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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2850
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2079-2083
Copyright © 2008 by The Endocrine Society

Visceral Adiposity without Overweight in Children Born Small for Gestational Age

Lourdes Ibáñez, Abel Lopez-Bermejo, Larisa Suárez, Maria Victoria Marcos, Marta Díaz and Francis de Zegher

Endocrinology Unit (L.I., L.S., M.D.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Diabetes, Endocrinology & Nutrition Unit (A.L.-B.), Dr. Trueta Hospital, 17007 Girona, Spain; Endocrinology Unit (M.V.M.), Hospital de Terrassa, 08227 Terrassa, Spain; and Department of Woman & Child (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Children born small for gestational age (SGA) tend to develop catch-up growth in infancy and become overweight by the age of 6 yr. Weight control is advocated as a preventive measure, but it is unknown whether such control suffices to prevent visceral fat excess and hypoadiponectinemia.

Setting: The study was performed at a university hospital.

Study Population and Design: A total of 64 children (32 matched pairs) aged 6 yr, of whom 32 were born appropriate for gestational age and 32 were born SGA, and had subsequently developed spontaneous catch-up growth were included in the study; matching was performed for gender, height, weight, and, thus, body mass index.

Main Outcomes: Fasting insulin, IGF-I, high molecular weight adiponectin, leptin, visfatin, and lean and fat mass were calculated by absorptiometry, and abdominally sc and visceral fat by magnetic resonance imaging.

Results: After strict matching, SGA children had a total lean mass, total fat mass, leptinemia, and visfatinemia comparable to those in the appropriate for gestational age children, but they still had higher fasting insulin and IGF-I levels (P < 0.01), much lower high molecular weight adiponectin levels (P < 0.0001), and a striking shift from abdominally sc to visceral fat (P < 0.0001). Fasting insulin (r = 0.52; P < 0.00001) was a major determinant of visceral fat in boys and girls, explaining 28% of its variance.

Conclusions: SGA children tend to be viscerally adipose and hypo-adiponectinemic, even if they are not overweight. Therefore, measures beyond weight control seem to be needed to allow most SGA children to normalize their body composition and endocrine-metabolic homeostasis.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Hyperinsulinemic insulin resistance and visceral adiposity emerge early in the sequences that ultimately lead to type 2 diabetes or metabolic syndrome (1). Among those sequences, a globally prevalent one starts with prenatal growth restraint and spontaneous catch-up of weight during infancy (2, 3). Children locked into such a sequence tend to be hyperinsulinemic and adipose by the age of 4 yr (4), have high IGF-I levels and an excess of visceral fat by the age of 6 yr (5), and have lower circulating levels of total adiponectin by the age of 10 yr (6). However, from the age of 5 yr onward, low birth weight children also tend to be overweight, if not obese (7). It is unknown whether low birth weight children are hyperinsulinemic, viscerally adipose, and/or hypo-adiponectinemic if they maintain a normal height and weight. Should such anomalies no longer be detectable in the absence of overweight, then the therapeutic focus may indeed be on weight control, as has been advocated (8); however, should such omina still be readily detectable, then the therapeutic focus may have to be broadened beyond weight control.

We compared the endocrine-metabolic state [including high molecular weight (HMW) adiponectin, leptin, and visfatin] and the body composition (including visceral fat) of children born small for gestational age (SGA) to those of children born appropriate for gestational age (AGA) after strict matching not only for gender but also for normal height and weight at the age of 6 yr.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population and ethics

The recruitment and matching flow is shown in Table 1Go. The total population consisted of 94 children: 51 participated in a longitudinal study starting at age 2 yr (no dropouts between age 2 and 6 yr) (5); and 43 were additionally recruited at the age of 6 yr to enable matching of AGA and SGA children for age, gender, height, weight, and body mass index (BMI). In total, 32 AGA-SGA pairs (16 for each gender) could be assembled for a total of 64 matched children.


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  		TABLE 1. Recruitment and matching flow within the study population of AGA and SGA girls and boys

 
Besides the age criteria (2 or 6 yr at recruitment), the inclusion criteria were: 1) birth at Hospital Sant Joan de Déu, Barcelona, after a term pregnancy (37–42 wk); and 2) birth weight either AGA (defined as –1 to +1 SD) or SGA (below –2 SD) (9).

Exclusion criteria were: clinical evidence for syndromatic, chromosomal, or infectious etiology of SGA; gestational diabetes; hypothyroidism; urogenital tract anomalies; systemic disease; or acute illness. All SGA children had experienced spontaneous catch-up growth and were growing along a normal percentile for midparental height.

Consecutive study protocols were approved by the Institutional Review Board of Barcelona University Hospital. Informed consent was given by the parents.

Auxology and assays

Birth weight and gestational age were obtained from hospital records to derive birth weight Z scores (5). Weight was in childhood measured to the nearest 0.5 kg, and height to the nearest 0.5 cm with a stadiometer, and SD score (SDS) for both parameters were derived (9). All endocrine-metabolic indices were measured in fasting state (4, 6). Insulin and IGF-I were assessed by immunochemiluminescence (IMMULITE 2000; Diagnostic Products Corp., Los Angeles, CA). The detection limit for insulin was 2.0 µU/ml. Below this limit, values were assigned as 1.9 µU/ml. The detection limit for IGF-I was 25 ng/ml. Insulin and IGF-I intraassay and interassay coefficients of variation (CVs) were less than 10%. Leptin was measured by RIA (LINCO Research, Inc., St. Charles, MO), as described (10). Visfatin and HMW adiponectin were assessed using commercially available ELISA kits, as reported (EIA kit; Phoenix Pharmaceutical, Belmont, CA, and LINCO Research, respectively); the intraassay and interassay CVs were less than 6% for visfatin, and less than 9% for HMW adiponectin.

Body composition and abdominal fat partitioning

Body composition was assessed by dual-energy x-ray absorptiometry, with a Lunar Prodigy coupled to Lunar software (version 3.4/3.5; Lunar Corp., Madison, WI) (4). CVs for scanning precision are 2.0 and 2.6% for fat and lean body mass, respectively, with an intraindividual CV for abdominal fat of 0.7%. Fat and lean mass were assessed; body composition was adjusted for height, according to Wells and Cole (11).

Subcutaneous and visceral adipose tissue (VAT) areas in the abdominal region were assessed by magnetic resonance imaging (MRI) using a multiple-slice MRI 1.5 Tesla scan (Signa LX Echo Speed Plus Excite; General Electric, Milwaukee, WI). Children were positioned within a torso-array device overlying the abdomen; sedation was not required. Axial T1-weighed images were then obtained through the abdomen and pelvis using a 400-cm field of view, with the following imaging parameters: 6-mm slice thickness, repetition time 360 msec, time to echo 21, two excitations, 90° flip angle, matrix 256 x 224, and bandwidth 8.33. Images were imported into the ADW 4.0 General Electric software package.

Subcutaneous adipose tissue and VAT areas were measured by fitting a spline curve to points on the border of the sc and visceral regions, selected by the same operator (blinded to the children’s birth weight). Nonfat regions within the visceral region were also outlined with a spline fit and subtracted from the total visceral region. The visceral fat region was subdivided into retroperitoneal and ip areas using the ascending and descending colon, the psoas muscles on each side of the spine, and the top of the vessels above the vertebrae as guides for the spline fit. The VAT area was calculated by subtracting the organ areas from the ip area, as described (5). All scans were performed by the same operator (blinded to the children’s birth weight), and all images were processed by the same radiologist (also blinded to birth weight). Images from a randomly selected subset of subjects (n = 10) were processed again by an independent radiologist, with {alpha}-reliability estimates more than 0.90 (Cronbach’s {alpha}-internal consistency analysis).

Statistics

Statistical analyses were performed using SPSS 12.0 (SPSS, Inc., Chicago, IL). Differences between AGA and SGA children were tested by the unpaired t test; gender effects were tested by analysis of covariance. Associations between continuous variables were studied by Pearson correlation analyses. Multiple stepwise regression models were used to identify independent contributions to body fat and visceral fat. Before comparing the subgroups, skewed data were log transformed into normal distributions. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 2Go summarizes the results in height-, weight-, and BMI-matched AGA and SGA children at the age of 6 yr. SGA children had a total lean mass, total fat mass, and both circulating leptin and visfatin comparable to those in AGA children, but they had higher IGF-I levels (P < 0.01) and fasting insulin (P = 0.001), much lower HMW adiponectin levels (P < 0.0001), and a marked shift from abdominally sc to visceral fat (P < 0.0001). Figure 1Go shows newly recognized AGA vs. SGA differences in matched children. Figure 2Go depicts independent gender and birth weight effects. Body fat, visfatin, and leptin were gender dependent (P < 0.01 to P < 0.001). Visceral fat and insulin (P < 0.01 to P < 0.001) were birth weight dependent, and HMW adiponectin and IGF-I were both gender and birth weight dependent (P < 0.01 to P < 0.001).


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  		TABLE 2. Results in 6-yr-old AGA vs. SGA girls and boys matched for height, weight, and BMI

 

Figure 1
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  		FIG. 1. Differences in clinical, endocrine-metabolic variables, and regional fat parameters in 6-yr-old AGA vs. SGA children matched for height, weight, and BMI (n = 64). Results are shown as Z scores calculated by dividing the individual values by the corresponding baseline SD in the AGA group. For birth weight (BW), the Z score was calculated using the corresponding SD in the general population. Plots represent means ± 95% confidence interval. **P ≤ 0.01 and ***P ≤ 0.001 for differences between groups by the Student’s t test. Adipo, Adiponectin; Subc, sc; Visc, visceral.

 

Figure 2
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  		FIG. 2. Effects of birth weight and gender in 6-yr-old children matched for height, weight, and BMI (n = 64) who were born either AGA (n = 32, 16 boys and 16 girls) or SGA (n = 32, 16 boys and 16 girls). Body fat and visfatin were gender dependent (upper-right panels). Visceral fat and insulin were birth weight dependent (lower-left panels). IGF-I and HMW adiponectin were both gender and birth weight dependent (lower-right panels). Plots represent mean values. **P ≤ 0.01 and ***P ≤ 0.001 for birth weight, and ##P ≤ 0.01 and ###P ≤ 0.001 for gender effects by two-way ANOVA.

 
Circulating IGF-I (r = 0.55; P < 0.00001) and leptin (r = 0.48; P < 0.00001) were major determinants of body fat, explaining respectively 29 and 10% of its variance; insulin (r = 0.52; P < 0.00001) and IGF-I (r = 0.49; P < 0.00001) were major determinants of visceral fat, explaining 28 and 10% of its variance.

The associations between circulating HMW adiponectin and indices of fat partitioning were gender specific. HMW adiponectin correlated inversely with visceral fat in boys (r = –0.45; P = 0.009) and with the visceral-to-sc fat ratio in girls (r = –0.49; P = 0.004). In girls, HMW adiponectin was a major determinant of the visceral-to-sc fat ratio, explaining 22% of its variance.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
After strict matching, post-catch-up SGA children were found to have a lean mass, total fat mass, leptinemia, visfatinemia, and even an abdominal fat mass (by MRI) comparable to those in matched AGA children. The body composition hallmark of SGA children appears to be a viscerotropic redistribution of abdominal fat, whereas the visceral-to-sc fat ratio was about 40–60% in AGA children, it was shifted to approximately 50–50% in SGA children. Our cross-sectional evidence does not allow to infer whether the sizes of both compartments diverge concomitantly in opposite directions, whether the relative excess of visceral fat precedes the relative deficit of sc fat, or whether a reverse sequence applies. By design, our study excludes the weight and length in childhood as responsible for any difference in the body composition of AGA and SGA children. Therefore, such differences at age 6 must somehow be related either to the slowdown of prenatal growth, the acceleration of postnatal growth, or both.

Nonoverweight SGA children at the age of 6 yr were found to have low circulating HMW adiponectin levels and elevated insulin and IGF-I levels, and to be viscerally adipose. These findings imply that, by age 6, weight control may in post-catch-up SGA children no longer suffice to prevent a hyperinsulinemic and hypo-adiponectinemic variant of visceral adiposity.

Both fasting insulin and circulating HMW adiponectin were independently linked to visceral fat and/or the visceral-to-sc fat ratio. These findings suggest that circulating HMW adiponectin, in contrast to leptin or visfatin, is a reflection of visceral adiposity rather than of total fat mass. Our observations align well with those in studies of obese adolescents and adults, showing a close relationship between HMW adiponectinemia and the development of the insulin resistance trait cluster (12, 13, 14).

Serum visfatin and HMW adiponectin were distinctively lower in boys than girls, independently of birth weight. To our knowledge, these sexual dimorphisms have not been reported yet at such a young age. Visfatin, an adipokine preferentially released by visceral fat, is thought to facilitate adipogenesis and have insulin-mimetic properties (15, 16). Total and HMW adiponectin is known to decrease during male puberty, possibly secondary to increasing testosterone levels (17, 18). Total adiponectin levels are also known to be higher in prepubertal girls than boys (at age 8 yr); the present findings indicate that the HMW fraction of adiponectin contributes to the elevated levels of total adiponectin in prepubertal girls, compared with boys (19, 20).

In conclusion, SGA children are viscerally adipose and hypo-adiponectinemic, even in the absence of overweight. Therefore, measures beyond weight control seem to be needed to allow most SGA children to normalize their body composition and endocrine-metabolic homeostasis.


   Acknowledgments
 
We thank Montserrat Visa for hormonal measurements.


   Footnotes
 
L.I., M.V.M., and M.D. are Clinical Investigators of Centro de Investigación Biomédica En Red de Diabetes y Enfermedades Metabólicas Asociades (Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Madrid, Spain). A.L.-B. is an Investigator of the Fund for Scientific Research "Ramon y Cajal" (Ministry of Education and Science, Spain). F.d.Z. is a Clinical Investigator of the Fund for Scientific Research (Flanders, Belgium).

Disclosure Statement: The authors have nothing to declare.

First Published Online March 11, 2008

Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; CV, coefficient of variation; HMW, high molecular weight; MRI, magnetic resonance imaging; SDS, SD score; SGA, small for gestational age; VAT, visceral adipose tissue.

Received December 27, 2007.

Accepted March 4, 2008.


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 Subjects and Methods
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 Discussion
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