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International Journal of Obesity (2003) 27, 1066–1071 & 2003 Nature Publishing Group All rights reserved 0307-0565/03 $25.00 www.nature.com/ijo

PAPER Adiponectin levels do not change with moderate dietary induced weight loss and exercise in obese postmenopausal women AS Ryan1,*, BJ Nicklas1, DM Berman1 and D Elahi2 1 Department of Medicine, Division of Gerontology at the University of Maryland School of Medicine, and the Baltimore Geriatric Research, Education and Clinical Center (GRECC), VA Maryland Health Care System, Baltimore, MD, USA; and 2Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

OBJECTIVE: The purpose of this study was to determine changes in adiponectin levels with moderate weight loss, weight loss plus aerobic exercise, or weight loss plus resistive exercise in overweight and obese, sedentary postmenopausal women. DESIGN: Longitudinal, clinical intervention study of 6-month (3  /week) program of either weight loss (WL, n ¼ 15), weight loss + aerobic exercise (WL+AEX, n ¼ 16), or weight loss + resistive exercise (WL+RT, n ¼ 9) SUBJECTS: We studied 40 sedentary, overweight and obese (body mass index, BMI ¼ 3271 kg/m2, X7s.e.m.) postmenopausal (5771y) women. MEASUREMENTS: Fat mass and fat-free mass (FFM) by dual-energy X-ray absorptiometry, plasma insulin, leptin, and adiponectin by radioimmunoassay. RESULTS: Age, body weight, BMI, waist and hip circumferences, waist-to-hip ratio, VO2max, percent fat, total body fat mass, FFM, and fasting plasma glucose, insulin, leptin, and adiponectin concentrations were similar among WL, WL+AEX, and WL+RT groups before the interventions. In all women combined, body weight, BMI, and waist and hip circumferences decreased (P o 0.001). There was a significant absolute decrease in percent body fat from 47 to 44%, representing a 13% decrease in total fat mass and a 1.6% change in FFM. Fasting concentrations of plasma adiponectin did not change (40716%, P ¼ NS), whereas fasting plasma glucose, insulin, and leptin all decreased (Po0.001). CONCLUSIONS: Plasma adiponectin levels do not change with a 6-month moderate weight reduction program even when accompanied by aerobic or resistive exercise training in overweight and obese postmenopausal women. International Journal of Obesity (2003) 27, 1066–1071. doi:10.1038/sj.ijo.0802387 Keywords: adiponectin; adipose tissue; physical activity; weight reduction; leptin

Introduction A sedentary lifestyle and the significant increase in obesity promote the development of cardiovascular disease and increase mortality risk among women.1,2 Recent estimates of the prevalence of obesity in women continue to escalate such that nearly 67% of women over the age of 50 y are considered overweight.3 The role of the adipose tissue for storage of fuel has recently been extended to include a contribution to whole-body metabolism because of the

*Correspondence: AS Ryan, Division of Gerontology, BT/18/GR, 10 N Greene St., Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA. E-mail: [email protected] Received 22 November 2002; revised 20 March 2003; accepted 16 April 2003

proteins secreted from this tissue including leptin, tumor necrosis factor (TNF)-a, and adiponectin.4–7 Isolated exclusively from adipose tissue, adipose most abundant gene transcript 1 or apM15 has a high similarity with collagens and complement factor Clq.5 Ironically, adiponectin is decreased in obesity8,9 and reduced in patients with type II diabetes and coronary heart disease,10 suggesting that it may have some protective effect against atherosclerosis.11,12 It has also been suggested that adiponectin is under feedback inhibition in obesity and that an intervention or treatment that increases adiponectin may be advantageous.13 Only three studies have examined changes in adiponectin levels with body weight reduction in humans.10,13,14 In these studies, large losses of body weight result in significant increases in plasma adiponectin concentrations.10,13,14 However, whether smaller losses of body

Adiponectin after weight loss and exercise AS Ryan et al

1067 weight loss elicit a change in adiponectin concentrations is unclear. Moreover, it is possible that exercise training when added to dietary-induced weight loss may also change adiponectin concentrations. An examination of changes in adiponectin after moderate weight loss alone or in combination with aerobic or resistive exercise in obese postmenopausal women has not been conducted. We tested the hypothesis that adiponectin levels would increase after moderate weight loss alone or in combination with aerobic or resistive exercise. Thus, the purpose of this study was to determine changes in adiponectin levels with weight loss, weight loss plus aerobic, or weight loss plus resistive exercise in overweight and obese, sedentary postmenopausal women. A second purpose was to examine whether changes in adiponectin concentrations correlate with changes in fasting plasma glucose, insulin, and leptin levels.

Methods All subjects were healthy, overweight and obese (body mass index, BMI 425 kg/m2; range 25–41 kg/m2) women between the ages of 50 and 70 y. The women were postmenopausal and had not menstruated for at least 1 y and/or had plasma FSH levels 430 mIU/ml. Only women who were weight stable (o2.0 kg weight change in past year) and sedentary (o20 min of aerobic exercise 2  /week) were recruited. Subjects were screened by medical history questionnaire, physical examination, fasting blood profile, and a graded exercise treadmill test in an attempt to exclude those with CVD. The women underwent a 2-h 75 g oral glucose tolerance test (OGTT).15 Blood samples were drawn at baseline and at the 2-h period for measurement of plasma glucose to exclude women with diabetes. All subjects were nonsmokers, showed no evidence of cancer, liver, renal, or hematological disease, or other medical disorders. A total of 63 women met all study criteria and were enrolled in either a dietary-induced weight loss only (WL, n ¼ 23), weight loss + aerobic exercise (WL+AEX, n ¼ 24), or weight loss + resistive exercise (WL+RT, n ¼ 16) for a period of 6 months. A total of 20 women dropped out of the program due to personal reasons, relocation, illness, and/or time constraints. Their characteristics were not different from the remaining women. Of the remaining 43 women who completed the study, 40 had blood samples analyzed for adiponectin and are included in this report. A total of 15 women completed WL (10 Caucasian; five African American), 16 women completed WL+AEX (13 Caucasian; three African American), and nine women completed WL+RT (all Caucasian). A total of 12 women (n ¼ 6 in WL; n ¼ 2 in WL+AEX; n ¼ 4 in WL+RT) were using hormone replacement therapy for at least 3 y prior to enrollment which did not change for the duration of the study. All methods and procedures for the study were approved by the Institutional Review Board of the University of Maryland. Each participant provided written informed consent to participate in the study.

Weight loss program During the 6-month weight loss intervention, all women attended weekly weight loss classes led by a registered dietitian for instruction in the principles of a hypocaloric diet that followed the American Heart Association (AHA) Step I16 guidelines. Compliance was monitored by weekly review of 7-day food records and 24-h dietary recalls. Women were instructed to restrict their caloric intake by 250– 350 kcal/day. The program focused on eating behavior, stress management, control of portion sizes, and modification of binge eating and other adverse habits.

Aerobic exercise program In addition to participating in the weight loss program, women in the AEX+WL intervention exercised at the Baltimore VA Medical Center GRECC exercise facility three times a week for 6 months using treadmills, cycle ergometers, and a track. Exercise sessions began at relatively low levels of aerobic capacity, based on the woman’s VO2max and subjective responses to the program. Each exercise session included a 10-min stretching and warm-up phase and a 10-min cool-down phase. They started to exercise at approximately 50–60% heart rate reserve and gradually progressed in duration and intensity until the women were able to exercise at 460% VO2max for 45 min. Women were taught to monitor their heart rate during exercise sessions and walk at speeds that produced an appropriate exercise intensity which was adjusted by personnel trained in CPR and exercise prescription to the target heart rate according to the Karvonen equation: Heart Rate Reserve (0.60–0.75) (HRmaxHRrest) + HRrest.17

Resistive training program In addition to participating in the weight loss program, the women in the WL+RT group exercised three times per week on nonconsecutive days for 6 months using eight exercises on pneumatic variable-resistance machines (Keiser K-250, Keiser Sports Health Inc., Fresno, CA, USA) and dumbbells at the Baltimore VA Medical Center GRECC exercise facility. Training began at a resistance of approximately five-repetition maximum (RM) or 90% of 3RM for the first three to four repetitions. Starting with the fourth or fifth repetition, resistance was reduced on the Keiser equipment just enough to permit the subject to complete a total of 15 repetitions.18 The training included the following exercises: leg press, chest press, leg curl, latissimus pull down, leg extension, chest press, seated butterfly, triceps extension (dumbbells), and biceps curl (dumbbells). After the entire circuit was completed, a second set of exercises was performed on the leg press, leg curl, and leg extension machines, but only one set was performed on the other exercises. Strength was measured in women in the WL+RT group before and after training. Prior to a strength assessment, the women participated in several training sessions using only International Journal of Obesity

Adiponectin after weight loss and exercise AS Ryan et al

1068 light resistance to become familiar with the equipment and the exercise techniques and to control for artificially high initial strength gains due to a motor learning effect. Upper body (chest press, latissimus pull down) and lower body (leg press, leg extension) strength was assessed by the 3RM test, defined as the maximum amount of weight that can be lifted successfully three times. Subjects attempted lifts with gradually increasing loads. Successive attempts were made with B30 s rest between attempts until failure to complete another repetition occurred. Approximately the same number of trials was used to reach the 3RM before compared to after training.

Maximal oxygen uptake (VO2max) VO2max was measured using a continuous treadmill test protocol as previously described.18 Briefly, speed was kept constant while the grade was increased from 0 to 4% at 2 min and then increased 2% every min after the third minute until the woman was unable to continue. Validation for attainment of VO2max included meeting two of the following three criteria: (1) a plateau in oxygen uptake with an increased work load as evidenced by a difference in oxygen uptake of o2 ml/kg min; (2) a respiratory exchange ratio 41.10; and (3) a maximal heart rate within 10 beats/min of the age-predicted maximal value.

Body composition Anthropometry: Height (cm) and weight (kg) were measured to calculate body mass index (BMI) as weight (kg)/height (m2). Waist circumference, measured at the narrowest point superior to the hip, was divided by the circumference of the hip, measured at its greatest gluteal protuberance, to obtain waist-to-hip ratio (WHR). Dual-energy X-ray absorptiometry (DXA): Fat mass, lean tissue mass, and bone mineral content (BMC) were determined by DXA (Model DPX-L LUNAR Radiation Corp., Madison, WI, USA). Fat-free mass (FFM) is reported as lean tissue plus BMC. All DXA scans were analyzed using the LUNAR Corporation Version 1.3z DPX-L extended analysis program for body composition analyses.

Blood sampling All subjects were weight stabilized (o1 kg) for at least 2 weeks prior to blood draws. They were also provided with a eucaloric diet for 2 days prior to blood draws by a registered dietitian. The composition of this diet was 50–55% carbohydrate, 15–20% protein, r30% fat and 300–400 mg of cholesterol per day, and a polyunsaturated to saturated fat ratio of 0.6–0.8. The number of calories given to each woman was estimated from the 7-day food records and estimates of energy expenditure were based on the Harris–Benedict equation.19 Blood draws were performed in the morning after a 12-h overnight fast. At the end of the 6-month International Journal of Obesity

program, the women in the WL+AEX or WL+RT groups were asked to continue the aerobic or resistive training 3 days/ week during the final testing period, and blood draws were performed 36–48 h after the last bout of exercise. Blood samples were collected in heparinized syringes and placed in prechilled test tubes containing 1.5 mg EDTA/ml of blood and aprotonin (400 kIU/ml) in a total volume that was 4% of the sample volume. The blood samples were centrifuged at 41C and a 1 ml aliquot of plasma was rapidly frozen (801C) for subsequent hormone analysis. All determinations were performed in duplicate. Plasma glucose was measured with the glucose oxidase method (Beckman Instruments, Fullerton, CA, USA). Immunoreactive insulin and leptin were determined as previously described.20 Human adiponectin levels were determined by a newly developed specific human adiponectin RIA (Linco Research Inc., St Charles, MO, USA). The inter- and intra-assay coefficient of variations are less than 10% at ED20, ED50, and ED80 concentrations of the standard range (1–200 ng/ ml). Since circulating levels are in mg/ml concentrations, samples were diluted 1/500 in assay buffer before estimation.

Statistical analyses Statistical significance between groups (WL vs WL+AEX vs WL+RT) was determined by ANOVA with simple contrasts. Following this, all women were combined into one group and changes in the variables of interest were calculated using paired t-tests. Adiponectin concentrations were log-transformed to achieve a more normal distribution. Relations between variables were determined by linear regression analyses and calculation of Pearson correlation coefficients. All data were analyzed by SPSS statistical software (SPSS Inc., Chicago, IL, USA). Data are expressed as mean 7 standard error of the mean (s.e.m.) and significance was set at the P o 0.05 level.

Results The physical characteristics of the women in each group before the interventions are presented in Table 1. Age, body weight, BMI, waist and hip circumferences, WHR, and VO2max were similar among WL, WL+AEX, and WL+RT groups. In addition, there were no differences in percent body fat, fat mass, and FFM between groups. Fasting plasma glucose, insulin, leptin, and adiponectin concentrations did not differ between groups before WL, WL+AEX, and WL+RT. ANOVA with simple contrasts revealed no significant differences in the change of body weight, BMI, circumferences, WHR, percent fat, fat mass, FFM, plasma glucose, insulin, leptin, and adiponectin levels between women in the WL, WL+AEX, or WL+RT groups. However, VO2max did not change with WL only or WL+RT, but increased with WL+AEX (1.7370.08 vs 1.8370.08 l/min, Po 0.05) and the change values were significantly different between groups

Adiponectin after weight loss and exercise AS Ryan et al

1069 Table 1

Physical and metabolic characteristics of women by intervention group Weight loss (n ¼ 15)

Age (y) Weight (kg) BMI (kg/m2) Waist circumference (cm) Hip circumference (cm) WHR VO2max (l/min) Percent body fat Fat mass (kg) Fat-free mass (kg) Fasting plasma leptin (ng/ml) Fasting plasma glucose (mmol/l) Fasting plasma insulin (pmol/l) Adiponectin (mg/ml) Log adiponectin (ng/ml)

Weight loss + aerobic exercise (n ¼ 16)

5671 89.973.8 33.671.2 95.372.8 119.773.3 0.8070.01 1.7870.09 48.170.9 43.272.5 45.671.4 33.973.4 5.5070.13 6479 4.5171.23 3.3970.14

5971 85.073.0 31.171.0 91.772.5 112.072.0 0.8270.01 1.7370.08 45.671.6 38.472.3 45.271.6 26.472.9 5.3670.10 5576 4.0671.68 3.2670.13

5772 85.974.9 31.471.2 94.573.5 114.073.5 0.8370.01 1.7270.13 47.371.7 40.573.0 44.872.6 29.873.7 5.4670.11 6375 3.7871.69 3.2970.17

BMI ¼ body mass index; VO2max ¼ maximal oxygen consumption; WHR ¼ waist-to-hip ratio. Values are means7s.e.m.

Discussion The results of the current study indicate that a 6-month program of weight loss alone, in combination with aerobic exercise training, or in combination with resistive training

All comparisons are nonsignificant.

20

15 Change in Adiponectin (µg/ml)

(Po 0.01). Upper body muscular strength increased 30% (134714 vs 167715 lb, Po0.001) and lower body strength increased 34% (436726 vs 537724 lb, Po0.001) in women in the WL+RT group. The physical and metabolic characteristics of the 40 women before and after the interventions are presented in Table 2. Body weight and BMI decreased by 7 and 6%, respectively (Po 0.001). Waist and hip circumferences both decreased by 3% (P’s o0.001), thus there was no change in the WHR. The changes in total body composition with the interventions demonstrate an absolute decrease in percent body fat of 3%, a 13% decrease in total fat mass (Po 0.001), and a small but significant –1.6% change in FFM (Po0.01). With the modest change of B6 kg with our perturbation, there was a significant decrease in fasting plasma glucose, insulin, and leptin (Po0.001). However, there was a very large variability in the change of fasting adiponectin (Figure 1) and thus, the average change (40716%) was not significant. There was also no significant change in adiponectin levels when women on hormone replacement therapy and/or when African-American women were removed from the analyses (PZ0.60, data not shown). We have previously reported the associations between log plasma adiponectin levels and BMI, percent body fat, fasting leptin, and fasting insulin across the age span in these and additional women.21 In the current study, the changes in body weight, body composition (percent body fat, fat mass, waist and hip circumferences, WHR), glucose, insulin, and leptin levels did not correlate with changes in adiponectin levels (data not shown).

Weight loss + resistive training (n ¼ 9)

10

5

0

-5

-10 Weight Loss

Weight Loss and Weight Loss and Aerobic Exercise Resistive Exercise

Figure 1 Change in adiponectin concentration for each postmenopausal woman after either weight loss (n ¼ 15), weight loss and aerobic exercise (n ¼ 16), and weight loss and resistive exercise (n ¼ 9).

are equally effective in reductions in body weight, total fat, and FFM in overweight and obese postmenopausal women. In addition, these behavioral dietary-induced weight loss (B6 kg) programs did not significantly change plasma adiponectin levels. To our knowledge, three studies have examined changes in adiponectin levels with body weight reduction. In two studies,13,14 plasma adiponectin concentrations increased 46 and 281% after severely obese patients underwent gastric partition surgery and lost a large amount (23 and –56 kg, respectively) of body weight. With a 10% decrease in BMI, adiponectin levels rose 42% in a small sample (n ¼ 13) of nondiabetic subjects who were hospitalized and placed on a calorie-restricted diet for 2 months.10 Although plasma adiponectin increased approximately 40% in our women, there was a large variability in the response as illustrated in International Journal of Obesity

Adiponectin after weight loss and exercise AS Ryan et al

1070 Table 2 Physical and metabolic characteristics before and after weight loss in postmenopausal women (n ¼ 40)

Age (y) Weight (kg) BMI (kg/m2) Waist circumference (cm) Hip circumference (cm) WHR Percent body fat Fat mass (kg) Fat-free mass (kg) Fasting plasma leptin (ng/ml) Fasting plasma glucose (mmol/l) Fasting plasma insulin (pmol/l) Adiponectin (mg/ml) Log adiponectin (ng/ml)

Before

After

5771 87.172.2 32.170.7 93.771.6 115.471.7 0.8170.01 46.970.8 40.771.5 45.371.0 30.071.9 5.4470.06 6074 4.1670.88 3.3270.08

F 81.472.0** 30.170.7** 90.471.6** 111.771.7** 0.8170.02 43.970.8** 35.671.4** 44.470.9* 22.171.9** 5.1170.08** 5173** 4.4071.09 3.3470.08

BMI ¼ body mass index; WHR ¼ waist-to-hip ratio. Values are means7s.e.m. Po0.01; **Po0.001.

*

Figure 1, and the change did not reach statistical significance. Perhaps, a greater amount of body weight loss is necessary to induce an increase in adiponectin levels as the losses in body weight were approximately one-fourth to onetenth that of subjects who underwent gastric bypasss.13,14 The amount of fat mass lost in the subjects in these previously published studies10,13,14 was not reported, so it is impossible to compare any differences in changes in fat mass per se. Yet, it is conceivable that because adiponectin may be under feedback inhibition in obesity, a greater loss of adipose tissue would result in a larger increase in adiponectin levels. It is also possible that differences in the subject selection contribute to the disparity in results. The subjects in the other studies had higher BMI values prior to weight reduction suggesting that more obese individuals who can and do lose more weight respond with an increase in adiponectin levels. Considering that our sample size was twice as great as the other studies,10,13 statistical power was not a concern. Our results also indicate that WL, WL+AEX, and WL+RT are equally effective in reductions of body weight and loss of total fat mass. The fact that loss of weight was not different between the weight loss only group and the WL+RT was expected because loss of body weight is not typical with resistive training alone.22 Yet, aerobic training can induce small amounts of fat mass loss,23 so it is possible that a slightly greater loss of fat mass could have occurred in the WL+AEX group. As there were no differences in the amount of body weight or fat mass loss between the three groups, we were able to combine the women to assess changes in adiponectin with weight loss. Although we did not observe changes in adiponectin levels, we did see a significant decrease in plasma glucose, insulin, and leptin concentrations with the interventions. The reported associations between leptin and insulin with International Journal of Obesity

adiponectin9,21,24 led us to expect that the drop in leptin and insulin would have been accompanied by an increase in adiponectin levels. Yet, we did not see correlations between changes in adiponectin and either glucose, insulin, or leptin concentrations. It is not clear why adiponectin is under feedback inhibition in obesity. Chronic administration of adiponectin in mice prevents a high fat diet-induced weight gain partially due to increased fatty acid oxidation in isolated muscle.25 Moreover, adiponectin treatment increases energy dissipation in lipoatrophic mice, increases the expression of enzymes involved in b-oxidation, as well as reduces hyperglycemia and hyperinsulinemia of obese mice suggesting that it reverses insulin resistance.26 In humans, neither the mechanisms for reported changes in adiponectin with weight reduction,10,13,14 nor whether or not these changes affect glucose utilization have been elucidated. We conclude from our data that plasma adiponectin levels do not change with a 6-month moderate weight reduction program even when accompanied by aerobic or resistive exercise training in overweight and obese postmenopausal women. It is possible that a larger amount of weight reduction achieved through very low-calorie dieting or gastric bypass/omentectomy surgery is necessary to elicit an increase in adiponectin levels. Additional studies are required to determine the mechanisms that are necessary or sufficient to change adiponectin concentrations with weight reduction.

Acknowledgements Our appreciation is extended to the women who participated in this study. We thank Adeola Donsumu, Dana Jones, Agnes Kohler, Gail Chin, and Elizabeth Misiura for laboratory assistance. This study was supported by funds from NIH Grants K01-AG00747 (ASR), R29-A614066 (BJN), K01AG00685 (DMB), the Department of Veterans Affairs, Geriatrics Research, Education, and Clinical Center at Baltimore.

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International Journal of Obesity

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