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PEDIATRICS Vol. 113 No. 5 May 2004, pp. 1273-1278

Serum Leptin Concentration Poorly Reflects Growth and Energy and Nutrient Intake in Young Children

Maarit Hakanen, MD*, Tapani Rönnemaa, MD, PhD{ddagger}, Sanna Talvia, MSc*, Leena Rask-Nissilä, MD, PhD§, Markku Koulu, MD, PhD||, Jorma Viikari, MD, PhD{ddagger}, Matti Bergendahl, MD, PhD§,¶ and Olli Simell, MD, PhD§

* The Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
{ddagger} Department of Medicine, University of Turku, Turku, Finland
§ Department of Pediatrics, University of Turku, Turku, Finland
|| Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
Department of Physiology, University of Turku, Turku, Finland


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. We studied whether the serum leptin concentration at age 2 years predicts changes in relative body weight by age 8 and whether the serum leptin concentration is associated with intake of energy and nutrients at age 5.

Methods. A total of 156 8-year-old participants of the Special Turku Coronary Risk Factor Intervention Project were chosen to represent children whose relative weight decreased, was stable, or increased during the preceding 6 years. Their serum leptin concentrations were measured in samples collected when they were 2 years. Serum leptin was also measured in 100 5-year-old children in the Special Turku Coronary Risk Factor Intervention Project whose energy and nutrient intakes were analyzed using 4-day food records.

Results. The boys whose relative weight decreased (n = 25), was stable (n = 28), or increased (n = 26) between 2 and 8 years of age had similar serum leptin concentrations at the age of 2 years. The girls whose relative weight decreased (n = 27) had higher serum leptin concentrations at 2 years than the girls whose relative weight remained stable (n = 26) but only when the leptin values were not adjusted for body mass index. The serum leptin concentration was higher in 5-year-old girls than in 5-year-old boys even when adjusted for body mass index. Serum leptin correlated with relative weight in girls and boys (r = 0.65 and r = 0.45, respectively). Serum leptin concentration adjusted for relative weight correlated poorly with intakes of energy, fat, saturated fat, carbohydrates, sucrose, and protein.

Conclusions. Serum leptin concentrations at age 2 poorly predicted changes in relative body weight during the following 6 years and poorly reflected the intake of energy or major nutrients at age 5.

Key Words: leptin • growth • dietary factors • childhood obesity

Abbreviations: BMI, body mass index • STRIP, Special Turku Coronary Risk Factor Intervention Project

An important obesity-related gene, ob, is expressed in adipose tissue, and the gene product leptin is thought to act as a long-term satiety signal transferring the message from the adipose tissue to the hypothalamus.1,2 Leptin deficiency, however, is rarely the cause of human obesity, although leptin-deficient patients clearly benefit from therapy with recombinant human leptin.3,4 It is interesting that most obese adults and children have higher serum leptin concentrations than their lean and normal-weight peers, and serum leptin concentrations correlate closely with the amount of body fat in adults and children.5–8 These findings suggest that the common type of human obesity is related to endogenous leptin insensitivity.

Serum leptin values change markedly during the years of human growth. When the values are adjusted for the fat mass, there are no gender differences in young children, but in Tanner’s pubertal stages IV and V, girls have higher serum leptin values than boys.7–11 The fat percentage-adjusted leptin concentration correlates directly with total energy expenditure adjusted for body weight, gender, and physical activity in prepubertal children, suggesting that the leptin concentration may affect energy expenditure in healthy children.

Dietary patterns influence serum leptin concentrations, as leptin values decrease after a 12-hour fast and increase again after refeeding.12 Serum leptin concentrations may also respond differently to meals that have identical energy contents but different glycemic indexes. The serum leptin concentrations decreased less in young, moderately overweight men who consumed an energy-restricted diet with a high glycemic index than in men who consumed a similar diet with a low glycemic index.13 Furthermore, dietary fatty acids seem to affect the serum leptin concentration profoundly, because the fatty acid content of the diet of men with type 1 diabetes can displace anthropometric variables in models that predict serum leptin concentration.14

During development of childhood obesity, the serum leptin concentration correlates only weakly with the weight gain of the preceding year, and the concentration does not predict future weight loss.15 Conversely, in obese women with no parental history of obesity, a high serum leptin concentration predicts moderate weight gain or even weight loss.16 In adult Pima Indians, a population exceptionally prone to obesity, leptin concentrations adjusted to the amount of body fat are lower in individuals who gain weight than in individuals whose weight is stable.17 Similarly, in a 12-month study on prepubertal children, plasma leptin concentrations correlated inversely with the z score changes of the body mass index (BMI),18 but in another study on obese girls, high serum leptin values were associated with a greater increase in the BMI z score during a 2.5-year follow-up than low values.19 It is also known that the serum leptin concentration in children aged 5 years explains only a minor part of the variance in the amount of body fat 5 years later, 20 showing that the predictive value of leptin regarding later weight gain remains controversial.

Little is known about the power of serum leptin concentration to predict obesity in children younger than 5 years. We thus measured leptin concentrations in serum samples drawn at age 2 from 156 children whose relative body weight by the age of 8 years had decreased, been stable, or increased. We also assessed whether the serum leptin concentration of 5-year-old children is associated with the amount of major nutrients consumed in an attempt to examine how strongly dietary factors influence serum leptin concentrations in prepubertal children.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects and Study Design
The study children were recruited from the Special Turku Coronary Risk Factor Intervention Project for Children (STRIP), which is a prospective and randomized trial to reduce the exposure of the intervention children to the known environmental risk factors of coronary heart disease. The details of the trial have been described.21,22 In short, the STRIP was launched in 1990, when 1062 children were recruited to the study at the age of 7 months from the well-infant clinics of the city of Turku, Finland (57% of the eligible age cohort). The children were randomized to an intervention (n = 522) or a control (n = 540) group. The intervention group received individualized dietary counseling, the goal of which was to keep the fat intake at 30% to 35% of daily energy intake between the ages of 1 and 2 years and at 30% thereafter and to modify the quality of fatty acids in the diet so that the saturated/monounsaturated/polyunsaturated fatty acid ratio would be 1:1:1. The control group did not routinely receive any detailed counseling focused on the known risk factors of coronary heart disease. At the ages of 5 and 8 years, 72% and 61% of the children, respectively, continued in the trial.

We selected from the STRIP cohort 156 children who were aged 8 years and whose relative weight during the preceding 6 years had decreased (n = 52; decrease in relative weight between 7% and 20% units on the growth curves of Finnish children),23 been stable (n = 54; change in relative weight ≤2% units), or increased (n = 50; increase in relative weight between 11% and 49% units). The serum leptin concentrations of these children were measured in serum samples drawn when the children were 2 years of age. A cohort of 100 5-year-old children in the STRIP (48 girls and 52 boys, 43 of the 100 children from the intervention group) were randomly chosen to analyze closely the effects of gender and intake of different nutrients on serum leptin concentrations.

The Joint Commission on Ethics of the Turku University and the Turku University Hospital approved the STRIP trial. Informed consent was obtained from the parents of the children.

Anthropometric Measurements
When the children were aged 2 years and once or twice a year thereafter, the height of the children was measured to the nearest millimeter with a wall-mounted Harpenden stadiometer (Holtain, Crymych, UK) and the body weight was measured to the nearest 0.1 kg with an electronic scale (S10; Soehnle, Murrhardt, Germany). Absolute height and relative height (deviation of height in standard deviation units from the mean height of healthy Finnish children of the same age and gender) and absolute weight and relative weight (deviation of weight in percentages from the mean weight of healthy Finnish children of the same height and gender) were recorded at each visit.23 The BMI was calculated as the weight (kg) divided by the square of the height (m).

Dietary Assessment
Dietary information was obtained from 4-day food records. The nutrient compositions of the diets were analyzed using the Micro-Nutrica PC program, which has been updated continuously (Research and Development Unit of the Social Insurance Institution, Turku, Finland). We assessed the total daily intake of energy and intakes of fat, saturated fatty acids, carbohydrates, sucrose, and protein as percentages of total daily energy intake.

Analytic Measurements
Nonfasting venous blood samples were collected when the children were 2 years of age, and fasting venous blood samples were collected when they were 5. The nonfasting samples were drawn between 8 AM and 4 PM, and the fasting samples were drawn in the morning after an overnight fast. Cutaneous anesthesia (EMLA; Astra, Södertälje, Sweden) preceded blood sampling. Serum was stored at –70°;C until analysis. Serum leptin is stable at this temperature (see the manufacturer’s instructions for the Human Leptin RIA Kit). The serum leptin concentration was determined in duplicate using a commercially available double-antibody radioimmunoassay kit (Human Leptin RIA Kit; Linco Research, St. Charles, MO). The detection limit of the assay was 0.5 ng/mL, when the sample size was 100 µL. The intra- and interassay coefficients of variation of the method were 8.3% and 6.2% at the level of 4.9 ng/ml, and 4.7% and 3.0% at the level of 15.7 ng/ml, respectively.

Statistical Methods
The results are expressed in the text as mean ± standard error of mean. The distribution of leptin was skewed; therefore, the data were double log (log10log10) transformed to normalize the distribution. Log10 transformation was used to correct for the skewness of the leptin values adjusted for BMI and of the daily energy intake. The associations between leptin values and gender and the STRIP trial group of the child (intervention group or control group) were studied with analysis of variance. The relationship between leptin values and intake of energy and nutrients in 5-year-old children was studied with Spearman partial correlation coefficient; the relative body weight was the partial variable. The gender distributions were compared with t test. For analyzing predictive value of the leptin concentrations measured at 2 years of age with regard to relative weight change, the 3 groups of weight-change patterns were compared after Tukey-Kramer adjustment of the values. The SAS statistical software was used (SAS, Cary, NC). P < .05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Serum Leptin Concentration and Prediction of Relative Body-Weight Change Between 2 and 8 Years of Age
Serum leptin concentrations measured at the age of 2 years predicted poorly the subsequent changes in relative body weight (Table 1). Because the relative weight-change groups had almost equal numbers of girls and boys, gender-related biases in the analysis were avoided. The girls who were aged 2 years and whose relative weight subsequently decreased had higher relative weight and BMI than the girls whose relative weight remained stable or whose relative weight increased during the follow-up (P ≤ .023 for relative weight and for BMI). Meanwhile, the girls with stable or increasing relative body weight did not differ from each other regarding weight, relative weight, or BMI at the age of 2 years. Similarly, the boys whose relative weight subsequently decreased had higher relative weight and BMI than the other boys (P ≤ .008), but the boys with a stable or increasing relative weight during the 6-year follow-up did not differ from each other in weight, relative weight, or BMI at the age of 2 years.


View this table:
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  		TABLE 1. Anthropometric Measures and Serum Leptin Concentrations of 52, 54, and 50 2-Year-Old STRIP Children Whose Relative Weight Decreased, Remained Unchanged, or Increased During Follow-up to Age 8 Years

 
The girls whose relative weight decreased during the 6 years of follow-up had a higher mean serum leptin concentration than the girls whose relative weight was stable (P = .019), but the difference disappeared when serum leptin concentrations were adjusted for BMI. Serum leptin concentrations were similar for the girls whose relative weight remained stable and for the girls whose relative weight increased between 2 and 8 years of age (P = .87). The serum leptin concentrations and BMI-adjusted leptin concentrations of the boys at 2 years did not differ in the 3 relative weight-change groups.

Serum Leptin Concentrations and Dietary Factors in 5-Year-Old Children
The 100 randomly chosen 5-year-old children in the STRIP (48 girls and 52 boys) covered a wide range of relative body weight (mean in girls: 2.3% [range: –18% to 27%]; mean in boys: 0.5% [range: –15%–19%]) and other anthropometric measures (Table 2). There was no interaction between gender and belonging to the intervention or the control group of the STRIP regarding serum leptin concentration or BMI-adjusted leptin concentration (P = .39 and P = .51, respectively). The intervention and control groups were consequently combined for additional analyses. Height, weight, relative weight, and BMI showed no gender differences in these 5-year-old children, but the girls had a higher serum leptin concentration (5.8 ± 0.6 ng/ml) than the boys (3.3 ± 0.2 ng/ml; P < .001). This gender difference persisted after adjustment for BMI (mean leptin/BMI ratio for girls and boys: 0.36 and 0.21, respectively; P < .001). The serum leptin concentration correlated with relative body weight and BMI in girls as well as in boys (P < .001).


View this table:
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  		TABLE 2. Anthropometric Measures and Dietary Energy and Nutrient Intake Values of 100 Randomly Chosen 5-Year-Old STRIP Participants

 
Well-kept and detailed 4-day food records were obtained from 48 girls and 50 boys. The daily energy intake was higher in boys than in girls (1457 ± 36 and 1340 ± 28 kcal, respectively; P = .017), but the daily intakes of fat, saturated fatty acids, carbohydrates, sucrose, and protein, expressed as proportion of the daily energy intake, showed no gender differences, although the variation was wide (Table 2). The serum leptin values correlated poorly with daily intake of energy, fat, saturated fatty acids, carbohydrates, sucrose, and protein (P > .10 in all for partial correlation coefficients).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
This study shows that serum leptin concentrations in a large group of healthy, normal-weight 2-year-old children poorly predicts changes in the relative body weight up to the age of 8 years. The 3 study groups were selected from children in the STRIP to represent subjects whose relative weight had decreased, had been stable, or had increased during 6 years of follow-up. When these children were 2 years of age, they had normal body weight, although the children whose relative weight subsequently decreased had a higher relative body weight and BMI than the other 2 groups of children. The serum leptin concentrations in the boys of the 3 groups were similar but the concentrations were higher among girls whose relative weight decreased during follow-up than in those whose relative weight remained stable. However, adjustment of the serum leptin values for BMI removed even these differences. Thus, the higher serum leptin concentration in the girls whose relative weight subsequently decreased seemed only to reflect their heavier body weight at the beginning of the study.

An important message from this study is also that serum leptin values measured in healthy 2-year-old children with a normal body weight poorly predict development of obesity (defined by a relative body weight exceeding 20% on the growth curves) in the prepubertal years, as the leptin values were almost identical in children whose relative weight remained stable or increased during the follow-up years. Our findings differ from an earlier study, which suggested that high serum leptin values do associate with strong increases in the z scores of the BMI values in girls.19 However, the children in that study were obese and older at the beginning of the study, and the follow-up time was shorter (2.5 years) than in our study. It is interesting that Byrnes et al18 found that serum leptin values in healthy prepubertal children correlated inversely with the change in the z scores of BMI; they had a follow-up of 1 year.

Prediction of future weight on the basis of serum leptin values measured in young children is prone to some errors when conventional anthropometric values are used. A major problem is that only indirect measures of adiposity (weight, relative weight, and BMI) are usually available, and more direct measures of the lean and adipose tissue mass would probably improve accuracy of such predictions. Furthermore, the individual measures of adiposity at the beginning of such studies may have a major influence on the outcome when relative changes are compared in a cohort. In our study, all children were regarded as having a normal relative weight at 2 years of age, and they probably formed a relatively uniform group as such. Nonfasting venous blood samples were used because of the age of the study children. However, it has been shown that leptin levels do not change acutely after a meal.24 Different dietary and lifestyle interventions during the study years may also modify the predictive value of serum leptin values. In this study, half of the subjects belonged to the intervention arm of the STRIP, and they received repeatedly nutritional counseling aimed at reducing exposure of the children to the dietary risk factors of coronary heart disease. However, the leptin values of these children did not differ from those of the control group. This suggests that the data are applicable to other children as well.

Our data show that serum leptin concentrations are higher in girls than in boys at the age of 5 years. The relative weights of the children in this STRIP cohort covered a wide range, although all boys were regarded as having a normal relative weight, ie, their relative weight was within –15% and 20% of the Finnish growth curves.23 The range in the girls was wider, but the vast majority of them were also within the normal range. Serum leptin concentrations have in previous studies been similar for boys and girls once the values have been adjusted for fat mass.10,11,18 In our study, there were clear gender differences also after adjustment of the values for BMI. This discrepancy may at least partly be caused by the fact that BMI is only an indirect measure of adiposity and does not take into account individual differences in the body composition (adipose tissue vs lean tissue). In our study, the serum leptin concentration correlated with BMI and relative body weight in boys and more strongly in girls, confirming earlier findings suggesting that serum gender-specific concentrations of leptin may be used to express the amount of fat in the body.5–11

The gender difference regarding serum leptin concentrations was similar in the children of the intervention group and the control group. The intervention group had received dietary and lifestyle counseling regularly since the subject was 8 months of age. The relative intakes of fat and saturated fatty acids were constantly lower in the intervention children than in the control children once the counseling had been started.22 Our current data show that this counseling, however, had no effect on serum leptin concentrations at least at the age of 5 years. Furthermore, we found no association between dietary intake values and serum leptin concentrations, confirming data obtained in earlier studies involving 7- to 11-year-old obese children.25 These studies suggest that fat mass rather than the dietary origin of the energy is a critical determinant of serum leptin concentration in children. It is interesting that in adults, serum leptin values seem to be sensitive to the glycemic indexes and dietary fatty acids,13,14 as well as habitual consumption of a high-fat or a low-fat diet.26


   CONCLUSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Serum leptin concentrations are higher in girls than in boys during the prepubertal years, correlate well with BMI and relative body weight in both genders but more strongly in girls, do not correlate with energy-adjusted intake of the major nutrients, and poorly predict the future development of obesity or other changes in the relative weight of the children.


   ACKNOWLEDGMENTS
 
This study was supported by grants from the Foundation for Pediatric Research, Finland; Yrjö Jahnsson Foundation; Juho Vainio Foundation; Sigrid Juselius Foundation; Finnish Academy; and Special Federal Grants for University Hospitals in Finland.

We thank the laboratory personnel of the Department of Pharmacology and Clinical Pharmacology for help in the analyses of serum leptin concentrations; Tommi Viitanen and Martti Arfman for statistical analyses; and Robert Paul, MD, PhD, for checking the language.


   FOOTNOTES
 
Received for publication Feb 12, 2003; Accepted Jul 8, 2003.

Reprint requests to (M.H.) Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail: maarit.hakanen{at}utu.fi


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics




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