Effect of Individualized Exercise Training Combined

Original Paper Ann Nutr Metab 2010;56:260–266 DOI: 10.1159/000275888

Received: January 8, 2009 Accepted after revision: June 23, 2009 Published online: April 22, 2010

Effect of Individualized Exercise Training Combined with Diet Restriction on Inflammatory Markers and IGF-1/IGFBP-3 in Obese Children Omar Ben Ounis a Mohamed Elloumi a Hassane Zouhal c Emna Makni a Myriam Denguezli a Mohamed Amri b Gérard Lac d Zouhair Tabka a a

Laboratoire des adaptations Cardio-circulatoires, Respiratoires, Métaboliques et Hormonales à l’Exercice Musculaire 99/UR/0867, Faculté de Médecine Ibn-El-Jazzar, Sousse, et b Laboratoire de Physiologie, Faculté des Sciences, Université El-Manar, Tunis, Tunisie; c Laboratoire Mouvement Sport Santé (M2S), UFR APS, Université Rennes-2, Rennes, et d Laboratoire Biologie B, Biologie des Activités Physiques et Sportives, Aubière, France

Key Words Childhood obesity ⴢ Diet ⴢ Exercise training ⴢ IGF-1 ⴢ IGFBP-3 ⴢ Inflammatory markers

Abstract Aims: The present study was designed to examine the possible changes in body composition, insulin-like growth factor 1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3) and inflammatory markers of obese children in response to a 2-month program of exercise training combined with dietary restriction. Methods: Twenty-eight obese children (age 13.2 8 0.7 years, body mass index 30.9 8 1.3) were randomly assigned to a diet/training group or a control group and were tested two times: once before and once at the end of the experimental period. They performed a progressive cycle ergometer test at each visit. Substrate oxidation was evaluated by indirect calorimetry. Training was individualized at the point when fat oxidation was maximal (Lipoxmax). Results: Diet/training induced a significant decrease in body weight and body fat (after vs. before, p ! 0.01). Plasma concentrations of IGF-1, IGFBP-3 and inflammatory markers were significantly decreased after the completion

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of the program. The diet/training program resulted in an increase in VO2max ACSM (24.6 8 2.5 to 33.1 8 3.1 ml/min/kg, p ! 0.001) at the end of the intervention period. Conclusion: These data suggest that in the presence of weight loss, exercise training improves inflammatory markers and IGF-1 and IGFBP-3 levels in obese children. Copyright © 2010 S. Karger AG, Basel

Introduction

Cytokines produced by adipocytes or by adipose tissue-infiltrating macrophages are able to induce low-grade inflammation, which could play a central role in obesity and type 2 diabetes-related insulin resistance and cardiovascular complications [1]. Some cytokines and inflammatory markers such as leptin, C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-␣ not only affect metabolism, but also act directly on the vessels to promote atherosclerosis [2, 3]. The pleiotropic IL-6 has been demonstrated to be an independent risk factor for cardiovascular mortality [4], and it is also involved in the development Omar Ben Ounis Physiology Laboratory Faculty of Medicine TN–4002 Sousse (Tunisia) Tel. +216 2070 3111, Fax +216 7322 4899, E-Mail omar_oda @ yahoo.fr

of insulin resistance [5]. The acute phase protein CRP has a pro-inflammatory effect and is a well-established risk factor for cardiovascular disease, hypertension and stroke [6]. The cytokine TNF-␣ has been shown to have a direct role in the metabolic syndrome by inducing insulin resistance, a precursor for the metabolic syndrome and type 2 diabetes [7]. Physical activity has long been prescribed to reduce the incidence of disease. A large body of evidence exists suggesting that individuals who are either more physically active or more aerobically fit tend to have a more favorable cytokine profile [8, 9]. Many of the controlled intervention studies addressing this issue have shown that exercise improves cytokine levels; however, most of these trials have reported concomitant improvements in body weight and/or composition that occurred during the exercise training period [10, 11] or did not include measures of body fatness [12]. Because adipocytes are the main mediators of these hormones, changes in body composition confound the data concerning the direct effects of exercise on these variables. A strong association between obesity and insulin resistance, characterized by hyperinsulinemia, has been well documented [13] and there is evidence that insulinlike growth factors (IGFs) are implicated in several human malignancies related to obesity [14], including childhood leukemia [15]. Physical exercise is a powerful stimulus for growth hormone (GH) secretion, many actions of which take place by way of growth factors called somatomedins, the principal one being somatomedin-C or IGF1. IGF-1 plays a role in many physiological processes [16], particularly in organism anabolism, which is related to bone and muscular growth [17]. About 80% of IGF-1 present in a ternary 150-kDa complex including insulinlike growth factor binding protein-3 (IGFBP-3) and a protein called acid-labile subunit, with less than 1% of IGF-1 being free [18–20]. It is well documented that circulating levels of IGF-1 and IGFBP-3 are regulated by nutrition, age, pregnancy, chronic diseases, insulin and GH [20–22]. A reduction in IGF-1 concentration is commonly associated with nutritional deficiency [22]. Several studies have shown that intensive training stimulates both circulating IGF-1 and IGFBP-3, since positive significant correlations exist between these factors and physical fitness levels [23]. However, data reviewed in the literature concerning the variation in IGF-1 and IGFBP-3 after exercise present conflicting results, depending on the type of exercise and the degree of training [19, 24–26].

Diet/Training and IGF-1/IGFBP-3

The aim of the present study was to examine the effect of exercise training combined with dietary restriction on cytokines, inflammatory markers and changes in IGF-1 and IGFBP-3 over a 2-month intervention period in obese children. We hypothesized that an increase in physical activity and a decrease in body fat would result in a decrease in markers of inflammation and plasma concentrations of IGF-1 and IGFBP-3. Materials and Methods Subjects After baseline testing, 28 obese children (body mass index, BMI, 197th percentile for age and sex) [27] were randomly assigned to either an 8-week period of supervised exercise training combined with dietary restriction or a control group. All participants and parents gave written informed assent and consent, and the study protocol was reviewed and approved by the Research Committee of the Faculty of Medicine of Sousse, Tunisia. Criteria for participation in the present study included: no past history of cardiovascular disease, no history of prescribed medicine and no regular exercise. Anthropometry Each subject came to the laboratory for a medical examination and anthropometric measurements performed by a pediatrician before and after the 2-month intervention. Body weight was assessed to the nearest 0.1 kg with a digital scale (Ohaus, Florham Park, N.J., USA). Height was measured with a standing stadiometer and recorded with a precision of 1 mm. BMI was calculated as body weight divided by height squared. Skinfold thicknesses were determined in triplicate at two sites (triceps and subscapular) using a standard, recently calibrated Harpenden calliper (Holtain, Crosswell, UK). The body fat percentage (BF%) was calculated using the equation of Slaughter et al. [28] for children with triceps and subscapular skinfolds !35 mm: Boys: BF% = 1.21 (sum of 2 skinfolds) – 0.008 (sum of 2 skinfolds)2 – 1.7 Girls: BF% = 1.33 (sum of 2 skinfolds) – 0.013 (sum of 2 skinfolds)2 – 2.5 and for children with triceps and subscapular skinfolds 135 mm: Boys: BF% = 0.783 (sum of 2 skinfolds) – 1.7 Girls: BF% = 0.546 (sum of 2 skinfolds) + 9.7. Medical examination included evaluation of pubertal stages according to the classification of Tanner et al. [29] and resting arterial tension and heart rate measurements. Exercise Test Methodology Subjects were tested on an electromagnetically braked cycle ergometer (Ergoline, Bitz, Germany) using the protocol of Brandou et al. [30]. A metabolic analyzer (ZAN 600; ZAN Messgeräte, Oberthulba, Germany) provided breath-by-breath gas exchange data. Ventilatory parameters (VO2 and VCO2) were recorded throughout the testing and over the last 3 min of each step during submaximal exercise testing. Theoretical maximal oxygen intake (VO2maxth) and theoretical maximal aerobic power (Wmaxth) were

Ann Nutr Metab 2010;56:260–266

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calculated using the prediction equations of Wasserman et al. [31], which take age, sex and anthropometric characteristics for obese children into account: Girl: VO2maxth (ml/min) = [52.8 ! body weight (kg)] – 303.4 Boy: VO2maxth (ml/min) = [28.5 ! body weight (kg)] + 288.1 and the following equation was used to calculate Wmaxth [31]: Wmaxth = {VO2maxth – 10 [body weight (kg)]}/10.3. Heart rate was monitored continuously using an electrocardiogram (ZAN ECG 800; ZAN Messgeräte). After a 3-min rest, the work rate was increased progressively through five 6-min stages corresponding to 20, 30, 40, 50 and 60% of Wmaxth [30]. The parameter representative of the whole-body lipid oxidation during exercise was calculated, which is the maximum lipid oxidation point (Lipox max), expressed in watts, which corresponds to the exercise intensity at which the highest rate of lipid oxidation is achieved (lipid oxidation at Lipox max, expressed in mg/min), according to the following equation [30]: Lipid oxidation (mg/min) = 1.6946 VO2 – 1.7012 VCO2 (with VO2 and VCO2 expressed in ml/min). In the present study, we calculated VO2max according to the American College of Sports Medicine [32] (VO2max ACSM) who advise to express VO2 as a linear function of heart rate during at least two stages of submaximal exercise and to extrapolate VO2max from the maximal theoretical heart rate [theoretical maximal heart rate = 220 – age (years)]. Dietary Protocol The energy requirements for our subjects were estimated using the tables provided by Torun [33]. Taking into account their age and habitual activity, the average energy needs of our study participants were estimated at 2,528 kcal/day [33]. Subjects recorded meal times and the quantities of all food eaten for a week prior to the program. Nutrient intakes were calculated using a Bilnut program (Nutrisoft, Cerelles, France) and the food composition tables published by the Tunisian National Institute of Statistics in 1978. The diet program (diet/training group) was set at –500 kcal/day below the initial dietary records. This daily caloric reduction may not compromise the regular growth of our subjects because their daily intake was 13,000 kcal, which is too much for this age group [33, 34]. The foods were composed of 15% proteins, 55% carbohydrates and 30% lipids. Carbohydrates were primarily in the form of high-fiber whole grains (65 servings/ day), vegetables (64 servings/day) and fruits (63 servings/day). Protein was primarily derived from plant sources, with non-fat dairy (^2 servings/day) and fish and fowl served in ⬃100-gram portions (4 days/week) and in soups or casseroles (2 days/week). The diet contained !100 mg of cholesterol, and caffeinated beverages were not allowed during the program. Sodium intake was limited to !1,600 mg/day. All foods except animal-derived protein sources were served ad libitum. The education program was conducted 4 h/week at two local churches in the community where the participants lived. Lectures using PowerPoint presentations, videos, games and role-play scripts were designed for trainers to use during the education program. Subjects of the control group (and their parents) were instructed to maintain current eating behaviors for the duration of the 8-week study.

ticipate in structured exercise and were instructed to maintain current levels of physical activity. All exercise training was supervised, occurred four times per week (90 min/day) for 8 weeks, and consisted of warming up, running, jumping and playing with a balloon. The exercise intensity was fixed at a participant’s heart rate corresponding to Lipox max assessed at the first visit. The intensity of the exercise was controlled by monitoring the heart rate with a Sport-tester device (Vantage NV; Polar Electro, Kempele, Finland). Serum Measurements Before testing, it was ascertained that none of the subjects had been ill or injured in the previous 2 weeks. Testing was performed in the morning after children had fasted for at least 12 h. Fasting blood samples were collected from a forearm vein while seated. Samples were placed in an ice bath and centrifuged immediately. Aliquots of the resulting plasma were stored at –80 ° C until analyzed. IGF-1 and IGFBP-3 values were determined by immunoradiometric assay (Immunotech Kit; Immunotech, Marseille, France). The intra- and interassay coefficients of variation were 6.3 and 6.8% for IGF-1 at a serum concentration of 2 ng/ml, respectively, and 6 and 9.5% for IGFBP-3 at a serum concentration of 50 ng/ml, respectively. Plasma leptin levels were determined using an ELISA kit (B Bridge International, Sunnyvale, Calif., USA). Plasma levels of IL6 and TNF- ␣ were measured with saline using Quantikine ELISA kits from R & D systems (catalogue Nos. HS600 and HSTA00C, respectively). The intra-assay coefficients of variation were !10% for TNF- ␣ and IL-6 and 3% for leptin. The interassay coefficients of variation were 12.2% for TNF- ␣, 18.2% for IL-6 and 3.2% for leptin. CRP concentration was measured by a high-sensitivity particle-enhanced turbidimetric assay using a validated commercial hsELISA kit from Kalon Biological (Kalon Biological, Guilford, UK). Statistical Analyses All values were expressed as means 8 SD. Paired t tests were used to compare means before the program and at the end of the 2-month program. Partial correlation (adjusted for age, sex, BMI and pubertal stage) was employed to test for relationships between variables. Significance was accepted at p ! 0.05.

Results

Anthropometric and Dietary Data The two groups were matched for anthropometric parameters, age and pubertal stage before the intervention. Daily energy intake was significantly (p ! 0.01) reduced during the program for the diet/training group without any change in the control group. After the 8-week intervention program, BF% was significantly decreased (11.3%) in the diet/training group (table 1).

Training Protocol Before the program, all children practiced only 1 h/week of physical activity in their school. The control group did not par-

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Ben Ounis /Elloumi /Zouhal /Makni / Denguezli /Amri /Lac /Tabka

Table 1. Anthropometric characteristics and dietary intake before and after the 8-week intervention

Variable

Age, years Sex, males/females Tanner stage, I/II–III/IV–V Body weight, kg BMI BF% Energy consumed, kcal/day Fat, % Protein, % CHO, %

Diet/training (n = 14)

Control (n = 14)

before

before

after

13.180.8 7/7 4/5/5 83.7812.8 31.181.1 39.884.6 3,1368216 3982 1782 4481

73.289.8*** 27.281.3** 35.385.4*** 2,6268178** 3182** 1581 5582**

13.380.6 7/7 4/6/4 82.689.7 30.781.6 39.184.1 3,2128123 3881 1781 4581

after

83.8810.4 31.181.8 39.885.3 3,3288117 3981 1682 4581

I = Prepubertal children; II–III = pubertal children; IV–V = postpubertal children; CHO = carbohydrates. ** p < 0.01, *** p < 0.001, vs. before.

VO2maxACSM

45

*** for ⌬

40

33.1

VO2 (ml/min/kg)

35 30

24.6

23.7

24.8

25

the 8-week intervention period, all cytokines measured were significantly decreased (p ! 0.01) in the diet/training group. There was no change in any of the inflammatory markers over the 8-week intervention period in the control group. Plasma IGF-1 and IGFBP-3 concentrations were also significantly lower (p ! 0.01) in the diet/training group at the end of the program.

20 15 10 5 0

Before Diet/training

After Control

Fig. 1. Changes in VO2max ACSM before and after the program in diet/training and control groups. *** p ! 0.001.

Correlations Figure 2 shows that at the end of the intervention period, the change in BF% was significantly positively correlated with leptin (p ! 0.01), IL-6 (p ! 0.05), TNF-␣ (p ! 0.01), CRP (p ! 0.05), IGF-1 (p ! 0.01) and IGFBP-3 (p ! 0.05). The VO2max ACSM was significantly negatively correlated with leptin (p ! 0.01), IL-6 (p ! 0.05), TNF-␣ (p ! 0.05), CRP (p ! 0.05), IGF-1 (p ! 0.05) and IGFBP-3 (p ! 0.05).

Discussion

VO2maxACSM The diet/training group demonstrated a significant increase in VO2max ACSM after the 8-week intervention program (p ! 0.001; fig. 1). No change was observed for this parameter in the control group.

The present study confirms our hypothesis that in diet/trained subjects the decrease in body fat and the increase in physical activity can achieve a reduction in markers of inflammation and plasma concentrations of IGF-1 and IGFBP-3.

Biochemical Analysis There were no baseline differences between the diet/ training and the control groups for any of the parameters measured, e.g. leptin, TNF-␣, IL-6 or CRP (table 2). After

Testing Procedures Exercise calorimetry appears to be valid for measurements of substrate oxidation during submaximal steadystate exercise bouts. Such measurements have shown that



263

Correlation coefficients 0.6 0.4 0.2 0

Fig. 2. Pearson correlation’s coefficient be-

tween both BF% and VO2max ACSM and other parameters after the diet/training program. * p ! 0.05, ** p ! 0.01.

Table 2. Cytokine levels, and plasma

IGF-1 and IGFBP-3 concentrations before and after the program in the study groups

–0.2

VO2maxACSM

** * ** ** * *

Leptin IL-6 TNF-␣ CRP Leptin IL-6 TNF-␣ CRP

IGF-1 IGFBP-3

–0.4 –0.6

Variable

TNF-␣, pg/ml IL-6, pg/ml Leptin, ng/ml CRP, mg/l IGF-1, ng/ml IGFBP-3, ng/ml

IGF-1 IGFBP-3

**

BF%

*

*

*

*

*

Diet/training (n = 14)

Control (n = 14)

before

before

6.184.6 4.382.7 23.285.4 4.681.8 376832 3,4138121

after 3.282.7** 2.181.4** 14.783.3*** 3.782.1** 312828** 3,078896**

7.684.1 5.684.1 21.185.2 5.381.7 392842 3,6168133

after 7.885.4 6.185.2 21.886.1 5.682.5 403837 3,5988142

** p < 0.01, *** p < 0.001, vs. before.

obese people oxidize fewer lipids at exercise than lean matched controls [35] and that low intensity exercise training markedly reverses this defect in both adult and adolescent obese subjects [30]. The intensities of effort were set using the equations of Wasserman et al. [31]; these approximate values of VO2maxth and Wmaxth could be over- or underestimated in some subjects, and this would modify the Lipoxmax points as reported in our study. However, this methodological problem is minimized because values for the two observation periods are compared for one given subject. The age of the patients (between 12 and 14 years) implies a degree of homogeneity with regard to puberty, a point that is not without importance since Bar-Or [36] reported modified substrate utilization at exercise with advancing age (children burn relatively more fat and less carbohydrates than adults). The increased function of the GH-IGF axis over the course of puberty is one of the physiologic changes likely to increase both lipolysis and fat oxidation [37]. More limitations in our design include the estimation of VO2max using the ACSM method (VO2max ACSM) because maximal heart rate has previously been shown to be significantly lower in obese than in lean young indi264


viduals [38]. Alterations in the catecholamine response to exercise, myocardial metabolism and left ventricular morphology in obese subjects have been propounded as factors likely to explain a decrease in maximal heart rate with obesity [39]. Hence, the use of a theoretical maximal heart rate predicted with the formula 220 – age (years) to estimate VO2max in obese young should be avoided in studies that aim at comparing obese to healthy young because it will underestimate the maximal fat oxidation point in the first ones whereas it will not in the latter. However, the use of a VO2max ACSM in obese young should be applicable when comparing the same subject before and after the intervention period. Moreover, Aucouturier et al. [40] demonstrated that the intensity of the Lipoxmax point occurred at 53.3% of VO2max measured during a graded exhaustive cycling exercise and at 46.5% of VO2max ACSM (p = 0.09), and showed a strong correlation between Lipox max expressed as percentage of VO2max and Lipoxmax expressed as percentage of VO2max ACSM (r = 0.78, p ! 0.001) in 24 obese children.


Effect of Diet/Training on Inflammatory Markers The identification of effective therapies that reduce chronic inflammation is important given the widespread adverse health effects of a chronically elevated inflammatory state. Therefore, the most important finding in this study is that besides improving fitness and body composition, exercise training associated with dietary restriction improves the cytokines profile in obese children. It has been postulated that physical activity combined with nutritional intervention may lower the risk of coronary heart disease in part by the prevention or reduction of excess inflammation [41]. It is important to note that in the current study, diet/training changed body composition measured by body weight, BMI and BF%. Combined with changes in body composition, exercise may have a strong effect on cytokines and inflammatory markers. Even the controlled intervention trials that have reported decreases in inflammatory markers with exercise training also report improvements in body composition [11, 42], which likely confounds the results. The results contradict suggestions that exercise, by itself, is an anti-inflammatory stimulus and that it improves the cytokine profile. In our study, the decreases in all cytokine levels were significantly positively correlated with the BF% decrease and significantly negatively correlated with the increase in VO2max ACSM. Effect of Diet/Training on IGF-1 and IGFBP-3 Another aim of the study was to investigate the effect of an 8-week diet/training program on IGF-1 and IGFBP3 levels. Participation in regular physical exercise generally increases serum concentrations of IGF-1 [23, 43]. Conversely, it has been observed that high intensity training or prolonged endurance activities provoke a longterm decrease in IGF-1 levels [24, 44]. It has also been

established that following reduced energy intake, or, more generally, when the energetic cost exceeds energy consumption, a fall in free IGF-1 levels occurs [45]. We observed similar results since, in subjects participating in the 8-week diet/training, the total IGF-1 levels were lower at the end of the program. This may be related to the lower food intake of these obese children. This prolonged physical training combined with low energy intake may explain the low IGF-1 levels. This is illustrated by the negative significant correlation found between the change in IGF-1 and the VO2max ACSM after the program. It has been proposed that exercise-induced IGFBP-3 proteolysis contributes significantly to the anabolic effects of exercise [46]. It has been documented that there was no change in IGFBP-3 after a short period (4–5 min) of intense exercise [19], but a decrease in IGFBP-3 was found after longer exercise [46]. The lower levels of IGFBP-3 after the 8-week diet/training seem to indicate excess training. Some studies found a decrease in IGFBP3 after 1 year of gymnastics training [44]. This is in agreement with the results from the present study since we also found a negative correlation between the VO2max ACSM and the serum levels of IGFBP-3 recorded after the 2month intervention program. In conclusion, the present study provides evidence that exercise training targeted at Lipox max combined with dietary restriction, in the presence of changes in body composition, improves the cytokine profile or inflammatory marker levels and decreases the levels of IGF-1 and IGFBP-3. Acknowledgments We thank the adolescents and parents for their assistance and availability. This study was supported by the Ministry of Higher Education, Scientific Research and Technology of Tunisia.

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