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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-1051
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 12 5113-5116
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

High Molecular Weight, Rather than Total, Adiponectin Levels Better Reflect Metabolic Abnormalities Associated with Childhood Obesity

Shunsuke Araki, Kazushige Dobashi, Kazuyasu Kubo, Kohtaro Asayama and Akira Shirahata

Department of Pediatrics (S.A., K.D., K.K., A.S.), School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan; and Kanagawa Health Service Association (K.A.), Yokohama 231-0021, Japan

Address all correspondence and requests for reprints to: Kazushige Dobashi, M.D., Department of Pediatrics, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail: kdobashi{at}med.uoeh-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Japanese are prone to obesity-induced metabolic derangement, which is linked to serum adipocytokine profile even in children.

Objective: The objective of the study was to determine whether high molecular-weight adiponectin (H-Adn) more specifically relates to metabolic derangement in obese children than total adiponectin (T-Adn).

Design and Setting: A case (n = 59) control (n = 28) study was performed at the pediatric clinic of a university hospital.

Patients: Japanese obese children (38 boys and 21 girls) were consecutively enrolled. The ages ranged from 5 to 15 (10.3 ± 0.3; mean ± SEM) yr. Nonobese children (15 boys and 13 girls) were assigned as age-matched controls.

Main Outcome Measures: Serum adiponectin multimeric complexes were assayed by an ELISA kit. The relationship of adiponectin to metabolic abnormalities was evaluated.

Results: T-Adn (5.1 ± 0.2 vs. 8.8 ± 0.4 µg/ml), H-Adn (1.3 ± 0.1 vs. 4.8 ± 0.4 µg/ml), and medium molecular weight-Adn were significantly lower in obese than in control children. After adjustment for age and sex, both T- and H-Adn were inversely correlated with insulin and homeostasis model of assessment-insulin resistance, whereas H-Adn (but not T-Adn) inversely correlated with visceral fat area, as determined by computed tomography. Seven obese children were estimated to have metabolic syndrome and showed selective decrease in H-Adn and H/T-Adn.

Conclusion: H-Adn reflects metabolic abnormalities due to obesity better than T-Adn in children. H-Adn is associated with the development of metabolic syndrome, even in childhood.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
RECENTLY, ADIPOSE TISSUE has been recognized as the biggest endocrine organ that secretes various adipocytokines (1). Enlargement of adipose tissue induces an imbalance in the secretion of adipocytokines, and this plays a key role in the development and progress of the lifestyle-related diseases. Adiponectin, which is an adipose-specific gene product comprising 244 amino acids, is the most abundantly secreted adipocytokine (2). It is unique in that the plasma concentration decreases, whereas those of most adipocytokines increase, in obesity, or more specifically by accumulation of visceral adipose tissue (VAT) (3, 4). Adiponectin is considered to be a key molecule for protection against metabolic syndrome (MS) (5) because it is antiatherogenic and insulinomimetic and it facilitates lipid oxidation (2). In fact, morbidity of MS is higher in those who are hypoadiponectinemic than in the general population (6).

Obesity in childhood induces real-time tissue damage in the cardiovascular system and enhances atherosclerotic risk (7). Evidence suggests that changes in the secretion of adipocytokines contribute to the development of metabolic derangement in obese children (8, 9, 10). We previously reported that plasma T-Adn concentration decreased with visceral fat accumulation and that it was restored toward normal by slimming in Japanese obese children (4).

The basic molecular structure for adiponectin is a trimer, but various multimers exist in circulating blood (2, 3). Recently, a new immunoassay method has been developed to selectively measure the high molecular weight (12–18 mer; H-Adn), medium molecular weight (6 mer; M-Adn), and low molecular weight (3 mer; L-Adn) adiponectin fractions (11, 12, 13). To our knowledge, there has been no report on adiponectin fractions with different molecular weights in obese children.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fifty-nine obese Japanese children (38 boys and 21 girls) who visited the Clinic for Obese Children in the University Hospital of Occupational and Environmental Health, Japan, were consecutively enrolled in the study. According to the criteria for obesity in childhood adopted by the Ministry of Health, Labor and Welfare in Japan, each child was considered to be obese when the body weight exceeded 120% of the standard body weight, which is defined as the mean body weight corresponding to the height for that age obtained from national statistics for Japanese school children in 2000. The age of the subjects ranged from 5 to 15 (10.3 ± 0.3; mean ± SEM) yr. Standard body mass index (BMI) for each age and sex was also obtained from national statistics for Japanese school children in 2000. BMI-SD ranged from 1.24 to 7.44 (3.76 ± 0.25; mean ± SEM) SD for obese boys and from 1.87 to 5.83 (3.81 ± 0.27) SD for obese girls; there was no sex-related difference. Subjects had no endocrine, metabolic, or kidney diseases. Concerning the pubertal status, 39 of 59 subjects were in Tanner stage I, 13 in stage II, and five in stage III; no subject was in stage IV or V. Blood was drawn after an overnight fast, and they were subjected to anthropometric measurements including height, body weight, and waist circumference. The age-matched control group for measuring adiponectin (mean age, 10.0 ± 0.6 yr) consisted of 28 nonobese children (15 boys and 13 girls). The BMI-SD for control children was –0.66 ± 0.13 and was significantly lower than BMI-SD in obese children.

Anthropometric measurement was performed using previously described methods (4). VAT was measured by computed tomography according to the method described previously (4). The Human Study Committee of the University of Occupational and Environmental Health, Japan, approved this study. Written informed consent was obtained either from each subject or from his or her parents as appropriate.

Biochemical measurement

Selective measurement of adiponectin multimeric complexes in human serum was assayed by an ELISA kit (Daiichi Pure Chemicals Co., Ltd., Tokyo, Japan). The treatment with different types of proteases enabled the selective determination of H-Adn, M-Adn, and L-Adn, as described previously (12, 13). Intraassay coefficients of variations for T-Adn and H-Adn were reported to be 5.3 and 3.3%, respectively (12, 13). The serum was stored frozen at –80 C until measurement. To reduce interassay variance, all samples were analyzed in one assay.

Definition of MS

There have been several reports on MS in children (14), but not within the Japanese population. We previously defined "obesity disease" in Japanese children (15) and determined the critical values for waist circumference (≥80 cm), VAT area (≥60 cm2), blood pressure (systolic ≥ 125 mm Hg; diastolic ≥ 70 mm Hg), alanine aminotransferase (ALT; ≥30 IU/liter), triglycerides (TG; ≥120 mg/dl), high-density lipoprotein-cholesterol (HDL-C; <40 mg/dl), and insulin (≥15 µU/ml). We have adopted the criterion for hyperglycemia (≥100 mg/dl) according to the concept of the International Diabetes Federation (16). In the present study, we have defined the MS as two of the three risk factors (hypertension, dyslipidemia, and hyperglycemia) in addition to abdominal obesity.

Statistics

Data are presented as the means and SEM. Because the data for TG, ALT, and insulin were skewed, they were transformed logarithmically before statistical analysis. Because there were no significant sex-related differences in the anthropometric and biochemical data in the obese and control children, males and females were combined in the same groups. The statistical differences were considered significant at P < 0.05. Partial correlation was calculated according to the analysis of covariance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Waist girth, VAT area, systolic and diastolic blood pressure for obese children were 85.1 ± 1.6 cm, 73.0 ± 3.6 cm2, 114.0 ± 1.7 mm Hg and 61.0 ± 1.3 mm Hg, respectively. Figure 1Go shows the serum levels of different fractions of adiponectin in obese and control children. T-Adn, H-Adn, and M-Adn are lower in the obese than in the control children. Conversely, L-Adn is higher in the obese than in the control children. The fractional adiponectin levels relative to T-Adn are shown in Fig. 1BGo. H/T-Adn level is lower in the obese than in the control children, whereas M/T-Adn and L/T-Adn are higher in the obese than in the control children. The fractional adiponectin levels are not different between sexes in obese and control children.


Figure 1
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  		FIG. 1. Serum levels of adiponectin with different molecular weights in obese (n = 59) and nonobese (n = 28) children. A, Absolute value of each fraction. B, Fractional ratios to total adiponectin. Statistical difference was evaluated by an unpaired t test for two groups. T, T-Adn; H, H-Adn; M, M-Adn; L, L-Adn.

 
Table 1Go summarizes the correlations between fractional adiponectin and anthropometric measures or clinical biochemistry data in obese children. In monovariate correlation analysis, T-, H-, and H/T-Adn negatively correlated with age, height, body weight, waist girth, and VAT area, but not with BMI-SD. After adjustment for age and sex, however, H-Adn (but not T- or H/T-Adn) negatively correlated with VAT area. ALT negatively correlated with T-, H-, and H/T-Adn, but the correlations were not significant after adjustment for age and sex. TG negatively correlated with T- and H-Adn after adjustment for age and sex. T-Adn, but neither H-Adn nor H/T-Adn, showed a significant correlation with HDL-C. Insulin and homeostasis model of assessment-insulin resistance (HOMA-IR) correlated with T-Adn, H-Adn, and H/T-Adn, and the correlations were significant even after adjustment with age and sex except in the case of HOMA-IR vs. H/T-Adn.


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  		TABLE 1. Correlation between adiponectin fractions and other variables in obese children

 
Only seven obese children (11.8%) were diagnosed with MS. H-Adn and H/T-Adn were lower in the MS, compared with non-MS, children (0.7 ± 0.09 vs. 1.37 ± 0.10, P < 0.001; and 0.17 ± 0.09 vs. 0.26 ± 0.11, P < 0.05, respectively). The following variables were not significantly different between groups: age, BMI-SD, and T-, M-, L-, M/T-, and L/T-Adn.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
T-Adn was decreased in obese children, as was found in our previous study (4). In addition, H-Adn was more markedly decreased in obese children than T-Adn, as evidenced by the significant decrease in H/T-Adn. Serum levels of adiponectin fractions are known to be negatively associated with the age of the subjects (4, 17), as was also the case in the present study. The inverse relationship witnessed between T-Adn and anthropometric measure, or VAT area, was lost after adjustment for age and sex. Both T- and H-Adn were negatively correlated with insulin and HOMA-IR, even after adjustment for age and sex. H-Adn, but not T-Adn, was negatively correlated with VAT area after adjustment for age and sex.

In adult studies, H/T-Adn and H-Adn have been reported to be increased in women more than in men (11). Xu et al. (18) reported that the serum level of H-Adn decreased in hypogonadal patients during testosterone replacement therapy, and that testosterone selectively decreased the secretion of H-Adn from rat adipocytes. Thus, decreased secretion of H-Adn by androgen may explain the sex-related difference observed in these adult studies. Serum T-Adn level was reported to be decreased in boys compared with girls at the sexual development of Tanner stage III (19). However, there was no such sex-related difference in the present subjects. Lack of sex-related difference appeared to be due to the fact that the present children were mostly preadolescent, as was the case in the previous series (4, 17). Effect of puberty on serum levels of adiponectin fractions needs to be elucidated in further studies.

VAT is considered to play a central role in the pathogenesis of the MS (16). Recently, the effect of accumulation of VAT and insulin resistance on serum level of T-Adn has been studied extensively. In an adult study (20), H-Adn better correlated with an index of visceral fat accumulation such as waist-hip ratio than BMI or total body fat. H-Adn correlated with the serum level of HDL-C and negatively with the TG level in adults (20), suggesting that H-Adn was a key molecule for protection against the MS among adiponectin fractions. In the present study, H-Adn, but not T-Adn, was negatively correlated with VAT area after being adjusted for age and sex. Furthermore, a selective decrease in H- and H/T-Adn was shown in the MS group, as was the case in a very recent adult study (12).


   Footnotes
 
This work was supported by Grant for Advanced Research H17–2 from the University of Occupational and Environmental Health, Japan.

Disclosure statement: The authors have nothing to disclose.

First Published Online September 19, 2006

Abbreviations: ALT, Alanine aminotransferase; BMI, body mass index; H-Adn, high molecular-weight adiponectin; HDL-C, high-density lipoprotein-cholesterol; HOMA-IR, homeostasis model of assessment-insulin resistance; L-Adn, low molecular-weight adiponectin; M-Adn, medium molecular-weight adiponectin; MS, metabolic syndrome; T-Adn, total adiponectin; TG, triglycerides; VAT, visceral adipose tissue.

Received May 15, 2006.

Accepted September 8, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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