Medicine & Science in Sports & Exercise:
Lifestyle-Induced Decrease in Fat Mass Improves Adiponectin Secretion in Obese Adults
KELLY, KAREN R.1,2; NAVANEETHAN, SANKAR D.3; SOLOMON, THOMAS P. J.1; HAUS, JACOB M.1,4; COOK, MARC1; BARKOUKIS, HOPE2; KIRWAN, JOHN P.1,2,4,5
1Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; 2Department of Nutrition, Case Western Reserve University, School of Medicine, Cleveland, OH; 3Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, OH; 4Department of Physiology, Case Western Reserve University, School of Medicine, Cleveland, OH; and 5Metabolic Translational Research Center, Cleveland Clinic, Cleveland, OH
Address for correspondence: John P. Kirwan, Ph.D., Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue/NE-40, Cleveland, OH 44195; E-mail: email@example.com
Submitted for publication May 2013.
Accepted for publication October 2013.
Purpose: Several studies have identified relationships between weight loss and adipokine levels; however, none have looked at the combined effect of aerobic exercise training with the consumption of a low- or a high-glycemic diet. We examined the effects of 12 wk of aerobic exercise combined with either a low–glycemic index diet (∼40 U) plus exercise (LoGIX) or a high–glycemic index diet (∼80 U) diet plus exercise (HiGIX) on plasma leptin and adiponectin (total and high molecular weight [HMW]) in 27 older obese adults (age = 65 ± 0.5 yr, body mass index = 34.5 ± 0.7 kg·m−2).
Methods: Insulin sensitivity was calculated from an oral glucose tolerance test. Fasting HMW adiponectin and leptin were quantified from plasma samples obtained before the insulin sensitivity index obtained from the oral glucose tolerance test. Glucose and insulin measures were obtained before and every 30 min during the test. Dual-energy x-ray absorptiometry and computerized tomography were used to determine body composition and to quantify subcutaneous and visceral abdominal adiposity, respectively.
Results: Fasting leptin was significantly decreased in both groups (LoGIX: preintervention = 33.8 ± 4.7, postintervention = 19.2 ± 4.5; HiGIX: preintervention = 27.9 ± 4.2, postintervention = 11.9 ± 2.2 ng·mL−1; P = 0.004), and HMW adiponectin was significantly increased (LoGIX: preintervention = 1606.9 ± 34.6, postintervention = 3502.3 ± 57; HiGIX: preintervention = 3704.8 ± 38.1, postintervention = 4284.3 ± 52.8 pg·mL−1; P = 0.003) after the 12-wk intervention. Total body fat was reduced after both interventions. Visceral fat mass was inversely correlated with HMW adiponectin, whereas subcutaneous fat correlated with leptin.
Conclusions: The data suggest that exercise training, independent of dietary glycemic index, favorably alters HMW adiponectin and leptin secretion and that a reduction in visceral fat mass is a key factor regulating HMW adiponectin in older obese persons.
Adipose tissue plays an active role in regulating energy homeostasis, and this is partly achieved through secretion of various adipokines including leptin, adiponectin, resistin, and visfatin (1,14). Lower adiponectin levels in obesity are associated with chronic inflammation, endothelial dysfunction, enhanced oxidative stress, and insulin resistance. More specifically, high molecular weight (HMW) adiponectin is the biologically active isoform that significantly correlates with insulin sensitivity and has been linked to inflammation. Recently, Kirwan et al. (15) showed that a low–glycemic index (GI) diet combined with exercise augments insulin sensitivity. Further, we have previously shown that aerobic exercise training combined with a low-glycemic diet alleviates inflammation in older obese persons (13). However, the mechanistic link between inflammation and insulin sensitivity and the role of GI diets in combination with exercise are not known. Adiponectin may be a candidate for the aforementioned connection as it has been shown to regulate both lipid and glucose metabolism in skeletal muscle (18). Moreover, elevated leptin levels are also associated with obesity and insulin sensitivity and exert adverse pleiotropic effects on several organ systems, including the heart, kidneys, and sympathetic nervous system. Adiposopathy, a term that describes pathogenic adipocytes, is characterized by adipocyte hypertrophy and adverse endocrine consequences that lead to the development of type 2 diabetes, hypertension, and cardiovascular disease (1,2).
Several studies have shown that both moderate- and high-intensity acute and short-term exercise (including one bout of exercise) improves insulin resistance (16,31). Recently, we reported that seven consecutive days of aerobic exercise improves insulin sensitivity, fat oxidation, and HMW adiponectin in obese individuals, independent of changes in body weight (12,31). Further, we found that insulin sensitivity was related to changes in adipokine secretion, specifically leptin and HMW adiponectin. Although there are data on the combined effects of diet and exercise on changes in leptin and improvements in insulin sensitivity, there is a paucity of data with respect to changes in HMW adiponectin. Previously, we found that 12 wk of exercise training decreased plasma leptin (32) and altered the adiponectin multimer ratio, favoring an increase in HMW oligomer ratio as compared with middle molecular and low molecular weight isoforms (25) in obese humans. Further, we showed that older insulin-resistant adults on a low-glycemic diet reduced pro-inflammatory cytokine secretion as compared with those on a high-glycemic diet (13). Cytokines that are known to target adipose tissue are also produced and secreted from adipocytes, inducing disruption in adipose tissue metabolism and function (1,2,8). Thus, if a low-glycemic diet can attenuate cytokine production, a low-glycemic diet may alter adipose tissue function.
Although there are data to show that obesity is associated with abnormal leptin and adioponectin levels, there is a gap in the literature regarding the effects of a low-glycemic diet combined with exercise on adiponectin and leptin levels in older obese insulin-resistant adults. A eucaloric low-glycemic diet has been shown to lower total fat mass and serum leptin levels in both overweight nondiabetic men (4) and insulin-resistant subjects (40). In the Health Professional’s Follow-up Study, a low dietary GI was associated with higher total plasma adiponectin concentrations (28). Furthermore, an 8-wk hypocaloric diet increased circulating adiponectin in obese subjects (6). However, none of the previous studies examined the combined effects of aerobic exercise and a low-glycemic diet on adipokines.
Thus, the purpose of this study was to determine the effects of a low-glycemic diet and aerobic exercise intervention on changes in HMW adiponectin and leptin in older obese, insulin-resistant adults. We hypothesized that (a) the effects of a low-glycemic diet plus exercise intervention would elicit greater improvements in circulating HMW adiponectin and leptin and reduce insulin resistance compared with a high-glycemic diet and exercise intervention and (b) increased insulin sensitivity would, be at least partially related to an increase in circulating HMW adiponectin concentrations.
Thirty-four older obese previously sedentary adults (age range = 60–75 yr, average age = 65 ± 0.5 yr, body mass index = 34.5 ± 0.7 kg·m−2) were recruited from the local community to undergo a 12-wk exercise training and diet intervention. Participants in this study were part of a larger randomized clinical trial, and some of the data from these subjects were reported in related studies (13,30). All volunteers underwent a medical history, a physical exam, an oral glucose tolerance test (OGTT), and a complete blood profile (lipid profile and hepatic/renal/hematological function tests). Individuals with heart, kidney, liver, thyroid, intestinal, and pulmonary diseases or those taking medications known to affect the outcome variables were excluded. Screening also excluded those with any contraindications to physical activity highlighted during a resting 12-lead electrocardiogram and a submaximal exercise stress test. Female subjects were postmenopausal and, based on self-report, were not using hormone replacement therapy. Prior physical activity levels were recorded using the Minnesota Leisure Time Physical Activity questionnaire (34); volunteers were deemed sedentary if their leisure time activity was less than 300 kcal·d−1. Subjects were required to be weight stable for at least the previous 6 months. Individual total caloric requirements were determined by the measurement of basal metabolic rate and the application of a standard activity factor of 1.2, which is consistent with a sedentary lifestyle (30,36). The study was approved by the Cleveland Clinic institutional review board, and all subjects provided signed informed written consent in accordance with guidelines for the protection of human subjects.
Subjects were randomized to one of two groups: either low-GI diet plus exercise (LoGIX) or high-GI diet plus exercise (HiGIX). All volunteers undertook 60 min of aerobic exercise 5 d·wk−1 for 12 wk. Exercise intensity was targeted at ∼85% of the maximum heart rate obtained during an incremental maximal aerobic exercise test (V˙O2max test). Every session was fully supervised by an exercise physiologist. All meals for the 12-wk intervention were provided to participants on a daily basis. Diets were designed by a registered dietitian and based on measured resting metabolic rate and activity, as previously described (13,30). Participants were in negative energy balance relative to the exercise session only; otherwise, diets were isocaloric to the subjects’ individual requirements. The dietary macronutrient composition (including fiber) was matched between groups; however, the diets were calculated so that the LoGIX subjects received a diet with an average GI of 40 U, whereas HiGIX subjects consumed foods with an average GI of 80 U as previously described (30). The primary difference between the two diets was the carbohydrate provided to achieve the GI and the load. An example of food substitution includes white rice (HiGIX) versus barley or quinoa (LoGIX). Adherence to the diet was determined via daily food container weigh backs, plus a weekly counseling session with the study dietitian. Dietary analysis was performed using Nutritionist Pro software (Axxya Systems, Stafford, TX).
Height and body weight were measured by standard techniques (26). Whole body adiposity (fat mass and fat-free mass) was measured by dual-energy x-ray absorptiometry (model iDXA; GE Healthcare Lunar, Madison, WI). Computerized tomography scanning was used to quantify subcutaneous (both deep and superficial) and visceral abdominal adiposity with a SOMOTOM Sensation 16 Scanner (Siemens Medical Solutions, Malvern, PA), as previously described (26).
An incremental, graded treadmill exercise test was used to determine maximal oxygen consumption (V˙O2max; Jaeger Oxycon Pro, Viasys, Yorba Linda, CA). Maximal heart rate recorded during this test was used to prescribe the correct exercise intensity during training as previously described (26). V˙O2max tests were also performed at weeks 4 and 8 to maintain the appropriate exercise intensity corresponding to changes in participants’ aerobic fitness. To control for the acute effects of exercise, preintervention V˙O2max tests were conducted >48 h before metabolic measures.
Inpatient control period
Pre- and postintervention assessments of body composition, aerobic fitness, glucose tolerance, and adipokines were performed during a 3-d inpatient stay in the Clinical Research Unit. During this period, participants received a weight maintenance eucaloric diet (total kilocalories per day = resting metabolic rate × 1.2; 55% carbohydrate, 28% fat, and 17% protein), as previously described (30).
Oral glucose tolerance test
A 75-g OGTT was performed after an overnight fast, pre- and postintervention. Fasting baseline samples were drawn to determine initial glucose and insulin concentrations. Following baseline draws, a 75-g glucose drink was ingested within a 10-min period. Blood samples were drawn at 30, 60, 90, 120, and 180 min after ingestion. Plasma glucose was determined immediately on a YSI 2300 STAT Plus analyzer (Yellow Springs, OH). The samples were stored at −80°C for subsequent substrate analysis. Plasma insulin was determined via radioimmunoassay (Millipore, Billerica, MA). Insulin sensitivity was determined using the Matsuda index (23).
Baseline blood samples were collected after an overnight fast before the OGTT. All blood samples were measured in duplicate, and each participant’s pre- and postintervention samples were analyzed per batch. Plasma leptin and total and HMW adiponectin were analyzed using enzyme-linked immunosorbent assay (Millipore).
Between-group (LoGIX vs HiGIX) comparisons were analyzed using a two-way (group × time) repeated-measures ANOVA. Baseline values for each variable were compared between groups using Student’s t-test. Bivariate correlation analyses were used to identify relationships between variables. Statistical significance was accepted when P < 0.05. Analyses were carried out using StatView for Windows 5.0.1 (SAS Institute Inc., Cary, NC), and all data are expressed as mean ± SEM.
Twenty-seven individuals (LoGIX, N = 12, 6 women/6 men; HiGIX, N = 15, 7 women/8 men) completed the 12-wk intervention. Seven subjects withdrew from the study for personal reasons and/or inability to comply with the diet and adherence to the exercise program.
Diet and exercise
Dietary analysis shows that diets for both groups were matched with respect to macronutrient composition, including fiber, with GI values of 40.1 ± 0.2 and 80.1 ± 0.5 U, respectively (Table 1). The glycemic responses to the study diets were confirmed and were reported in a separate publication (31). Diet and exercise compliance was high (∼97%). Exercise was performed at 83.2% ± 0.5% of HRmax, and after the study, there was an increase in V˙O2max in both groups (LoGIX, preintervention: 39.3 ± 1.6, postintervention: 44.4 ± 3.4; HiGIX, preintervention: 39.6 ± 1.4, postintervention: 45.7 ± 1.8 mL·kg−1 fat-free mass per minute, P = 0.0003).
Subject groups were well matched for body mass index before the onset of the intervention (P > 0.05). After the study, both groups significantly reduced body weight, and there was no difference between the groups for weight loss achieved (Table 2). Whole body fat mass was markedly reduced in both groups, as was total abdominal, subcutaneous, and visceral fat mass (Table 2).
The lifestyle intervention reduced fasting plasma glucose and insulin in both the LoGIX and the HiGIX groups (Table 2; all P < 0.05). Further, there was a significant improvement in insulin sensitivity in both groups as determined by the Matsuda index (LoGIX: preintervention = 1.8 ± 0.3, postintervention = 3.5 ± 0.4; HiGIX: preintervention = 2.5 ± 0.5, postintervention = 4.7 ± 0.8, P < 0.0001)
Fasting plasma leptin was significantly decreased in both groups (LoGIX = Δ14.6 ± 4.6, HiGIX = Δ16.0 ± 3.2 ng·mL−1, P = 0.004; Fig. 1A), and HMW adiponectin was significantly increased (LoGIX = Δ1895.4 ± 45.9, HiGIX = Δ579.2 ± 45.5 pg·mL−1, P = 0.003; Fig. 1B) after the 12-wk intervention. There was no change in total adiponectin for either group (P = 0.75). The HMW adiponectin to leptin ratio was significantly increased after the intervention (LoGIX: preintervention = 0.06 ± 0.03, postintervention = 0.46 ± 0.08; HiGIX: preintervention = 0.2 ± 0.05, postintervention = 1.2 ± 0.1; preintervention; P = 0.04; Fig. 1C), with no difference between groups.
There was an inverse correlation between changes in leptin and HMW adiponectin after the intervention (r = −0.46, P = 0.02). Further, there was a strong positive correlation between total adiponectin and HMW adiponectin (r = 0.62, P = 0.003). Although there was no significant change in total adiponectin, the increase in HMW isoform indicates a shift in isomer distribution that favors posttranslational processing of the active form of the protein. There was no association between pre-HMW levels and visceral fat (r = 0.025, P = 0.9); however, after the intervention, the HMW form of the protein was inversely correlated with visceral fat (r = −0.48, P = 0.01; Fig. 2). Further, the improvement in insulin sensitivity correlated with the change in body weight (r = −0.57, P = 0.005), specifically the change in total fat mass (r = −0.63, P = 0.001) and the change in total abdominal fat (r = −0.42, P = 0.04). As expected, changes in total abdominal fat were related to changes in both visceral and subcutaneous fat (r = 0.57, P = 0.003; r = 0.84, P < 0.001, respectively).
The primary finding from this study is that 12 wk of aerobic exercise combined with weight loss favorably alters adipokine secretion independent of the dietary GI, contrary to the original hypothesis that a low-glycemic diet would elicit changes as compared with a high-glycemic diet. HMW adiponectin is inversely associated with metabolic syndrome, insulin resistance, and blood lipids (11,39). We recently reported that 12 wk of aerobic exercise training combined with either a low- or high-glycemic diet improved peripheral and hepatic insulin resistance and severity of metabolic syndrome (22,30) and that short-term aerobic exercise increased circulating HMW adiponectin and reduced circulating leptin (12). Herein, we demonstrate that regular exercise training, independent of diet, not only increases HMW adiponectin but also induces changes in HMW adiponectin that are related to change in visceral fat and changes in leptin.
It has been suggested that circulating HMW adiponectin may be influenced by the magnitude of weight loss and correlates with body mass (6,17); however, we found no associations between HMW adiponectin and weight loss. This suggests that it is not the magnitude of weight loss but rather the location from which the fat is reduced, or rather the change in fat distribution, that regulates leptin and adiponectin concentrations (17,33). Evidence suggests that the accumulation of intra-abdominal visceral fat can lead to dysfunctional adipocytes, resulting in metabolic disease (1,2,8). We report that participants in this study significantly reduced total abdominal fat, subcutaneous fat, and visceral fat and that changes in adipose tissue distribution are related to changes in adipokine secretion. Recently, Kishida et al. (17) and Tamei et al. (33) reported that visceral fat was inversely related to plasma HMW adiponectin in obese people. Our findings concur with these reports suggesting that HMW adiponectin concentrations are dependent on visceral fat mass. In addition, we found a direct correlation between leptin and subcutaneous fat. Although both adipose tissue depots produce and secrete leptin and adiponectin, subcutaneous adipose tissue has been shown to be the major site of leptin secretion, and strong correlations between leptin secretion and subcutaneous adipocyte cell size and secretion rate have been found (35). Moreover, there are consistent observations that enlarged adipocytes are independent markers of insulin resistance (21,27), and it has been shown that adipocyte cell size decreases with aerobic exercise training and diet-induced weight loss (38). We measured changes in body weight, total abdominal fat mass (CT scan), and total body fat mass (DEXA) and showed that these changes correlated with changes in insulin sensitivity. Previous data suggest that the modification of dietary carbohydrate intake can reduce both systemic levels and adipose tissue production of inflammatory cytokines (3,10,37); thus, we hypothesized that those randomized LoGIX group would have greater improvements in adipokine regulation than those in the HiGIX intervention
However, herein we report that 12 wk of exercise training, independent of dietary composition, leads to the normalization of adipokine secretion and insulin sensitivity, possibly due to a decrease in adipocyte cell size. Although diet may influence cytokine release from adipose tissue, the present data suggest there is no dietary influence on adipokine secretion. The variance in protein secretion is likely due to the different cell sources within adipose tissue; cytokines are released from nonfat tissue, whereas leptin and adiponectin are secreted from adipocytes. We also found that changes in HMW adiponectin were related to the change in leptin. In human obesity, these two adipokines are reciprocally related: circulating adiponectin is depressed, whereas leptin is elevated (14). Further, the adiponectin-to-leptin ratio is known to correlate with insulin resistance, atherogenesis, and metabolic syndrome (7,29) and is therefore likely to reflect the overall balance of adipocyte function and health. Bays et al. (2) recently coined the term “adiposopathy” to describe abnormal endocrine function in obesity and suggested that the adiponectin/leptin index can provide an indication of the health of the adipocyte. Adiposopathy can be translated as representing “sick fat,” and this term emphasizes that adipose tissue has as much of a pathogenic potential to cause ill health as the pathologic dysfunction of other body tissues. Morphologically, adiposopathy manifests as enlarged adipocytes with a concomitant increase in visceral and/or ectopic fat deposition. Physiologically, adiposopathy is characterized by adverse endocrine and immune function, including aberrant adipokine and cytokine production, which can contribute to chronic diseases such as type 2 diabetes and cardiovascular disease (2). Our results show that the increase in HMW adiponectin-to-leptin ratio after exercise and weight loss is independent of dietary GI and that there is an inverse correlation between the changes in HMW adiponectin and leptin. Thus, it can be surmised that after 12 wk of aerobic exercise with moderate weight loss, adipocyte health and function are enhanced and adipocyte size is likely reduced, resulting in the favorable changes in adipokine secretion.
Both groups showed favorable improvements in adipokine secretion and insulin sensitivity independent of diet; thus, from these data, it seems that dietary GI did not influence the regulation of leptin and adiponectin in this older obese population. However, improvements in diabetes, cardiovascular disease, and obesity-related parameters have been documented in people consuming low-glycemic foods (5,19,20). Recently, low-glycemic diets alone have been shown to modestly increase adiponectin and reduce leptin (24), whereas other studies have shown that these changes are independent of dietary composition (9). The diets that were used in the current study were matched for the percentage composition of macronutrients in the diet as well as fiber, with the only variable being the GI of the carbohydrates. Therefore, the contrary findings in this study as compared with others may be because the only dietary difference was the quality of the carbohydrate, suggesting that postprandial blood glucose concentrations may not be the driving factor in adipokine regulation.
In conclusion, our results show that quantitative change in fat mass, after exercise and weight loss, seems to be the more important factor regulating adipokine production and secretion in older obese persons. We found no additional benefit of including a low-glycemic diet with exercise on insulin sensitivity or plasma adipokine concentrations. Further, the favorable changes in HMW adiponectin and leptin coupled to the changes in fat mass and insulin sensitivity suggest an improvement in adipocyte health and function. Adipocytes are of crucial importance, buffering the daily influx of dietary fat while regulating secretion of factors that act in an endocrine as well as autocrine/paracrine manner. Our data provide further evidence that the relationship between adiposity and adipokine production can be regulated by exercise, and these favorable improvements in adipocyte function can improve health in the older obese.
The authors thank the research volunteers for their outstanding dedication and effort, the nursing staff of the Clinical Research Unit, and the staff and students who helped with the implementation of the study and data collection. They also acknowledge their clinical research coordinator, Julianne Filion, B.S.N., R.N., for her excellent nursing and organizational assistance.
The authors report no conflict of interest.
This research was supported by the National Institutes of Health (NIH) (grant no. RO1 AG12834 to JPK) and was supported in part by the NIH National Center for Research Resources (grant no. CTSA 1UL1RR024989), Cleveland, Ohio. KRK and JMH were supported by NIH grant nos. T32 DK007319 and T32 HL007887, respectively.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
All authors contributed in writing the manuscript. K. R. Kelly, T. P. J. Solomon, and J. M. Haus performed data collection, analysis, and interpretation. S. D. Navaneethan performed data analysis and interpretation. M. Cook performed data collection. H. Barkoukis contributed in the design of the study and performed data collection and interpretation. J. P. Kirwan contributed in the design of the study and performed data collection, analysis, and interpretation.
Karen R. Kelly is now affiliated with the Naval Health Research Center in San Diego, Department of Warfighter Performance.
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ADIPONECTIN; LEPTIN; AEROBIC EXERCISE; GLYCEMIC DIET
© 2014 American College of Sports Medicine
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