Plasma Adiponectin Levels in Overweight and ... - Wiley Online Library

Plasma Adiponectin Levels in Overweight and Obese Asians Wei-Shiung Yang,*† Wei-Jei Lee,§ Tohru Funahashi,¶ Sachiyo Tanaka,¶ Yuji Matsuzawa,¶ Chia-Ling Chao,‡ Chi-Ling Chen,* Tong-Yuan Tai,* and Lee-Ming Chuang*†

Abstract YANG, WEI-SHIUNG, WEI-JEI LEE, TOHRU FUNAHASHI, SACHIYO TANAKA, YUJI MATSUZAWA, CHIA-LING CHAO, CHI-LING CHEN, TONG-YUAN TAI, AND LEE-MING CHUANG. Plasma adiponectin levels in overweight and obese Asians. Obes Res. 2002;10:1104 –1110. Objective: Hypoadiponectin has been documented in subjects with obesity, diabetes mellitus, or coronary heart disease, suggesting a potential use of plasma adiponectin in following the clinical progress in subjects with metabolic syndrome (MS). In this study, we investigated the plasma adiponectin levels in relation to the variables of MS among overweight/obese Asian subjects. Research Methods and Procedures: The plasma adiponectin, anthropometric and biochemical measurements, oral glucose tolerance tests (OGTT), and modified insulin suppression tests were performed on 180 overweight/obese Asian subjects [body mass index (BMI) ⱖ 23 kg/m2], including 47 subjects with morbid obesity (BMI ⱖ 40 kg/m2). Results: The plasma adiponectin levels negatively correlated with BMI, waist-to-hip ratio, fasting plasma glucose, insulin, triglyceride, uric acid levels, hyperinsulinemia, and glucose intolerance in OGTT, but positively with highdensity lipoprotein-cholesterol. In contrast, they were not related to blood pressure and total cholesterol. Moreover, insulin sensitivity, measured by quantitative insulin sensitivity check index (QUICKI) or in insulin suppression tests, significantly correlated with the plasma adiponectin levels. Among morbidly obese subjects, only the waist-to-hip ratio

Received for review April 24, 2002. Accepted for publication in final form July 30, 2002. *Department of Internal Medicine, National Taiwan University Hospital; †Graduate Institute of Clinical Medicine, College of Medicine; and ‡Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; §Department of Surgery, En Chu Kong Hospital, Taipei Hsien, Taiwan; and ¶Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan Address correspondence to Lee-Ming Chuang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: [email protected] Copyright © 2002 NAASO

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correlated with the plasma adiponectin levels. Using multivariate linear regression models, the area under curve of plasma glucose in OGTT and high-density lipoprotein-cholesterol among the overweight/obese subjects and WHR among the morbidly obese subjects were significantly related to the plasma adiponectin levels after adjustment for other variables. Discussion: In overweight/obese Asians, the plasma adiponectin levels significantly correlated with various indices of MS except hypertension. Whether the plasma adiponectin level could be a suitable biomarker for following the clinical progress of MS warrants further investigation. Key words: insulin resistance, metabolic syndrome, adiponectin, adipocytokines, obesity

Introduction Adiponectin is an adipose-specific plasma protein that has recently drawn substantial attention in the research of metabolic syndrome (MS) (1,2). In vitro studies using cell cultures have shown that it may have anti-inflammatory and antiatherogenic activities (3–5). Injections of recombinant adiponectin protein into mice acutely lowered plasma fatty acids and glucose, as well as improved insulin sensitivity, probably through a postreceptor mechanism (6,7). Chronic administration of the recombinant adiponectin in mice also reduced body weight (8). Lower plasma levels of adiponectin relative to the normal controls were documented in human subjects with obesity, type 2 diabetes (DM), or coronary heart disease (CHD) in several studies (3,9,10). The plasma levels of adiponectin were demonstrated to correlate positively with the measurements of insulin sensitivity in a human clamp study (11). Decline of the plasma adiponectin was also reported to parallel the development of DM in Rhesus monkeys (12). Furthermore, lifestyle change or medical interventions may modulate the plasma adiponectin levels (13–17). We previously reported a 46% increase in the plasma adiponectin levels after a 21% weight loss among 22 severely obese

Plasma Adiponectin Levels in Asians, Yang et al.

subjects who received gastric partition surgery (13). We also recently demonstrated in a double-blind randomized placebo-controlled trial that the treatment of rosiglitazone in DM patients raised the plasma adiponectin by more than 2-fold (14). The other investigators have also reported similar adiponectin raising-effects of the other thiazolidinediones (15–17). Taken together, these studies suggest that plasma adiponectin may potentially be a clinically useful biomarker to follow the progress of subjects with MS. Previous studies, however, have primarily focused on the differences of plasma adiponectin between the “disease” and the “nondisease” subjects separately with different disease entities (3,9,10). Because of wide variation in the plasma adiponectin levels in humans, probably from 1 to 20 ␮g/mL (3,9,11,13,14), determination of plasma adiponectin levels may not be useful for a diagnostic purpose. Therefore, we chose in this study to correlate the plasma adiponectin levels with various metabolic indices in a group of 180 overweight/ obese subjects who have more clinical relevance.

Research Methods and Procedures Subjects One hundred and eighty subjects (119 women and 61 men) were recruited at their yearly routine health check-ups or at the metabolic clinics for referral at National Taiwan University Hospital (NTUH). The characteristics of these subjects are shown in Table 1. Being overweight was defined as having a body mass index (BMI) ⱖ23 kg/m2, whereas obesity was defined as ⱖ25 kg/m2 based on the Asia-Pacific criteria set by the World Health Organization (18). Among them, 47 (28 women and 19 men) met the criteria for morbid obesity (BMI ⱖ 40 kg/m2; Table 2). No subjects were using any antihypertensive, antihyperglycemic, or lipid-lowering drugs before the evaluation in this study. Informed consent was obtained. The study was approved by the Medical Ethics Committee of NTUH. DM was defined as fasting plasma glucose ⱖ7 mM or 2-hour plasma glucose ⱖ11.1 mM measured during oral glucose tolerance tests (OGTT); hypertension was measured as systolic blood pressure (SBP) ⱖ140 mm Hg or diastolic pressure (DBP) ⱖ90 mm Hg; dyslipidemia was measured as fasting triglyceride ⱖ2.25 mM or high-density lipoproteincholesterol (HDL-C) ⬍0.88 mM; hypercholesterolemia was measured as total cholesterol ⱖ6.0 mM; and hyperuricemia was measured as serum uric acid ⬎357 mM in women and 446 mM in men (based on the laboratory references at NTUH). Anthropometrics and Biochemical Measurements The 75-g OGTT and a modified insulin suppression test to assess insulin-mediated glucose disposal reflected by the steady-state plasma glucose (SSPG) were given as previously described (13). The other measurements, including plasma levels of adiponectin, fasting concentrations of

Table 1. Means ⫾ SD of selected characteristics among 180 overweight/obese subjects and correlation analyses with plasma adiponectin levels showing correlation coefficients and p values Correlation with adiponectin n

Mean ⴞ SD

␥

p

180 180

5.34 ⫾ 2.10 43.6 ⫾ 10.3

0.22

0.0025

Waist (cm) Hip (cm) WHR DBP (mm Hg) SBP (mm Hg) PG 0 hours (mM) PG 0.5 hours (mM) PG 1 hour (mM) PG 1.5 hours (mM) PG 2 hours (mM) AUCg (mM) PI 0 hours (pM) PI 0.5 hours (pM) PI 1 hour (pM) PI 1.5 hours (pM) PI 2 hours (pM) AUCi (pmol 䡠 h/L) QUICKI SSPG (mM) TG (mM) Total cholesterol (mM)

180 177 177 177 180 180 180 124 162 124 162 124 178 123 161 123 159 120 178 176 179 180

34.08 ⫾ 7.65 107.8 ⫾ 18.7 113.0 ⫾ 16.3 0.95 ⫾ 0.09 75.1 ⫾ 13.8 127.7 ⫾ 21.7 6.58 ⫾ 2.20 9.91 ⫾ 2.40 11.22 ⫾ 3.47 10.46 ⫾ 3.91 9.04 ⫾ 3.58 19.6 ⫾ 5.9 95.7 ⫾ 79.2 545.3 ⫾ 459.8 647.3 ⫾ 471.5 717.6 ⫾ 560.7 513.5 ⫾ 480.5 1385 ⫾ 917 0.38 ⫾ 0.05 14.8 ⫾ 4.7 1.95 ⫾ 1.40 4.83 ⫾ 1.18

⫺0.23 ⫺0.24 ⫺0.15 ⫺0.22 0.11 ⫺0.03 ⫺0.13 ⫺0.17 ⫺0.17 ⫺0.20 ⫺0.12 ⫺0.20 ⫺0.30 ⫺0.041 ⫺0.18 ⫺0.22 ⫺0.18 ⫺0.21 0.284 ⫺0.21 ⫺0.26 ⫺0.093

0.0017 0.0014 0.043 0.0039 0.14 0.72 0.081 0.065 0.030 0.029 0.12 0.028 0.0000 0.65 0.025 0.017 0.024 0.023 0.0000 0.0059 0.0004 0.21

HDL-C (mM) Uric acid (mM)

176 1.30 ⫾ 0.42 0.37 164 434.1 ⫾ 119.4 ⫺0.23

Variables Adiponectin (␮g/mL) Age (years) BMI (kg/m2)

0.0000 0.003

BMI, body mass index; WHR, waist-to-hip ratio; DBP, diastolic blood pressure; SBP, systolic blood pressure; PG, plasma glucose; AUCg, area under curve of glucose; PI, plasma insulin; AUCi, area under curve for insulin; QUICKI, quantitative insulin sensitivity check index; SSPG, steady-state plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein-cholesterol. p ⬍ 0.05 was considered significant.

plasma glucose, total cholesterol, triglyceride, serum uric acid, and insulin levels, and insulin resistance index by homeostasis model assessment (HOMA), were performed as described (13). The insulin sensitivity by QUICKI model OBESITY RESEARCH Vol. 10 No. 11 November 2002

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Table 2. Means ⫾ SD of selected characteristics among 47 morbidly obese subjects and correlation analyses with plasma adiponectin levels showing correlation coefficients and p values Correlation with adiponectin Variables

n

Mean ⴞ SD

␥

p

Adiponectin (␮g/mL) Age (years) BMI (kg/m2) Waist (cm) Hip (cm) WHR DBP (mm Hg) SBP (mm Hg) PG 0 hours (mM) PG 0.5 hours (mM) PG 1 hour (mM) PG 1.5 hours (mM) PG 2 hours (mM) AUCg (mmol 䡠 h/L) PI 0 hours (pM) PI 0.5 hours (pM) PI 1 hour (pM) PI 1.5 hours (pM) PI 2 hours (pM) AUCi (pmol 䡠 h/L) QUICKI SSPG (mM) TG (mM) Total cholesterol (mM) HDL-C (mM) Uric acid (mM)

47 47 47 47 47 47 47 47 47 42 42 42 42 42 47 41 41 41 40 40 47 45 47 47 47 47

5.51 ⫾ 2.19 43.8 ⫾ 10.3 32.54 ⫾ 8.34 104.1 ⫾ 20.4 110.5 ⫾ 16.9 0.94 ⫾ 0.10 74.4 ⫾ 13.7 125.8 ⫾ 22.2 6.41 ⫾ 2.13 9.81 ⫾ 2.35 10.94 ⫾ 3.42 10.16 ⫾ 3.88 8.84 ⫾ 3.48 19.2 ⫾ 5.8 88.5 ⫾ 77.2 520.0 ⫾ 444.5 608.0 ⫾ 464.7 659.4 ⫾ 555.8 513.5 ⫾ 480.5 1839 ⫾ 1094 0.39 ⫾ 0.07 14.2 ⫾ 5.0 1.68 ⫾ 0.86 4.74 ⫾ 1.25 1.33 ⫾ 0.45 426.2 ⫾ 121.4

0.21 ⫺0.003 ⫺0.06 ⫺0.27 ⫺0.34 0.29 0.27 ⫺0.024 ⫺0.041 ⫺0.071 ⫺0.004 ⫺0.030 ⫺0.043 ⫺0.21 ⫺0.03 ⫺0.22 ⫺0.08 ⫺0.25 ⫺0.15 0.098 0.23 ⫺0.11 0.11 0.26 ⫺0.089

0.16 0.99 0.70 0.070 0.019 0.047 0.068 0.87 0.80 0.66 0.99 0.85 0.79 0.17 0.86 0.17 0.62 0.12 0.34 0.51 0.13 0.48 0.47 0.077 0.55

BMI, body mass index; WHR, waist-to-hip ratio; DBP, diastolic blood pressure; SBP, systolic blood pressure; PG, plasma glucose; AUCg, area under curve of glucose; PI, plasma insulin; AUCi, area under curve for insulin; QUICKI, quatitative insulin sensitivity check index; SSPG, steady-state plasma glucose; TG, triglycerides; HDL-C, high-density lipoprotein-cholesterol. p ⬍ 0.05 was considered significant.

was calculated as described (19). Because both the HOMA and QUICKI models gave similar results and the QUICKI model correlated with the plasma adiponectin slightly better than HOMA, we did not show the results from the HOMA. 1106


Statistical Analyses Data are presented in means and SDs. Statistical analyses including two-sample Student’s t test, correlation analyses, and multivariate linear regression analyses were performed using the PC version of the Stata statistical software: Release 6.0 (StataCorp., College Station, TX). Correlation matrix of all the clinical characteristics and plasma adiponectin levels was performed. Differences in means of plasma adiponectin between groups of different phenotypic categories were tested by Student’s t test. Several multivariate linear regression models were performed using plasma adiponectin level as the dependent variable and using age, gender, BMI, waist circumference, fasting plasma glucose, insulin, triglycerides, HDL-C, area under curve of glucose and insulin in OGTT, SBP and DBP, and serum uric acid levels as independent variables.

Results We investigated the relationship between plasma adiponectin levels and the selected clinical variables of MS or CHD risk factors among 180 overweight/obese Asian subjects (BMI ⱖ 23 kg/m2). The plasma levels of adiponectin correlated negatively with BMI, waist and hip circumferences, waist-to-hip ratio (WHR), fasting plasma insulin, triglycerides, and serum uric acid levels, but correlated positively with HDL-C levels (Table 1). The fasting plasma glucose was inversely related to the plasma adiponectin levels with a borderline significance (Table 1). In contrast, no correlation with both SBP and DBP and total cholesterol levels was noted (Table 1). OGTTs were performed in the overweight/obese subjects. The plasma glucose level at 0.5 hour correlated inversely with the plasma adiponectin levels, although not statistically significant (Table 1). The plasma glucose levels at 1 and 1.5 hours correlated significantly with the plasma adiponectin levels, whereas that at 2 hours did not (Table 1). In contrast, the plasma insulin levels at every time-point in the OGTT except at 0.5 hours correlated significantly with the plasma adiponectin levels (Table 1). The areas under curve of both the plasma glucose (AUCg) and insulin (AUCi) levels in OGTT also correlated inversely with the plasma adiponectin levels (Table 1). Using the QUICKI, we estimated the indices of insulin sensitivity among 178 overweight/obese subjects. The plasma adiponectin levels correlated positively with the insulin sensitivity index with QUICKI (Table 1). We further measured the SSPG in a modified insulin suppression test as an index for insulin-mediated glucose disposal among 176 overweight/obese subjects. The plasma adiponectin levels correlated negatively with SSPG (Table 1). Using multivariate linear regression analyses, only the AUCg and HDL-C were related significantly to the levels of plasma adiponectin after adjustment of the other variables among the overweight/obese subjects (Table 3;


Table 3. Multivariate linear regression models among overweight/obese or morbidly obese subjects showing regression coefficients ⫾ SE of plasma adiponectin levels as the dependent variable with age, gender, BMI, WHR, fasting plasma glucose, insulin, areas under the curve of glucose or insulin in OGTT, fasting triglycerides and HDL-C, diastolic and systolic blood pressures, and uric acid as dependent variables Dependent variable: adiponectin Independent variables Age (years) Gender BMI (kg/m2) WHR G0 (mg/dL) I0 (pM) AUCg (mg 䡠 h/dL) AUCi (pmol 䡠 h/mL) TG (mg/dL) HDL-C (mg/dL) DBP (mm Hg) SBP (mm Hg) Uric acids (mM)

Overweight/obese (n ⴝ 103)

Morbid obese (n ⴝ 40)

␤ ⴞ SE

p

␤ ⴞ SE

p

0.06 ⫾ 0.03 ⫺0.44 ⫾ 0.45 ⫺0.02 ⫾ 0.03 ⫺2.8 ⫾ 2.2 0.37 ⫾ 0.29 ⫺0.004 ⫾ 0.004 ⫺0.19 ⫾ 0.06 ⫺0.00001 ⫾ 0.00027 0.04 ⫾ 0.25 1.97 ⫾ 0.62 0.04 ⫾ 0.02 ⫺0.003 ⫾ 0.016 ⫺0.0006 ⫾ 0.0017

0.025 0.33 0.53 0.20 0.21 0.31 0.002 0.97 0.87 0.002 0.11 0.88 0.27

0.08 ⫾ 0.04 ⫺0.11 ⫾ 0.58 0.12 ⫾ 0.10 ⫺10.6 ⫾ 4.4 ⫺0.12 ⫾ 0.66 ⫺0.003 ⫾ 0.005 ⫺0.03 ⫾ 0.10 ⫺0.000007 ⫾ 0.0003 ⫺0.11 ⫾ 0.44 1.37 ⫾ 0.93 0.04 ⫾ 0.03 0.01 ⫾ 0.02 0.001 ⫾ 0.003

0.048 0.85 0.25 0.023 0.85 0.54 0.79 0.98 0.81 0.15 0.25 0.47 0.79

BMI, body mass index; WHR, waist-to-hip ratio; G0, fasting plasma glucose; I0, fasting plasma insulin; AUCg, area under curve for glucose; AUCi, area under curve for insulin; TG, triglycerides; HDL-C, high-density lipoprotein-cholesterol; DBP, diastolic blood pressure; SBP, systolic blood pressure. p ⬍ 0.05 was considered significant.

Figure 1, A and B). Taken together, the plasma adiponectin levels seem to be related to various MS phenotypes among which the postglucose load glucose tolerance and HDL-C seem to be most strongly related in overweight/ obese Asian subjects. Among subjects with morbid obesity (BMI ⱖ 40 kg/ m2), only the WHR remained significantly correlated with the plasma adiponectin levels in a negative manner (Table 2). The hip circumference and HDL-C correlated with the plasma adiponectin with a borderline significance (Table 2). Surprisingly, both the SBP and the DBP turned out to correlate positively with the plasma adiponectin levels in subjects with morbid obesity (Table 2). However, the plasma adiponectin levels were only related to the WHR among the morbidly obese subjects in regression analysis (Table 3; Figure 1C). The blood pressures were no longer related to the plasma adiponectin levels after the adjustment (Table 3). In fact, the DBP was no longer related to the plasma adiponectin levels simply by adjusting for the SBP in regression analysis (data not shown). Among the morbidly obese subjects, none of the variables in the OGTT, QUICKI, and SSPG stayed significantly

correlated with the plasma adiponectin levels (Table 2). For all the variables in Table 2, the findings were similar to those with a BMI ⱖ40 kg/m2 when the criterion of morbid obesity was lowered to 35 kg/m2 (n ⫽ 84, data not shown). In Table 4, the overweight/obese subjects were categorized by the selected phenotypes of MS or CHD risk factors. The mean plasma adiponectin level was significantly lower in subjects with dyslipidemia (Table 4). In addition, it was lower in subjects with DM, although not statistically significant (Table 4). In contrast, no difference in mean plasma adiponectin levels was noted between subjects with or without hypertension, hypercholesterolemia, or hyperuricemia (Table 4). Because plasma adiponectin levels were related to the three major risk factors of CHD (obesity, diabetes, and dyslipidemia), we categorized the subjects based on the number of CHD risk factors they had. The means of plasma adiponectin levels were progressively lower with increasing numbers of risk factors (Figure 2). Using multivariate linear regression, the plasma adiponectin levels would decrease by 0.54 ␮g/mL (p ⫽ 0.001) with every additional CHD risk factor after adjusting for age and sex among the overweight/obese subjects. OBESITY RESEARCH Vol. 10 No. 11 November 2002

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Figure 1: The relationship between the plasma adiponectin and (A) area under curve for glucose (AUCg) among the overweight/ obese subjects, (B) high-density lipoprotein-cholesterol (HDL-C) among the overweight/obese subjects, and (C) waist-to-hip ratio (WHR) among the morbidly obese subjects.

Discussion Adiponectin is an adipose tissue-specific plasma protein (1,2). Interestingly, plasma levels of adiponectin were reported to decrease in obese or type 2 diabetic subjects, even though these subjects tend to have more adipose tissue (3,9,10). Plasma adiponectin levels were also reported to be related to various phenotypic variables of MS and measurements of insulin sensitivity (3,9 –11). As expected, we found in overweight/obese Asian subjects that the plasma adiponectin levels correlated negatively with BMI, waist circumference, WHR, fasting plasma glucose, insulin, triglyceride and uric acid levels, and postglucose load hyperinsulinemia and glucose intolerance, but positively with 1108


HDL-C. The plasma adiponectin levels also correlated positively with the physiological estimates of insulin sensitivity. Mean plasma levels of adiponectin were indeed lower in the subjects with clinically defined diagnoses of diabetes and dyslipidemia. Although serum uric acid levels were related to the plasma adiponectin levels in correlation analysis, the mean level of plasma adiponectin was only slightly lower in the hyperuricemic overweight/obese subjects, without reaching the level of statistical significance. A study with a larger sample size may be necessary to conclusively address whether the plasma adiponectin levels may be reduced in subjects with hyperuricemia. On the other hand, our results clearly demonstrated that the plasma adiponectin levels were not related to blood pressure and total cholesterol levels. To our knowledge, this is the first report to claim that the plasma adiponectin levels are not related to hypertension, one of the major components of MS and CHD risk factors. Seemingly contradictory to our finding, a recent report showed that the plasma adiponectin levels were lower in healthy college men with “high-normal” blood pressure than those with optimal blood pressure (SBP ⬍ 120 mm Hg and DBP ⬍ 80 mm Hg) (20). The subjects in our study apparently were older, more obese, and with more clinical conditions of MS than the healthy young men in that study. In animal studies, the effects of recombinant adiponectin on body weight, glucose, and triglyceride metabolism were clearly demonstrated (6 – 8). However, no such experiment documenting its effect on blood pressure regulation was reported. The delineation of the relation between adiponectin and blood pressure requires more study. Another significant finding of ours is that plasma adiponectin levels seem to be most strongly related to HDL-C among all the other variables. The mean level of plasma adiponectin in the dyslipidemic overweight/obese subjects was clearly lower. Also interesting is that the plasma adiponectin levels seem to be positively related to age after adjusting for the other variables. It was previously reported that the plasma adiponectin levels were not correlated with age after adjusting for BMI (9). Could our results be caused by selection bias that more young obese women were included? In the regression analyses, the effects of gender and BMI were adjusted (Table 3). In fact, the mean age of morbidly obese subjects was not different from that of the whole group (Tables 1 and 2). The female/male ratio was lower in the morbidly obese group than that of the overweight/obese subjects. Therefore, it is not likely to be caused by the inclusion of more young obese women in this study. The resolution of this issue and its biological and clinical significance require more investigation. In addition, the correlation between the plasma adiponectin and the variables related to obesity and dyslipidemia remained significant among subjects ⱖ50 years old (above 75 percentile) in this study (data not shown). In contrast, the variables,


Table 4. The differences of mean plasma adiponectin levels between two groups of subjects with or without selected phenotypes Mean ⴞ SD of adiponectin (␮g/mL) Phenotypes Hypertension Diabetes mellitus Dyslipidemia Hypercholesterolemia Hyperuricemia

Absence (n)

Presence (n)

p

5.28 ⫾ 2.14 (136) 5.49 ⫾ 2.19 (121) 5.74 ⫾ 2.30 (116) 5.24 ⫾ 2.02 (158) 5.57 ⫾ 1.77 (49)

5.52 ⫾ 1.98 (44) 5.02 ⫾ 1.87 (59) 4.51 ⫾ 1.41 (59) 6.05 ⫾ 2.54 (22) 5.21 ⫾ 2.19 (115)

0.74 0.079 0.0005 0.96 0.15

p ⬍ 0.05 was considered significant.

such as plasma glucose and insulin, were not correlated with the plasma adiponectin, possibly because of reduced sample size in this subgroup analysis. Previously it was reported that plasma adiponectin levels were higher in women than in men (9). In view of the potential cardiovascular protective effects of adiponectin (3–5,21,22), higher plasma adiponectin levels in women may in part explain the protective effects of female gender against CHD. In our study, the mean plasma adiponectin level of the 119 overweight/obese females was slightly higher than that of the 61 overweight/obese males (5.49 ⫾ 2.30 vs. 5.04 ⫾ 1.63, p ⫽ 0.086, one-tailed t test). No relation between the plasma adiponectin levels and gender was noted after further adjustment for the other variables in linear regression models. Whether this could be responsible for the elimination of female advantage for CHD in the clinical conditions associated hypoadiponectinemia, such as DM (23), warrants further investigation. In the morbidly obese subjects, most variables were not significantly related to the plasma adiponectin levels except

Figure 2: The mean ⫾ SEM plasma adiponectin levels among overweight/obese subjects with various numbers of coronary heart disease (CHD) risk factors. ANOVA, p ⫽ 0.036.

WHR. This may be because of the relatively small sample size of this group (n ⫽ 47). However, the findings were similar even when the definition of morbid obesity was lowered to 35 kg/m2 to increase the sample size (n ⫽ 84, data not shown). Alternatively, this may simply imply that “body-weight factors” could be more important than the others in term of modulating the plasma adiponectin levels in this specific group. Consistent with this, we previously found that weight reduction in a group of obese subjects (mean BMI ⫽ 39.57 kg/m2) increased the plasma adiponectin (13). The increase in plasma adiponectin was only significantly related to the changes in BMI, waist and hip circumferences, and SSPG, but not to the other variables, such as fasting plasma glucose, insulin, triglycerides, and HDL-C (13). Although the plasma adiponectin levels were closely related to the clinical variables of MS that are commonly used in practice, we strongly suggest that adiponectin may still be a good biomarker to follow the progress of patients. Weight reduction by surgery in nondiabetic obese subjects or by lifestyle intervention in diabetic patients increased plasma adiponectin (10,13). Treatment of type 2 diabetic patients with sulfonylurea alone did not increase plasma adiponectin (14). In contrast, treatment with sulfonylurea plus glitazone drastically increased plasma adiponectin in the diabetic patients (14). In an interesting comparison, body-weight loss in Rhesus monkeys secondary to poor glycemic control without concomitant improvement in insulin sensitivity did not raise the plasma adiponectin levels (12). This indicates that plasma adiponectin may be a good marker for monitoring insulin sensitivity independent of the markers for glycemic control or body weight. In addition, we showed the plasma adiponectin levels were also related to the numbers of CHD risk factors that patients had, suggesting monitoring plasma adiponectin may be useful in subjects at risk of CHD. Whether interventions of risk reduction, OBESITY RESEARCH Vol. 10 No. 11 November 2002

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especially by using lipid-lowering drugs, may increase the plasma adiponectin levels warrants further investigation. Hypoadiponectinemia was demonstrated in subjects with CHD (3). In this study, we showed that hypoadiponectinemia was associated with increasing CHD risk factors. However, in vitro studies in cultured cells also suggest potential direct roles of adiponectin in atherosclerosis in vivo beyond the association with these risk factors (3–5). Extensive effort should be also devoted to this issue in the future.

Acknowledgments This work was supported by the Program for Promoting Academic excellence of Universities (89-B-FA01-1-4) from the Department of Education and a grant from the National Science Council (NSC 90-2314-B-002-145) of the Republic of China. References 1. Berg AH, Combs TP, Scherer PE. ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab. 2002;13:84 –9. 2. Havel PJ. Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin. Curr Opin Lipidol. 2002;13:51–9. 3. Ouchi N, Kihara S, Arita Y, et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 1999;100:2473– 6. 4. Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kappaB signaling through a cAMP-dependent pathway. Circulation. 2000;102:1296 –301. 5. Ouchi N, Kihara S, Arita Y, et al. Adipocyte-derived plasma protein, adiponectin, suppress lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation. 2001;103:1057– 63. 6. Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941– 6. 7. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947–53. 8. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA. 2001;98:2005–10. 9. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79 – 83. 10. Hotta K, Funahashi T, Arita Y, et al. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol. 2000;20: 1595–9.

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