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Plasma Adiponectin Levels and Metabolic Factors in Nondiabetic Adolescents Kuo-Chin Huang,* Bee-Horng Lue,*§ Ruoh-Fang Yen,† Christopher G. Shen,¶ Shiuh-Rong Ho,¶ Tong-Yuan Tai,‡ and Wei-Shiung Yang‡¶**

Abstract HUANG, KUO-CHIN, BEE-HORNG LUE, RUOH-FANG YEN, CHRISTOPHER G. SHEN, SHIUH-RONG HO, TONG-YUAN TAI, AND WEI-SHIUNG YANG. Plasma adiponectin levels and metabolic factors in nondiabetic adolescents. Obes Res. 2004;12:119 –124. Objectives: The relationship of plasma adiponectin levels with various anthropometric and metabolic factors has been surveyed extensively in adults. However, how plasma adiponectin levels are related to various anthropometric indices and cardiovascular risk factors in adolescents is not as vigorously studied. In this study, we investigated this among healthy nondiabetic adolescents. Research Methods and Procedures: Two hundred thirty nondiabetic subjects (125 boys and 105 girls, ⬃10 to 19 years old) were included. The plasma adiponectin, fasting plasma glucose, insulin, lipids and anthropometric indices including body height, weight, waist circumference, and hip circumference were examined. Body fat mass (FM) and percentage were obtained from DXA scan. The homeostasis model assessment was applied to estimate the degree of insulin resistance. Results: The plasma adiponectin levels were significantly higher in girls (30.79 ⫾ 14.48 ␮g/mL) than boys (22.87 ⫾ 11.41 ␮g/mL). The plasma adiponectin levels were negatively related to BMI, FM, FM percentage, waist circumference, waist-to-hip ratio, insulin resistance, plasma insulin, triglycerides, and uric acid levels, but positively with high-density lipoprotein cholesterol (HDL-C) with the ad-

Received for review April 28, 2003. Accepted in final form November 12, 2003. Departments of *Family Medicine and †Nuclear Medicine and ‡Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; §Department of Social Medicine and ¶Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; and **Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Address correspondence to Wei-Shiung Yang, Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, No. 1, Chang-Teh St., Taipei 100, Taiwan. E-mail: [email protected] Copyright © 2004 NAASO

justment for age and gender. Using different multivariate linear regression models, only age and HDL-C were consistently related to the plasma adiponectin levels after adjustment for the other variables. Discussion: The relationship between plasma adiponectin and various anthropometric indices and metabolic factors, especially HDL-C, previously reported in adults was present in the healthy nondiabetic adolescents. Whether variation of plasma adiponectin levels in healthy nondiabetic adolescents may influence their future coronary artery disease risk warrants further investigation. Key words: adiponectin, BMI, high-density lipoprotein cholesterol, adolescence

Introduction The prevalence of obesity in children and adolescents has been rising greatly worldwide (1). The prevalence of overweight among the adolescents in the United States, for example, has increased from 5% to 15.5% between the 1960s and 1999 to 2000 (2). In addition to increasing mortality, adult obesity has also been known to be associated with hypertension, diabetes, dyslipidemia, and higher cardiovascular risk (3–5). As with adults, obesity in childhood is closely related to hypertension, dyslipidemia, type 2 diabetes, and insulin resistance (IR)1 syndrome (6 – 8). Furthermore, obese children have been found to be at increased risk of becoming obese adults (9). Taken together, obese children and adolescents tend to develop serious medical and psychosocial complications and also are at a greater risk of adult morbidity and mortality. Therefore, the research on obesity during adolescence is especially important in the prevention and treatment of obesity and its related disorders in adulthood.

1 Nonstandard abbreviations: IR, insulin resistance; CAD, coronary artery disease; FM, fat mass; HDL-C, high-density lipoprotein cholesterol; WC, waist circumference; WHR, waistto-hip ratio; TG, triglyceride; UA, uric acid; TCHO, total cholesterol; LDL-C, low-density lipoprotein cholesterol; RIA, radioimmunoassay.

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Plasma Adiponectin in Adolescents, Huang et al.

Adiponectin, also referred to as adipocyte complement related protein-30, Adipo-Q, and adipose tissue most abundant gene transcript-1, is an adipose-specific plasma protein that has drawn substantial attention recently in the research of obesity and metabolic syndrome (10,11). The relationship of adiponectin with most metabolic factors pertinent to the metabolic syndrome and coronary artery disease (CAD) has been studied extensively in adults (12–19). Hypoadiponectinemia was found to be associated with obesity, type 2 diabetes, dyslipidemia, and CAD (12,14,15,17–19). In animal experiments, the findings from most studies were consistent with the observations in human studies (20 –27). The potential impact of low plasma adiponectin on cardiovascular system cannot be overemphasized. Ouchi et al. found that the plasma adiponectin levels were lower in CAD patients than normal controls (19). We reported previously that the plasma adiponectin levels were inversely related to the numbers of CAD risk factors in overweight or obese adults (12). Therefore, low plasma adiponectin may predispose the subjects to CAD simply because of its association with various adverse metabolic profiles (12–18). In addition, several studies using adiponectin knockout mice have demonstrated the potential effects of adiponectin directly on the vascular wall in favor of adiponectin as a cardiovascular protective adipocytokine (22,23,26,27). The process of atherosclerosis is now well taken to start very early in childhood (28). Therefore, the levels of plasma adiponectin in earlier life, no matter through the association with various CAD risk factors or through direct effects on the vessel walls, may influence the risk of CAD in adulthood. However, the plasma adiponectin in younger healthy subjects who do not have any metabolic diseases has not been as rigorously studied as in adults. Previously, it was reported that the plasma adiponectin levels at the ages of 5 and 10 among Pima Indian children were inversely related to fasting plasma insulin levels and percent body fat (29). Recently, plasma adiponectin levels were reported to be negatively related to BMI, fat mass (FM), and fasting insulin and positively to high-density lipoprotein cholesterol (HDL-C) among 30 Hispanic and Asian-American children (30). In this study, we examined the relationships between plasma adiponectin, anthropometric indices, and various metabolic factors among 230 healthy nondiabetic adolescents.

Research Methods and Procedures Subjects and Characterization The study was cross-sectional, and students in three high schools of Taipei city were selected in 1999. Two hundred thirty nondiabetic subjects (125 boys and 105 girls, ⬃10 to 19 years old) voluntarily joined this study (Table 1). The anthropometric measurements, including height, weight, and waist and hip circumferences were performed as de120


Table 1. The basic characteristics of the subjects categorized by gender Variables Age (years) Body weight (kg)‡ Body height (cm)‡ BMI (kg/m2)‡ WC (cm)‡ HC (cm)‡ WHR‡ Tanner stage 1 2 3 4 5 FM (kg) FM percentage‡ Glucose (mM)‡ Insulin (pM) IR (HOMA) TCHO (mM) HDL-C (mM)‡ LDL-C (mM) TG (mM)* TCHO/HDL ratio* UA (M)‡ Adiponectin (␮g/ mL)‡

Boys (n ⴝ 125)

Girls (n ⴝ 105)

15.7 ⫾ 1.8 76.5 ⫾ 16.0 170.2 ⫾ 7.0 26.3 ⫾ 4.6 83.7 ⫾ 11.6 101.5 ⫾ 9.2 0.82 ⫾ 0.06

15.4 ⫾ 1.9 58.1 ⫾ 12.0 158.4 ⫾ 6.3 23.1 ⫾ 4.0 71.2 ⫾ 11.5 94.4 ⫾ 9.0 0.75 ⫾ 0.07

6 (4.9%) 5 (4.1%) 36 (29.3%) 56 (56%) 20 (20%) 25.6 ⫾ 10.6 32.5 ⫾ 8.4 5.60 ⫾ 0.38 106.2 ⫾ 56.1 3.72 ⫾ 2.02 4.29 ⫾ 0.89 1.32 ⫾ 0.25 2.52 ⫾ 0.71 0.97 ⫾ 0.52 3.3 ⫾ 0.8 489.5 ⫾ 89.7

0 3 (2.9%) 25 (24.3%) 46 (44.7%) 29 (28.2%) 23.8 ⫾ 7.6 39.7 ⫾ 6.0 5.42 ⫾ 0.40 99.5 ⫾ 55.8 3.37 ⫾ 2.02 4.50 ⫾ 0.72 1.52 ⫾ 0.35 2.58 ⫾ 0.57 0.83 ⫾ 0.45 3.1 ⫾ 0.7 359.5 ⫾ 78.2

22.87 ⫾ 11.41

30.79 ⫾ 14.48

Data are means ⫾ SD. IR (HOMA), IR index by HOMA. Statistics were computed by Student’s t or ␹2 test: * p ⬍ 0.05; ‡ p ⬍ 0.001.

scribed (31). BMI is used to reflect body fatness amounts, whereas waist circumference (WC) and waist-to-hip ratio (WHR) are used as surrogates for body fat centralization. The stage of sexual development of each of the subject was self-assessed according to Tanner’s standard photographs (32). This was completed under the supervision of a school nurse. Whole-body composition containing total FM and percentage was measured by DXA instrument with the Norland XR-26 densitometer (Norland Co., Fort Atkinson, WI). A venous blood sample was taken after 12 hours of fasting for measuring plasma glucose, insulin, triglycerides (TGs), uric acid (UA), total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), and HDL-C by an auto-analyzer (Hitachi 7250 Special; Hitachi, Tokyo, Ja-


pan). The homeostasis model assessment [(homeostasis model assessment) ⫺ IR ⫽ insulin/22.5e⫺ln(glucose), where “ln” indicates natural log] was applied to estimate the degree of IR (33), where insulin is expressed in microunits per milliliter, and glucose is expressed in millimoles per liter. Fasting plasma adiponectin was measured in duplicate with the radioimmunoassay (RIA) kits following the manufacturer’s protocols (Linco Research Inc., St. Louis, MO). The values were obtained from the means of two tests of the same samples. Both the intra-assay and interassay coefficients of variation were ⬍10%. Informed consents were signed by students’ parents or legal guardians. The study has been reviewed and supported in grant by the National Science Council of Taiwan. Statistical Analysis Data were presented in means and SDs, unless indicated otherwise. All except those of adiponectin were in SI units (Syste´ me international d’unite´ s). Log transformation was performed for variables with significant deviation from normal distribution before further analyses. Statistical analyses including two-sample Student’s t test, correlation analyses, and multivariate linear regression analyses were performed using the SPSS/PC statistical program (version 10.0 for Windows; SPSS, Inc., Chicago, IL). Correlation of all the clinical characteristics and plasma adiponectin levels was performed with adjustment of age and gender. Several multivariate linear regression models were performed using plasma adiponectin levels as the dependent variable and using age, gender, BMI, WC, fasting plasma glucose, insulin, TGs, and HDL-C as independent variables. Adjusted R2 that corrected for the number of variables and the sample size was used to estimate the variance explained in each model.

Results In Table 1, we noted that boys were taller and heavier than girls, although their ages were similar. However, girls still had a higher percentage of FM. Plasma adiponectin and HDL-C levels were significantly higher in girls than in boys (Table 1). We found that the plasma adiponectin levels negatively correlated with BMI, WC, WHR, FM, FM percentage, plasma insulin, TGs, UA levels, and IR index with the adjustment for age and gender (Table 2). Only the plasma HDL-C levels positively correlated with the plasma adiponectin levels (Table 2). Using multivariate linear regression models, the WC appeared to be more closely related to the plasma adiponectin levels than BMI (model 1 in Table 3). The insulin seemed to be more closely related to the plasma adiponectin levels than the plasma glucose levels (model 2 in Table 3). The HDL-C seemed to be more closely related to the plasma adiponectin levels than the TG levels (model 3 in Table 3).

Table 2. Correlation coefficients of plasma adiponectin levels (log transformed), versus BMI, WC, WHR, FM, FM percentage, plasma insulin, glucose, lipid levels, UA, and IR in these adolescents (n ⫽ 230) with the adjustment for age and gender Variables

R

Log-BMI Log-WC WHR FM FM percentage Log-glucose Log-insulin Log-IR Log-TCHO LDL-C Log-HDL-C Log-TG TCHO:HDL ratio UA

⫺0.404‡ ⫺0.437‡ ⫺0.373‡ ⫺0.326‡ ⫺0.227‡ ⫺0.120 ⫺0.362‡ ⫺0.359‡ 0.024 ⫺0.081 0.365‡ ⫺0.198† ⫺0.293‡ ⫺0.215†

Statistics were tested by Pearson’s correlations: † p ⬍ 0.01; ‡ p ⬍ 0.001.

Interestingly, age and HDL-C turned out to be the only two variables significantly related to the plasma adiponectin levels with the adjustment for all these factors in model 4 of Table 3. Judged by the adjusted R2 of each model, model 4 was probably the best model to explain the variation of the plasma adiponectin levels. Furthermore, using multivariate linear regression models with adiponectin as an independent variable, the plasma adiponectin levels were significantly negatively related to the plasma insulin and IR and positively related to HDL-C with the adjustment for the other variables including age, gender, BMI, WC, and Tanner stage (data not shown).

Discussion In this study, we found that plasma adiponectin levels were negatively related to various anthropometric indices representing body fatness and central fat distribution and various metabolic factors related to adverse CAD risk in healthy nondiabetic adolescents. These were consistent with the previous reports in adults (12–19) and the two studies in children (29,30). Previously, we also found that among the overweight/obese adults, HDL-C was still significantly related to the plasma adiponectin levels after the adjustment of the other metabolic variables (12). The biological mechanisms linking plasma adiponectin to HDL-C levels remain OBESITY RESEARCH Vol. 12 No. 1 January 2004

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Table 3. Multivariate linear regression models showing regression coefficients ⫾ SE, using plasma adiponectin levels (log transformed) as the dependent variable, with age, gender, log-BMI, log-WC, log-glucose, log-insulin, log-TG, and log-HDL-C as independent variables Independent variables Age Gender Log-BMI Log-WC Log-Glucose Log-Insulin Log-TG Log-HDL-C

Model 1¶ 2 Radj § ⴝ 0.317

Model 2** 2 Radj ⴝ 0.242

Model 3†† 2 Radj ⴝ 0.249

Model 4‡‡ 2 Radj ⴝ 0.337

⫺0.205 ⫾ 0.412‡ 0.064 ⫾ 0.072 ⫺0.318 ⫾ 0.406 ⫺1.094 ⫾ 0.475*

⫺0.100 ⫾ 0.017‡ 0.237 ⫾ 0.065‡

⫺0.071 ⫾ 0.017‡ 0.153 ⫾ 0.067*

⫺0.061 ⫾ 0.018‡ 0.045 ⫾ 0.073 ⫺0.227 ⫾ 0.400 ⫺0.826 ⫾ 0.482 0.028 ⫾ 0.448 ⫺0.099 ⫾ 0.074 0.086 ⫾ 0.073 0.532 ⫾ 0.161‡

⫺0.178 ⫾ 0.471 ⫺0.310 ⫾ 0.063‡ ⫺0.081 ⫾ 0.071 0.795 ⫾ 0.162‡

* p ⬍ 0.05. ‡ p ⬍ 0.001. § R adj2, adjusted R 2 . ¶ Model adjusted for weight factors. ** Model adjusted for insulin/glucose factors. †† Model adjusted for lipid factors. ‡‡ Model adjusted for weight, insulin/glucose and lipid factors.

obscure. It was demonstrated that adiponectin enhanced fatty acid ␤-oxidation by the activation of adenosine monophosphate-activated protein kinase (20). The effects of adiponectin on HDL-C could be indirectly mediated by its effects on TG metabolism. Whether adiponectin may increase HDL-C by direct modulation of the reverse cholesterol transport pathway has not been explored yet. Low plasma adiponectin may predispose children to increased CAD risk in adulthood not simply through the association with the adverse metabolic profiles. Adiponectin was shown in vitro to modulate adhesion molecule gene expression in cultured endothelial cells, thereby reducing monocyte attachment to endothelial cells (19). Adiponectin also suppresses cholesterol ester accumulation in cultured macrophages (34). Adiponectin may decrease neointimal formation by modulating smooth muscle cell proliferation (23,27). Recently, it was reported that overexpression of adiponectin reduced atherosclerosis through attenuating endothelial inflammatory response and macrophage-to-foam cell transformation in apolipoprotein E-deficient mice (22). In addition, impaired endothelial function has been found to be associated with low plasma adiponectin levels in humans (35). The incidence of cardiovascular death was higher in patients with lower plasma adiponectin compared with those with higher adiponectin levels among patients with end-stage renal disease (36). Ouchi et al. noted that the plasma adiponectin levels were lower in CAD patients than normal controls (19). Moreover, Kumada et al. also found 122


that hypoadiponectinemia was associated with the prevalence of CAD independent of other well-known CAD risk factors (37). Therefore, adiponectin seems to have direct anti-atherogenic properties. Previously, we and others have documented a positive correlation between plasma adiponectin levels and age in adults (12,38). In this study, we noted that plasma adiponectin levels decreased with increasing age in adolescents. Interestingly, the plasma adiponectin concentrations have been found to decline with aging in Rhesus monkeys (39). IR during puberty has been demonstrated in previous studies (40,41). Pubertal IR may be explained by an increase in BMI and adiposity during puberty (42,43). Taken together, these results suggest that changes in circulating adiponectin may be related to the development of IR in puberty. However, we did not find the Tanner’s stage to be related to plasma adiponectin levels. The mean plasma adiponectin concentrations in adolescents measured by RIA in this study seemed to be higher than those in children and adults measured using an enzyme-linked immunoassay in previous reports (12–19,29,30). Our subjects were younger in age and in general healthier in metabolic profile; therefore, they were expected to have higher plasma adiponectin levels. Age effect may also explain at least a part of it. In the chronological observation of Rhesus monkeys, the plasma adiponectin concentrations were ⬃2- to 3-fold higher in childhood than those in adulthood (39). In this study, we observed the same relationship


of plasma adiponectin with almost all anthropometric indices and metabolic variables previous reported in adults (12–14,17–19), suggesting that the RIA is good at least for research purposes. In conclusion, we demonstrated that the relationship between the plasma adiponectin levels and the anthropometric indices and the CAD risk factors previously found in adults was also present in healthy nondiabetic adolescents 10 to 19 years old. Potentially, hypoadiponectinemia, just like the other risk factors, may influence the progression of atherosclerosis very early in childhood and modulate the risk of CAD in their adulthood. Although our study was limited by the cross-sectional design and there was potential bias for the participation by the adolescents, our results suggest whether plasma adiponectin levels in childhood can serve as an independent risk factor for the development of metabolic syndrome or CAD in adulthood merits further investigation. Moreover, whether raising plasma adiponectin by lifestyle change or medical or surgical interventions in specific groups of subjects with hypoadiponectinemia (17,44,45) may modify their risk also awaits further study.

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