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Normal Weight Obesity Is Associated with Metabolic
Syndrome and Insulin Resistance in Young Adults from a
Middle-Income Country
Francilene B. Madeira1, Antônio A. Silva2*, Helma F. Veloso2, Marcelo Z. Goldani3, Gilberto Kac4,

Viviane C. Cardoso5, Heloisa Bettiol5, Marco A. Barbieri5

1 Physical Education Undergraduate Course, State University of Piauı́, Teresina, Brazil, 2 Department of Public Health, Federal University of Maranhão, São Luı́s, Brazil,

3 Department of Pediatrics and Puericulture, Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil, 4 Department of Social and Applied

Nutrition, Josué de Castro Nutrition Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, 5 Department of Puericulture and Pediatrics, Faculty of Medicine of

Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

Abstract

Objective: This population-based birth cohort study examined whether normal weight obesity is associated with metabolic
disorders in young adults in a middle-income country undergoing rapid nutrition transition.

Design and Methods: The sample involved 1,222 males and females from the 1978/79 Ribeirão Preto birth cohort, Brazil,
aged 23–25 years. NWO was defined as body mass index (BMI) within the normal range (18.5–24.9 kg/m2) and the sum of
subscapular and triceps skinfolds above the sex-specific 90th percentiles of the study sample. It was also defined as normal
BMI and % BF (body fat) .23% in men and .30% in women. Insulin resistance (IR), insulin sensitivity and secretion were
based on the Homeostasis Model Assessment (HOMA) model.

Results: In logistic models, after adjusting for age, sex and skin colour, NWO was significantly associated with Metabolic
Syndrome (MS) according to the Joint Interim Statement (JIS) definition (Odds Ratio OR = 6.83; 95% Confidence Interval CI
2.84–16.47). NWO was also associated with HOMA2-IR (OR = 3.81; 95%CI 1.57–9.28), low insulin sensitivity (OR = 3.89; 95%CI
2.39–6.33), and high insulin secretion (OR = 2.17; 95%CI 1.24–3.80). Significant associations between NWO and some
components of the MS were also detected: high waist circumference (OR = 8.46; 95%CI 5.09–14.04), low High Density
Lipoprotein cholesterol (OR = 1.65; 95%CI 1.11–2.47) and high triglyceride levels (OR = 1.93; 95%CI 1.02–3.64). Most
estimates changed little after further adjustment for early and adult life variables.

Conclusions: NWO was associated with MS and IR, suggesting that clinical assessment of excess body fat in normal-BMI
individuals should begin early in life even in middle-income

countries.

Citation: Madeira FB, Silva AA, Veloso HF, Goldani MZ, Kac G, et al. (2013) Normal Weight Obesity Is Associated with Metabolic Syndrome and Insulin Resistance
in Young Adults from a Middle-Income Country. PLoS ONE 8(3): e60673. doi:10.1371/journal.pone.0060673

Editor: Reury F.P Bacurau, University of São Paulo, Brazil

Received November 23, 2012; Accepted March 1, 2013; Published March 28, 2013

Copyright: � 2013 Madeira et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This study was supported by the Brazilian Research Council (CNPq, Brazilian acronym), the University of São Paulo and the São Paulo Research
Foundation (FAPESP, Brazilian acronym) grant number 00/09508-7. The funders had no role in study design, data collection and analysis, decision to publish, or
preparation of the manuscript.

Competing Interests: The authors have declared that no competing interest exists.

* E-mail: aasilva@ufma.br

Introduction

The prevalence of obesity (Body Mass Index – BMI $30 kg/m
2
)

has increased worldwide over the past decades [1,2], although

more recent data suggest a slowing or levelling off of this trend [3].

In Brazil, from 1974–1975 to 2008–2009, the prevalence rates of

obesity increased more than fourfold among men (2.8% to 12.4%)

and more than twofold among women (from 8.0% to 16.9%) [4].

Obesity, defined as excess body fat (BF) [5,6], has been

evaluated in both clinical and epidemiological studies, using

predominantly BMI [7,8]. Studies have shown an association

between extreme values of BMI and increased mortality [9,10].

However, because BMI does not differentiate lean from fat mass,

this indicator has limited accuracy for diagnosing individuals with

excess BF presenting BMI within the normal range [11–13].

In the early eighties, Ruderman et al. described a specific type of

obesity defined as metabolically obese normal weight subjects

(MONW). These individuals were characterized by normal body

weight and BMI, but presented hyperinsulinemia, insulin-

resistance, and increased type 2 diabetes, hypertriglyceridemia

and cardiovascular diseases predisposition [14,15]. Few years later,

De Lorenzo et al. [16] among other authors [17,18] used the term

normal weight obesity (NWO) to identify individuals who have

normal body weight and BMI but high % BF, accompanied by

total lean mass deficiency. Therefore, MONW is a subset of NWO

and from a conceptual and clinical perspective it is important to

differentiate these two conditions.

Some other studies have reported associations between NWO

and metabolic disorders [16,18–27]. In a study of the US

population, individuals aged .20 years with NWO were four

PLOS ONE | www.plosone.org 1 March 2013 | Volume 8 | Issue 3 | e60673

times more likely to develop metabolic syndrome (MS) than those

with normal BMI and normal BF [18]. In another study carried

out in Switzerland, which included only females of Caucasian

origin aged 35–75 years, women with NWO had a higher

cardiometabolic risk and higher prevalences of low high-density

lipoprotein (HDL) cholesterol, high waist circumference (WC),

high triglycerides and hyperglycaemia but a similar prevalence of

hypertension compared to lean women [20].

However, to our knowledge, there are few studies reporting an

association between NWO and metabolic disorders exclusively in

young adults or coming from low and middle-income countries

[28–30]. Studies in young populations are important because if

NWO is associated with metabolic imbalances at an early age,

clinical evaluation should change and preventive public policy

actions should be redrawn and begin earlier in order to limit

complications, as NWO individuals get older [6,15,31].

The objective of the present study was to evaluate the

association between NWO and MS and insulin resistance (IR) in

young adults from a population-based birth cohort performed in a

middle-income country undergoing rapid nutrition transition, with

adjustment for several early and adult life variables.

Methods

Ethics Statement
The project was approved by the Research Ethics Committee of

the Clinics Hospital, Faculty of Medicine of Ribeirão Preto,

University of São Paulo, Brazil. All participants signed an

informed consent form.

Study design and participants
Data were abstracted from the first Ribeirão Preto birth cohort

study, Brazil, which started in 1978/79. Data were obtained at

birth and at young adult age (23–25 years)

[32].

A total of 9067 liveborn infants, delivered at the eight maternity

hospitals of Ribeirão Preto, from June 1st 1978 to May 31, 1979

(corresponding to 98% of all live births), participated in this study.

Losses due to refusal or early discharge amounted to 3.5%. All

infants whose families did not reside in the city (2094) and twins

(146) were excluded, leaving a total of 6827 live births [33].

From the original cohort of 6827 singleton liveborns, 343

participants were found to be deceased and 819 could not be

traced, leaving 5665 singletons. One in three subjects belonging to

the same geographic area was invited for medical examination.

The first of every three names was selected from a list sorted by

birth date in each geographic region and, if unavailable, the next

name down was selected. In this traced group, losses to follow-up

(N = 705) occurred because of refusal to participate, imprison-

ment, death after 20 years of age, or failure to attend the interview.

Losses were replaced using the same sampling frame, resulting in

2,063 young adults (1,068 females) [32]. For this study, only

subjects with normal BMI (18.5 to 24.9 kg/m
2
)[6] were included,

comprising a total of 1,222 young adults. Details of the

methodology have been published elsewhere [32,33].

Variables and data collection
At the time of their children’s birth, the mothers answered a

standardized questionnaire. Maternal schooling (#4, 5 to 8, 9 to

11, $12 years), parity (1, 2 to 4, $5), type of delivery (vaginal,

caesarean) and maternal smoking during pregnancy (yes, regard-

less of the number of cigarettes smoked, and no) were abstracted

from this questionnaire. Birth weight was measured within 30

minutes of birth. Newborns were weighed naked on weekly

calibrated mechanical scales with 10-g precision (Filizola, São

Paulo, Brazil). Gestational age at birth in complete weeks was

derived from the last normal menstrual period reported by the

mother.

Participants answered a questionnaire containing information

on socioeconomic, demographic and behavioural variables, and

underwent physical examination when they were 23–25 years of

age. The variables collected in adulthood were: age, sex, self-

reported skin colour (classified as white/non-white), family income

measured in minimum wages and classified into three categories

(,5, 5 to 9.9 and $10), schooling in years (#8, 9 to 11 and $12),

marital status (single, cohabiting), smoking (yes, regardless of the

number of cigarettes smoked and no), alcohol consumption in

grams per day (none, #31 and .31), percentage of fat in the diet

(measured with a food-frequency questionnaire and derived from

equations using the Dietsys software, version 4.0 (National Cancer

Institute, Bethesda, MD, USA) [34] and physical activity

(sedentary, sufficiently active and active), according to the

International Physical Activity Questionnaire (IPAQ) guidelines

[35,36]. A missing category was added to the family income

variable because 91 participants did not report their income.

Anthropometric measurements were taken by physicians or

trained nurses with individuals wearing light clothing and no

shoes, using a standard protocol [37]. Weight was measured to the

nearest 100 g using mechanical scales (Filizola, São Paulo, Brazil).

Height was measured to the nearest 0.1 cm using a freestanding

wood stadiometer (University of São Paulo, Ribeirão Preto,

Brazil). BMI was calculated as weight in kilograms divided by

height in meters squared (kg/m
2
). A D-loop non-stretch fiberglass

tape was used for WC and hip circumference (HC) measures. WC

was measured as the smallest circumference between the ribs and

the iliac crest while the participant was standing with the abdomen

relaxed, at the end of a normal expiration. Where there was no

natural waistline, the measurement was taken at the level of the

umbilicus. HC was measured at the maximum circumference

between the iliac crest and the crotch while the participant was

standing. The triceps and subscapular skinfolds were measured

with the Lange adipometer (Beta Technology, Santa Cruz, CA,

USA), following Lohman’s protocol [37]. Acceptable inter- and

intra-observer agreement was achieved. For blood pressure

measurements we used an Omron digital sphygmomanometer

model 740 (Omron Healthcare, Lake Forest, IL, US), with 15-

minute intervals between measurements, with the participants

seated. This procedure was performed three times and the average

of the last two measurements was used.

A 40 ml blood sample was collected from the subject after a

12 hour fast by a trained technician. Fasting blood glucose was

measured by the GOD/PAP human diagnostic enzymatic

calorimetric method (Chronolab AG, Zug, Germany) with a

coefficient of variation of 4.2%. Low density lipoprotein (LDL)

cholesterol, HDL-cholesterol and triglycerides were determined by

an enzymatic calorimetric method using the Dade Behring XPand

apparatus (Dade Behring, Liederbach, Germany) and reagents of

Dade Behring Dimension clinical chemistry. Fasting insulin was

measured by radioimmunoassay (insulin kit, DPC, Los Angeles,

CA, USA) with a coefficient of variation of 7.9% [38].

MS was defined according to the Joint Interim Statement (JIS)

of the IDF Task Force on Epidemiology and Prevention, National

Heart, Lung and Blood Institute, American Heart Association,

World Heart Federation, International Atherosclerosis Society and

International Association for the Study of Obesity. The JIS

criterion requires the presence of any three of the following: 1)

central obesity (WC $90 cm for men and $80 cm for women,

cut-off points used for South American populations); 2) increased

triglycerides $150 mg/dL, use of lipid medications or self-

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reported diagnosis of hypertriglyceridemia; 3) low HDL-choles-

terol (,40 mg/dL for men and ,50 mg/dL for women); 4)

increased blood pressure (BP) (systolic pressure $130 mmHg and/

or diastolic pressure $85 mmHg, current usage of antihyperten-

sive drugs or previous diagnosis of hypertension); and 5) high

fasting blood glucose ($100 mg/dL), current use of anti-diabetic

medication or previously diagnosed diabetes [39].

IR was evaluated by the Homeostasis Model Assessment index

[40]. HOMA2 insulin resistance, HOMA2 insulin sensitivity (the

opposite of insulin resistance) and insulin secretor activity

(HOMA2 b cell function) were determined using the HOMA2
computer model, which uses correctly solved nonlinear solutions

(available from http://www.dtu.ox.ac.uk/index.php?maindocZ/

homa/) and takes into account variations in hepatic and

peripheral glucose resistance, increases in the insulin secretion

curve for plasma glucose concentrations above 10 mmol/L

(180 mg/dL) and the contribution of circulating proinsulin [41].

The cut-off proposed by the Brazilian Metabolic Syndrome Study

(BRAMS) were used for the diagnosis of HOMA2-IR (.1.8) [42].

Since there were no cut-offs described for the Brazilian population,

HOMA2 insulin sensitivity was considered to be low when ,10
th

percentile and HOMA2 b cell function was considered to be high
if .90

th
percentile of the study sample distribution.

The subjects whose BMI was 18.5 to 24.9 kg/m
2

and whose

sum of triceps and subscapular skinfolds was .90
th

percentile of

the study sample for each sex were classified as NWO,

corresponding to .23.1% BF in men and .33.3% BF in women.

We also defined NWO as a normal BMI and % BF .23% in men

and .30% in women, using Slaughter’s equations (derived for

adolescents 8–18 years) from the sum of triceps and subscapular

skinfolds [43].

Statistical analysis
Statistical analysis was performed using the statistical package

Stata version 12.0. Mean 6 standard deviation or the 1st quartile,

median and the 3rd quartile were presented when appropriate.

Differences in mean values of demographic, dietetic, anthropo-

metric and metabolic parameters according to the presence or

absence of NWO were tested by the Student t-test when variables

had a normal distribution or by the Mann-Whitney non-

parametric test otherwise. Statistical differences in categorical

variables according to NWO were evaluated using the chi-square

test. Subsequently, we fitted logistic regression models, using

NWO as the explanatory variable and separate models for each

response variable – MS, its components (high WC, low HDL-

cholesterol, high triglycerides, high blood pressure and high blood

glucose), insulin resistance, insulin sensitivity, and b cell function.
Three sequential models were presented: model 1 (adjusted for

age, sex and skin colour), model 2 (adjusted for age, sex, skin

colour and early life variables – birth weight, gestational age at

birth, maternal schooling, parity, type of delivery and maternal

smoking during pregnancy) and model 3 (adjusted for age, sex,

skin colour, early and adult life variables (alcohol consumption,

family income, schooling, marital status, smoking, percentage of

fat in the diet and physical activity). Additional models were also

further adjusted for WC to verify if associations between NWO

and low HDL-cholesterol, high triglycerides, high blood pressure,

high blood glucose, insulin resistance, low insulin sensitivity and

high insulin secretion were independent from measures of central

obesity. The models were not stratified by sex because no

significant interactions between NWO and sex on MS or IR were

detected. Odds ratios (OR) and their 95% confidence intervals

(CI) were estimated.

Results

The prevalence of MS according to the JIS definition was 3.1%

(95%CI 1.8%–4.9%) for males and 0.9% (95%CI 0.3%–1.9%) for

females. The prevalence of HOMA2-IR was 2.0% (95%CI 1.0%–

3.6%) for men and 2.6% (95%CI 1.5%–4.1%) for women. The

prevalence of MS was higher for males than for females (3.1% vs.

0.9%, P = 0.004). Low HDL-cholesterol was significantly higher

among women (38.0%) than men (31.2%), whereas high blood

pressure was much higher among men (28.9%) than women

(3.3%). High blood glucose was also higher among men (4.4%)

than women (1.7%). IR, high WC and triglycerides did not differ

by sex (Table 1).

Table 1. Prevalences of metabolic syndrome, its components
and insulin resistance by sex among young adults with body
mass index within the normal range, 1978/79 Ribeirão Preto
birth cohort.

Variables Males (n = 546) Females (n = 676)

n % n %

Metabolic
Syndrome – JISb

0.004

No 529 96.9 670 99.1

Yes 17 3.1 6 0.9

Waist
circumference

c
0.852

Normal 509 93.2 632 93.5

High 37 6.8 44 6.5

HDL-cholesterol
d

0.014

Normal 373 68.8 413 62.0

Low 169 31.2 253 38.0

Triglycerides
e

0.439

Normal 509 93.9 618 92.8

High 33 6.1 48 7.2

Blood pressuref ,0.001

Normal 388 71.1 654 96.8

High 158 28.9 22 3.3

Blood Glucoseg 0.004

Normal 520 95.6 656 98.4

High 24 4.4 11 1.7

HOMA2-IRh 0.539

#1.8 528 98.0 642 97.4

.1.8 11 2.0 17 2.6

Abbreviations: HDL, High Density Lipoprotein; HOMA, Homeostasis Model
Assessment; IR, Insulin Resistance.

a
P value calculated by the chi-square test.

b
defined according to the Joint Interim Statement (JIS) of the IDF Task Force on

Epidemiology and Prevention, National Heart, Lung and Blood Institute,
American Heart Association, World Heart Federation, International
Atherosclerosis Society and International Association for the Study of Obesity.
c
waist circumference ($90 cm for men and $80 cm for women).

d
increased

triglycerides ($150 mg/dL, use of lipid medications or self-reported diagnosis
of hypertriglyceridemia). elow HDL-cholesterol (,40 mg/dL for men and
,50 mg/dL for women).

f
increased blood pressure (BP) (systolic pressure

$130 mmHg and/or diastolic pressure $85 mmHg, current usage of
antihypertensive drugs or previous diagnosis of hypertension). ghigh fasting
blood glucose ($100 mg/dL), current use of anti-diabetic medication or
previously diagnosed diabetes.

h
Cut-off point based on the Brazilian Metabolic

Syndrome Study – BRAMS criterion (2009). Numbers may not add up to total
because of missing values.
doi:10.1371/journal.pone.0060673.t001

Normal Weight Obesity and Metabolic Disorders

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Subjects with NWO did not differ from those without NWO

according to early life variables (Table 2). Subjects with NWO did

not differ by sex, age, family income, schooling, marital status,

smoking or alcohol consumption compared to those without

NWO. Individuals of white skin colour (10.5% vs. 6.2%,

P = 0.013) and with a sedentary life style (10.8% vs. 5.3%,

P = 0.010) presented a higher prevalence of NWO than their

counterparts. Mean percentage of fat in the diet was higher among

NWO subjects than among their peers without NWO (Table 3).

Subjects with NWO presented higher mean values of BMI,

WC, hip circumference, waist to hip ratio, LDL-cholesterol,

triglycerides, diastolic blood pressure, subscapular and triceps

skinfolds, blood glucose, HOMA2-IR and insulin secretion, and

lower values of insulin sensitivity than those without NWO. There

were no differences in mean systolic blood pressure. HDL-

cholesterol was lower among men with NWO compared to their

counterparts but there were no differences among women

(Table 4).

NWO was significantly associated with MS according to the JIS

definition (OR = 6.83; 95%CI 2.84-16.47, P,0.001). NWO was

also significantly associated with HOMA2-IR (OR = 3.81; 95%CI

1.57-9.28, P = 0.003), low insulin sensitivity (OR = 3.89; 95%CI

2.39-6.33, P,0.001), and high insulin secretion (OR = 2.17;

95%CI 1.24-3.80, P = 0.007). Significant associations between

NWO and some components of MS were also detected: high WC

(OR = 8.46; 95%CI 5.09-14.04, P,0.001), low HDL-cholesterol

(OR = 1.65; 95% 1.11-2.47, P = 0.014) and high triglycerides

(OR = 1.93; 95% 1.02-3.64, P = 0.042). Most estimates changed

little after adjustment for early and adult life variables: the

associations of NWO with low HDL-cholesterol and high

triglycerides lost statistical significance and the association of

NWO with high blood glucose became statistically significant.

After further adjustment for WC, associations of NWO with high

blood glucose and high insulin secretion were no longer significant

whereas associations of NWO with HOMA2-IR and insulin

sensitivity nearly halved but continued to be significant (Table 5).

Table 6 presents models using % BF .23% for men and .30%

for women to define NWO. NWO was consistently associated with

MS, IR, insulin sensitivity and secretion in all adjusted models.

Discussion

In our study, NWO, defined by the combination of excess BF

(sum of triceps and subscapular skinfolds .P90 of the study

sample) and normal BMI was associated with MS according to the

JIS definition (OR = 6.83), HOMA2-IR (OR = 3.81), low insulin

sensitivity (OR = 3.89) and high insulin secretion (OR = 2.17) in

young adults (23–25 years) from Brazil, a middle-income country.

Adjustment for early and adult life variables did not change the

estimates appreciably. When we defined NWO as normal BMI

and % BF.23% for men and .30 for women results were

consistent. Our data suggest that counting only on BMI to identify

subjects who are at risk of metabolic disorders later in life may fail

to identify an important fraction of the population who, despite

having a normal BMI, present excess BF and are also at high risk

of metabolic imbalances. It seems that, together with the epidemic

of high-BMI obesity [3], there is a normal-BMI obesity epidemic

that begins at a young age and is also evident in middle-income

countries.

Our study showed that NWO is associated with a high risk of

having MS at an early adult age. A 2004 US study also reported

that NWO individuals were at increased risk of having MS [21]. A

more recent study, carried out in the US using data from the

Third National Health and Nutrition Examination Survey

(NHANES III), including adults .20 years, showed that NWO

was associated with a four-fold increase in the prevalence of MS

Table 2. Normal weight obesity according to early life variables, 1978/79 Ribeirão Preto birth cohort.

Variables Normal weight obesity
a

No (n = 1111) n (%) Yes (n = 111) n (%)

Maternal schooling (years) 0.786
b

#4 484 (91.7) 44 (8.3)

5 to 8 284 (90.5) 30 (9.5)

9 to 11 189 (90.9) 19 (9.1)

$12 130 (89.0) 16 (11.0)

Maternal parity 0.101b

1 405 (88.6) 52 (11.4)

2 to 4 595 (92.3) 50 (7.8)

$5 87 (92.5) 7 (7.5)

Type of delivery 0.521
b

Vaginal 768 (90.6) 80 (9.4)

Cesarean 343 (91.7) 31 (8.3)

Maternal smoking during pregnancy 0.384
b

No 819 (91.3) 78 (8.7)

Yes 268 (89.6) 31 (10.4)

Birth weight (grams) 32386500
c

32996436
c

0.220
d

Gestational age at birth (weeks) 39.061.8
c

39.361.3
c

0.071
d

a
Normal weight obesity defined as a BMI from 18.5 to 24.9 kg/m

2
and the sum of triceps and subscapular skinfolds .90

th
percentile of the study sample for each sex.

b
P

values calculated by the chi-square test. cValues are mean 6 standard deviation. dP values calculated by the Student t-test. Numbers may not add up to total because of
missing values.
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(16.6% vs. 4.8%) [18]. Our study has some different characteristics

compared to that investigation. It is important to note that we

measured BF by means of the sum of triceps and subscapular

skinfolds, whereas in the American study BF was measured by

bioelectrical impedance. Also the criterion for categorization of

excess BF differed: we considered those above the sex-specific 90
th

percentile of the sum of skinfolds as presenting excess BF while in

the US study excess BF was defined by the highest sex-specific

tertiles of BF percentage. The US study included subjects .20

years old whereas in our study only young adults, aged 23–25

years were included. For the diagnosis of MS the updated NCEP-

ATPIII definition was used in the American study [18], whereas in

our study we used the new JIS definition. These factors may

explain the differences in risk estimates between NWO and MS in

the two studies.

We used the JIS definition because it reflects the new emerged

consensus to define MS. Furthermore, because our study sample

only included young adults more stringent criteria for identifica-

tion of central obesity would be more appropriate to detect

metabolic disorders earlier [44]. Furthermore, the use of lower

cut-off points increases the power to detect statistically significant

differences in case they exist, while sensitivity increases albeit

specificity decreases.

Our study also showed that NWO was associated with an

increased risk of presenting high WC (OR = 8.46), high triglycer-

ides (OR = 1.93), and low HDL-cholesterol (OR = 1.65) in young

adults. However, no association was observed between NWO and

high blood pressure or high blood glucose, although the latter was

associated with NWO in the fully adjusted model. The US

population-based study, which included a sample of males and

females for a total of 6,171 subjects, also showed a significant

association between NWO and higher risk of dysregulation of the

components of MS (central obesity, high triglycerides, low HDL-

cholesterol, high blood pressure and high fasting plasma glucose)

Table 3. Normal weight obesity according to adult life variables, 1978/79 Ribeirão Preto birth cohort.

Variables Normal weight obesity
a
P

No (n = 1,111) n (%) Yes (n = 111) n (%)

Age 23.960.71b 24.060.68b 0.485c

Sex 0.935
d

Male 496 (90.8) 50 (9.2)

Female 615 (91.0) 61 (9.0)

Skin colour 0.013
d

White 731 (89.5) 86 (10.5)

Non-white 380 (93.8) 25 (6.2)

Family income (minimum wages) 0.563
d

,5 329 (90.1) 36 (9.9)

5 to 9.9 345 (89.9) 39 (10.1)

$10 353 (92.4) 29 (7.6)

Missing 84 (92.3) 7 (7.7)

Schooling (years) 0.303d

#8 152 (92.1) 13 (7.9)

9 to 11 551 (91.8) 49 (8.2)

$12 408 (89.3) 49 (10.7)

Marital Status 0.307
d

Single 792 (91.5) 74 (8.5)

Cohabiting 319 (89.6) 37 (10.4)

Smoking 0.065
d

No 927 (90.3) 100 (9.7)

Yes 185 (94.4) 11 (5.6)

Physical activity 0.010
d

Sedentary 544 (89.2) 66 (10.8)

Sufficiently active 220 (89.4) 26 (10.6)

Active 342 (94.7) 19 (5.3)

Alcohol consumption (g/day) 0.723d

None 296 (90.2) 32 (9.8)

#31 595 (90.7) 61 (9.3)

.31 212 (92.2) 18 (7.8)

Percentage of fat in the diet 35.865.6
b

37.565.4
b

0.002
c

a
Normal weight obesity defined as a BMI from 18.5 to 24.9 kg/m
2
and the sum of triceps and subscapular skinfolds .90
th
percentile of the study sample for each sex.

b
Values are mean 6 standard deviation.

c
P values calculated by the Student t-test.

d
P values calculated by the chi-square test.

doi:10.1371/journal.pone.0060673.t003

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[18]. Another study, carried out in Switzerland, which included

women only, also showed that NWO was associated with

abnormalities in the components of MS [20]. In contrast to the

American [18] and the Swiss study [20], our study did not observe

an association between NWO and high blood pressure. This could

be due to the much younger age of our sample.

Young adults with NWO showed a higher prevalence of IR, as

measured by the HOMA-2 model, than those without NWO

(OR = 3.81). NWO was also associated with increased IR and low

insulin sensitivity. The reduced sensitivity to insulin has been a

feature found in subjects with NWO [15,18,45]. We also found, in

agreement with the American study [18], that increased b cell
function was detected among individuals with NWO. Possibly the

high insulin secretion is a compensatory response to the reduced

insulin sensitivity found in individuals with NWO [46]. Associa-

tions between NWO with HOMA2-IR and insulin sensitivity were

not totally explained by central obesity because after further

adjustment for WC, these associations nearly halved although

continued to be significant.

Another recent study, which measured BF with air displacement

plethysmography, although not using clinical cut-off points to

assess metabolic dysregulation, also reported that non-obese

subjects by the BMI criterion but obese by % BF had higher

values of WC, blood pressure, triglycerides, glucose, insulin,

HOMA and lower values of HDL-cholesterol compared to those

with normal BMI and non-obese based on % BF [23].

Strengths and limitations
We consider the strength of this study to be the fact that it is a

population-based cohort study, conducted in a sample of young

adults. Adjustment was performed for several adult life variables.

In addition, this study incorporates early life factors that have been

implicated in the pathogenesis of obesity and IR. These facts

allowed us to estimate the association between excess BF and

metabolic disorders at an early adult age in subjects with BMI in

the normal range in a middle-income country that is undergoing

rapid nutrition transition [47]. The narrow age group (from 23 to

25 years of age) shall not be considered a limitation but a

particular strength because it eliminates the confounding effect of

age and many other age-dependent covariates that may have

affected the analysis. Standardized methods were used to assess IR

and measurements of body weight, skinfolds, lipids and others.

A potential limitation of our study is related to the method of

categorization of excess BF. The sum of subscapular and triceps

skinfolds above the sex-specific 90
th

percentiles of the study sample

was used as a proxy for estimating excess BF. It is an arbitrary cut-

off, and a definition of NWO different from those used in other

studies [18–20,23]. However, results using % BF .23% in men

and .30% in women produced consistent results regarding MS

and IR. Furthermore, agreement between these two definitions of

NWO (.90
th

of the sum of triceps and subscapular skinfolds and

high percent body fat estimated by Slaughter’s formula-based

equation) was high (kappa = 0.879). Although using three or more

Table 4. Normal weight obesity according to anthropometric and metabolic parameters, 1978/79 Ribeirão Preto birth cohort.

Variables Normal weight obesity
a
P

No (n = 1,111) Yes (n = 111)

Body mass index (kg/m2) 21.761.7b 23.661.1b , 0.001c

Waist circumference (cm)

Males 80.465.3
b

87.664.9
b

, 0.001
c

Females 71.564.7b 77.264.5b , 0.001c

Hip circumference (cm) 96.864.9
b

101.164.5
b

, 0.001
c

Waist to hip ratio (cm)

Males 0.8360.04b 0.8660.05b , 0.001c

Females 0.7460.05
b

0.7760.05
b

, 0.001
c

High density lipoprotein (mg/dL)

Males 46.2611.0b 42.869.8b 0.033c

Females 54.6613.1
b

51.6612.1
b

0.092
c

Low density lipoprotein (mg/dL) 91 (76–110)
d

104 (88–129)
d

, 0.001
e

Triglycerides (mg/dL) 69 (52–95)d 89 (64–117)d , 0.001e

Systolic blood pressure (mmHg)

115613
b

0.851
c

Diastolic blood pressure (mmHg) 6868
b

7067
b

0.008
c

Subscapular skinfold (mm) 12.763.3b 20.963.5b , 0.001c

Triceps skinfold (mm) 11.764.6
b

18.964.6
b

, 0.001
c

Sum of triceps and subscapular skinfolds (mm) 24.366.9
b

39.866.4
b

, 0.001
c

Blood glucose (mg/dL) 81 (77–87)d 87 (80–91)d , 0.001e

HOMA-2 insulin resistance 0.54 (0.36–0.87)
d

0.77 (0.49–1.22)
d

, 0.001
e

HOMA-2 insulin sensitivity 185.7 (115.3–275.5)
d

129.1 (81.8–203.1)
d

, 0.001
e

HOMA-2 b cell function 78.3 (58.0–106.6)d 90.9 (65.4–130.1)d 0.002e

Abbreviations: HOMA, Homeostasis Model Assessment.
a

Normal weight obesity defined as a BMI from 18.5 to 24.9 kg/m
2

and the sum of triceps and subscapular
skinfolds .90

th
percentile of the study sample for each sex.
b
Values are mean 6 standard deviation.
c
P values calculated by the Student t-test.

d
Values are median (1st

quartile – 3rd quartile). eP values calculated by the Mann-Whitney non-parametric test.
doi:10.1371/journal.pone.0060673.t004

Normal Weight Obesity and Metabolic Disorders

PLOS ONE | www.plosone.org 6 March 2013 | Volume 8 | Issue 3 | e60673

measures of skinfold thickness is a validated method to estimate %

BF [48,49], measures of other skinfolds were not available in our

database to estimate % BF in adults. We thus estimated % BF

using the Slaughter’s equations based on the sum of two skinfolds

(triceps and subscapular). It is important to note that our sample is

composed of young adults aged 23/25 years and the Slaughter’s

equations were derived for adolescents. We used these equations

assuming that % BF would have changed little from 18 to 23/25

years of age. We did not find any other suitable equation to

estimate % BF from the sum of triceps and subscapular skinfolds

for young adults.

However, the use of subscapular and triceps skinfolds provides a

valid indication of excess fat in young people [31]. Selective losses

have occurred comparing subjects followed up with those not

followed up. Follow-up rates were slightly higher for women, those

born preterm, those from better-off families and those whose

mothers smoked or were married at the time of the participant’s

birth. Although statistically significant, these differences were small

[32].

Consequences
These results suggest important questions about the isolated use

of BMI to assess obesity. After all, having a normal BMI does not

Table 5. Associations between normal weight obesity defined as the sum of the triceps and subscapular skinfolds .90th

percentile with metabolic syndrome and its components and insulin resistance, insulin sensitivity and b cell function, 1978/79
Ribeirão Preto birth cohort.

Normal
weight
obesity %

Model 1
a

OR
(95% CI) P

e
Model 2

b
OR

(95% CI) P
e

Model 3
c

OR
(95% CI) P

e
Model 4

d
OR

(95% CI) P
e

Metabolic Syndrome – JIS
f

No 1.3 1 1 1

Yes 8.1 6.83 (2.84–16.47) ,0.001 7.22 (2.92–17.85) ,0.001 8.89 (3.32–4.47) ,0.001

High waist circumferenceg

No 4.4 1 1 1

Yes 28.8 8.46 (5.09–14.04) ,0.001 8.37 (5.01–13.99) ,0.001 9.27 (5.32–16.15) ,0.001

Low High Density Lipoproteinh

No 33.9 1 1 1 1

Yes 45.0 1.65 (1.11–2.47) 0.014 1.55 (1.02–2.33) 0.038 1.53 (1.00–2.34) 0.053 1.09 (0.69–1.72) 0.721

High triglyceridesi

No 6.2 1 1 1 1

Yes 11.9 1.93 (1.02–3.64) 0.042 1.91 (1.01–3.63) 0.048 1.89 (0.97–3.70) 0.062 1.18 (0.57–2.45) 0.649

High blood pressurej

No 14.6 1 1 1 1

Yes 16.2 1.11 (0.62–1.97) 0.729 1.19 (0.66–2.13) 0.565 1.17 (0.65–2.13) 0.598 0.87 (0.46–1.67) 0.680

High blood glucosek

No 2.6 1 1 1 1

Yes 5.5 2.10 (0.84–5.23) 0.110 2.24 (0.89–5.69) 0.089 2.68 (1.01–7.12) 0.048 1.60 (0.54–4.76) 0.395

HOMA2- Insulin resistancel

No 1.9 1 1 1 1

Yes 6.5 3.81 (1.57–9.28) 0.003 4.01 (1.63–9.87) 0.003 4.91 (1.85–13.04) 0.001 2.94 (1.00–8.68) 0.005

Low HOMA2- Insulin sensitivitym

No 8.4 1 1 1 1

Yes 26.2 3.89 (2.39–6.33) ,0.001 4.01 (2.45–6.57) ,0.001 4.14 (2.45–6.99) ,0.001 2.22 (1.25–3.96) 0.007

High HOMA2- b cell functionn

No 9.4 1 1 1 1

Yes 16.8 2.17 (1.24–3.80) 0.007 2.48 (1.27–3.97) 0.005 2.26 (1.25–4.08) 0.007 1.58 (0.83–3.00) 0.162

Abbreviations: OR, Odds ratio; CI, Confidence Interval; HOMA, Homeostasis Model Assessment. aadjusted for age, sex and skin color. badjusted for age, sex, skin colour
and early life variables (birth weight, gestational age at birth, maternal schooling, parity, type of delivery and maternal smoking during pregnancy).

c
adjusted for age,

sex, skin colour, early and adult life variables (alcohol consumption, family income, schooling, marital status, smoking, percentage of fat in the diet and physical activity).
dadjusted for age, sex, skin colour, early and adult life variables plus WC. eP value calculated by the log-likelihood ratio test. fdefined according to the Joint Interim
Statement (JIS) of the IDF Task Force on Epidemiology and Prevention, National Heart, Lung and Blood Institute, American Heart Association, World Heart Federation,
International Atherosclerosis Society and International Association for the Study of Obesity.

g
high waist circumference ($90 cm for men and $80 cm for women).

h
low

HDL-cholesterol (,40 mg/dL for men and ,50 mg/dL for women). iincreased triglycerides ($150 mg/dL, use of lipid medications or self-reported diagnosis of
hypertriglyceridemia).

j
increased blood pressure (BP) (systolic pressure $130 mmHg and/or diastolic pressure $85 mmHg, current usage of antihypertensive drugs or

previous diagnosis of hypertension).
k
high fasting blood glucose ($100 mg/dL), current use of anti-diabetic medication or previously diagnosed diabetes.

l
Based on the

Brazilian Metabolic Syndrome Study – BRAMS criterion (2009) – HOMA2- Insulin resistance .2.8.
m

HOMA2- Insulin sensitivity was considered low if ,90th percentile and
normal otherwise.

n
HOMA2- b cell function was considered high if .90th percentile and normal otherwise.

doi:10.1371/journal.pone.0060673.t005

Normal Weight Obesity and Metabolic Disorders

PLOS ONE | www.plosone.org 7 March 2013 | Volume 8 | Issue 3 | e60673

mean no risk for metabolic disorders and consequently for

cardiovascular diseases [45]. A BMI cut-off of $30 kg/m
2

has

good specificity but misses more than half the people with excess

fat [11,12]. This situation reveals the need for changes in routine

clinical evaluation, requiring the incorporation of other simple

low-cost measures, like skinfolds or WC, or bioelectrical imped-

ance to evaluate excess BF percentage in individuals with BMI

within the normal range. The strong associations found in this

study reinforce the need to adopt screening for increased BF as

early as possible[13], given that metabolic changes associated with

NWO were observed in young adults with normal BMI early in

the life course, even in a middle-income country where the burden

of obesity-related diseases is not as high as in some developed

countries. Although the prevalence rate of MS is low in this young

population [50], changes in health care and educational programs,

especially encouraging the adoption of a healthy lifestyle, including

physical activity and the development of healthy eating habits, are

highly advisable in an attempt to halt the spread of future

epidemics of obesity in normal-BMI individuals [3,31].

Conclusion

In conclusion, our study found associations between NWO and

MS and IR early in life in young adults with BMI within the

normal range. This implies that using only BMI for the assessment

of risk factors for cardiovascular diseases may lead to false-

negatives and suggests the need to include the assessment of BF in

the routine clinical evaluation of individuals at an early age, even

in middle-income countries. Even though prevalence rates of

metabolic disorders are low in this population of young adults, as

nutrition transition is rapid and as they get older, the burden of

obesity-related diseases would tend to be high in the future. Thus,

early detection and prevention of this epidemic of normal weight

obesity is highly desirable.

Acknowledgments

The authors are indebted to the Laboratories of Endocrinology, Nutrition

and Paediatrics of the University Hospital, Faculty of Medicine of Ribeirão

Preto, which performed the biochemical tests in the blood samples.

Author Contributions

Review the manuscript for intellectual content: FBM AAS HFV MZG GK

VCC HB MAB. Conceived and designed the experiments: AAS MAB HB.

Analyzed the data: FBM AAS HFV. Contributed reagents/materials/

analysis tools: AAS MZG GK HB MAB. Wrote the paper: FBM AAS

HFV MZG GK VCC HB MAB.

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doi:10.1371/journal.pone.0060673.t006

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