions. When these variations exist in at least 1% of the
population, they are classified as polymorphisms. The
most common genetic variations are the single nucleo-
tide polymorphisms (SNPs), characterized by changes
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in a single DNA nucleotide. There are common poly-
morphisms that occur in up to 50% of the population.
These genetic variations can either be silent and not
change gene expression, or they may result in the pro-
duction of altered proteins that can influence several
metabolic processes.47
Several studies have investigated the relationship
between genetic polymorphisms and the development
of NWO in an attempt to better understand NWO and
its associated health risks (Table 2).7,11–13
Di Renzo et al.7 investigated the frequency of the
variable-number tandem repeat polymorphism in the
IL-1 receptor antagonist gene, an anti-inflammatory cy-
tokine that competes with IL-1 for its cell receptors.
Polymorphisms in this gene have been linked to auto-
immune diseases, immune system disorders, atheroscle-
rosis, and gastric cancer, and individuals who carry the
A2 allele are at increased risk of developing these disor-
ders.7,48 The study in 110 Italian women revealed a sim-
ilar frequency of the A1 allele in all groups.7 The A2
allele was identified more frequently in the NWO
(12.5%) and overweight/obesity groups (17.5%) than in
the normal-BMI group (6.7%). The A3 and A4 alleles
were not found in any group and the A5 allele was ob-
served only in normal-weight and NWO subjects, but
Prevalence in Prevalence in Associated metabolic
NWO individuals control group alterations
12.5% 6.7% "IL-1b in NWO and over-
weight/obesity groups
4.2% 28.8% Not evaluated
14.3% 36.8%
59.0% 61.0% Increased IL-6 levels only in
NWO or obese individuals
NWO GG carriers had higher
HOMA-IR compared with
C-allele carriers
73.3% 76.5% Lean body mass was lower in
NWO group than in control
group
567
not in overweight and obese individuals. In the NWO
and overweight/obesity groups, A2 allele carriers had
higher levels of IL-1b compared with noncarriers. In
the normal-BMI group, there was no significant differ-
ence in IL-1b concentrations between A2 allele carriers
and noncarriers. No significant differences in IL-1a lev-
els between the groups were found.7
Another study in Italian women investigated the
presence of polymorphisms in the methylenetetrahy-
drofolate reductase gene in subjects with NWO.11
Methylenetetrahydrofolate reductase is a regulatory en-
zyme of the carbon cycle, and its activity is altered by
the C677T SNP (exchange of an alanine for a valine at
codon 222), which gives rise to a more labile protein
with reduced enzymatic function. Because of this
change, carriers of the variant allele (T) present lower
folate concentrations, higher homocysteine levels and,
hence, higher risk of developing noncommunicable dis-
eases. Di Renzo et al.,11 however, observed a lower fre-
quency of the variant homozygous genotype (TT) in the
NWO group (4.2%) than in the control group (28.8%).
The same study evaluated the presence of the SNP
rs3136618 (G/A) in the IL-15 receptor a (IL-15Ra) gene
in individuals with NWO. Interleukin 15 is a cytokine
involved in various inflammatory processes and appears
to interfere in the metabolic regulation of adipose and
muscle tissue by controlling the deposition of body fat
and acting anabolically in skeletal muscle. This relation-
ship might be due to the presence of IL-15Ra in adipose
tissue. Like the methylenetetrahydrofolate reductase
SNP, the variant homozygous genotype (GG) was less
frequent in the NWO group (14.3%) than in the control
group (36.8%). Thus, the authors reported an associa-
tion between the NWO phenotype and the presence of
wild alleles of methylenetetrahydrofolate reductase and
IL-1 receptor antagonist genes, indicating the need for
further studies to evaluate the frequency of these poly-
morphisms in subjects with NWO as well as the possi-
ble metabolic consequences.11
Di Renzo et al.13 evaluated the relationship between
the TNF-a G308A SNP and sarcopenia in subjects with
NWO. Sarcopenia is defined as the loss of muscle mass
associated with a decline in strength and physical per-
formance. Tumor necrosis factor-a, a cytokine involved
in chronic inflammation, is able to induce insulin resis-
tance, anorexia, and weight loss. Furthermore, TNF-a
appears to be involved in the metabolic regulation of
muscle tissue and in the communication between mus-
cle tissue and adipose tissue. Individuals with a high
body fat percentage tend to have higher TNF-a levels.
In this study, the genotype frequencies were 73.68% GG
and 26.32% GA. However, there was no significant dif-
ference in the frequency of these genotypes between the
NWO group and the control group. HOMA-IR and
568
TNF-a levels were similar in both the NWO group and
the normal-BMI/body fat percentage group. The GG
genotype was associated with the development of sarco-
penia only in the obese group. Among the GG carriers,
those with NWO had a lower amount of lean body
mass when compared with the control group.13
In another study, Di Renzo et al.12 evaluated the re-
lationship between the IL-6 174G/C SNP and the pro-
gression of insulin resistance in subjects with NWO.
Interleukin 6, a cytokine secreted by adipose tissue, has
proinflammatory and, in some cases, anti-inflammatory
roles. Polymorphisms in its gene appear to increase the
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risk of development of insulin resistance and type 2 dia-
betes. In this study in 150 Italian women, the genotype
distribution (GG/GC/CC) was similar between groups
(NWO subjects and controls). Individuals with NWO
showed higher IL-6 levels than those with normal BMI
and adequate body fat percentage. When the groups
were separated according to genotype, the GG genotype
was associated with increased IL-6 levels only in NWO
or obese individuals. In the group with normal BMI
and adequate body fat percentage, IL-6 levels were not
different between genotypes. The authors reported a
positive correlation between IL-6 concentrations and
body fat percentage in GG carriers, while this correla-
tion was negative in CC carriers. The authors also
showed that the presence of one or two C alleles pro-
vides protection against insulin resistance, which may
be related to the lower IL-6 secretion in these individ-
uals. Regarding HOMA-IR, there were no differences
attributed to the genotype in the control group; how-
ever, among subjects with NWO, GG carriers had
higher HOMA-IR than the C-allele carriers.12
The studies described here indicate that individuals
with NWO may present unique characteristics with re-
gard to the presence of genetic polymorphisms and
their relation to health. Further studies can help identify
the risk markers that determine the vulnerability of
these individuals to the development of disease.
CONCLUSION
Normal-weight obesity is a metabolic condition recently
described and widely studied in order to evaluate its as-
sociation with the risk of disease development.
However, affected individuals are seldom identified
through routine healthcare because of the limited obe-
sity classification, which is based solely on anthropo-
metric parameters (BMI). Accurate diagnosis of NWO
is paramount, as there is sufficient scientific evidence
linking excessive body fat to a higher risk of cardiovas-
cular mortality and other associated health conditions.
Although most studies evaluate only women, and
some present controversial results, many of them have
Nutrition ReviewsV Vol. 74(9):558–570
R
pointed to clear health risks for individuals with NWO.
Further epidemiological studies on NWO are needed in
order to refine the diagnostic criteria for different popu-
lations. Such research would help healthcare providers
to evaluate individuals with NWO and to counsel them
about preventive care and early treatment.
Acknowledgments
The authors thank André Hedlund for reviewing the
English of the manuscript.
Author contributions. L.P.F. and C.C.M drafted the
manuscript. C.C. provided supervision and critical revi-
sion of the manuscript. All authors contributed to and
approved the final version of the manuscript.
Funding/support. Master’s (L.P.F.) and doctoral (C.C.M.)
students receive scholarships from the Brazilian funding
agency “Coordenaç~ao de Aperfeiçoamento de Pessoal de
Nıvel Superior.” No specific funding was received for
writing this review.
Declaration of interest. The authors have no relevant
interests to declare.
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