| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Neurology (M.K.K.) and Cardiovascular Research Unit (S.R.), and Departments of Pharmacology and Clinical Pharmacology (M.K., U.P.), Pediatrics (H.N., L.R.-N., O.S.), and Medicine (T.R.), University of Turku, 20520 Turku, Finland
Address all correspondence and requests for reprints to: Matti Karvonen, M.D., Ph.D., Kiinamyllynkatu 4-8, 20520 Turku, Finland. E-mail: matti.karvonen{at}tyks.fi.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Objective: The objective of this study was to analyze the connection between Leu7Pro polymorphism and relative weight, nutrient intakes, and serum lipids in early childhood. We closely followed 647 healthy Finnish children participating in the Special Turku Risk Factor Intervention Project through their first 9 yr of life.
Results: Leu7Pro polymorphism showed no relation to intakes of energy, macronutrients, or the relative weight in either gender. However, Pro7 substitution was associated with serum triglyceride concentration in boys at the ages of 5, 7, and 9 yr.
Conclusion: The functional Leu7Pro polymorphism is not likely to be involved in the regulation of adiposity or major nutrient preferences in childhood. In boys, the Pro7 variant may have impact on serum triglyceride concentration.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In animals, neuropeptide Y (NPY) is one of the most potent inducers of feeding, even when administered during satiety (4). NPY especially promotes the intake of carbohydrates and decreases energy expenditure. However, in man, the role of NPY in the regulation of food intake, nutrient preferences, and energy balance is less clear. NPY receptors have been targets in some novel antiobesity therapies. Although NPY receptor-selective compounds are effective in experimental models, results have failed to support the major regulatory role of NPY in man. The NPY gene has been linked to obesity in Mexican Americans (5) and the Y5-receptor gene in Pima Indians (6), but the NPY system has not been associated consistently with obesity in men.
We have recently identified a functional Leu7Pro polymorphism in the signal peptide of NPY (7). The consequence of Pro7 substitution on prepro-NPY peptide function is not fully known, but Pro7 substitution has an impact on NPY processing, on circulating NPY levels, on GH secretion, and on serum cholesterol levels (7, 8, 9, 10). In our previous studies, we have found no associations between the Leu7Pro polymorphism and obesity-related parameters, except with a slightly increased birth weight in newborn boys (11). Interestingly, Mattevi et al. (10) and Ding et al. (12) have reported that the Pro7 is associated with body size. Finally, Batterham et al. (13) show that Y2-receptor activation induced satiety in man. Collectively, these studies suggest that the NPY system has a role in the regulation of human feeding and energy balance, but the exact mechanisms are unclear.
Theoretically, children genetically predisposed for increased NPY stimulation might thus consume more energy, which could then lead to the increase in body weight. We thus studied whether the diets of children having Pro7 substitution differ from those who do not have Pro7 substitution and whether these two groups of children differ in weight gain before the age of 9 yr.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study population was comprised of 346 boys and 301 girls participating in the Special Turku Coronary Risk Factor Intervention Project. Detailed description and the objects of the study have been published (14). Because our primary aim was to investigate the effect of Leu7Pro on nutrient intake, relative body weight, and weight gain, the number of participants was determined primarily by the availability of nutrient intake records, and therefore, the numbers differ from those of our previous study (12). The number of the participating children declined slowly as their age increased, so that, at the age of 9 yr, the study was comprised of 267 boys and 239 girls. Previous analyses suggest that the children and families that dropped out of the study did not differ from those who continued in measured risk factors or socioeconomic status. The DNA extraction and genotype analysis have been described (7, 12). The study was approved by the Joint Committee on Ethics of Turku University and Turku University Central Hospital.
Determination of relative weight, nutrient intake, and serum lipids
Instead of absolute body weight or body mass index, relative weight was used. It expresses the weight deviation as a percentage of the mean weight of healthy Finnish children of the same height and gender (15). In our previous study (12), birth weights were collected from well-baby clinics. For improved accuracy, birth weights used in this study were taken directly from the files of the maternity hospitals in Turku.
Twice a year, the parents and the personnel of the day care centers recorded the children’s food consumption for 4 consecutive days. Children aged 1 yr, 3 months through 9 yr were studied. Ambiguous and missing data were double checked. Collected data were stored on the computer and analyzed with Micro Nutrica software (Research and Development Centre of the Social Insurance Institution, Turku, Finland; version 2.5), as described (16). Nonfasting serum cholesterol at 1–4 yr of age and fasting serum cholesterol and triglycerides at 5, 7, and 9 yr of age were determined by enzymatic methods as described (14).
Statistical analyses
Three children who were homozygous for the T1128C substitution in the NPY gene, resulting in a Leu7 to Pro7 substitution in the prepro-NPY, were combined with the group of heterozygous carriers of Pro7 for statistical analyses. The effect of Pro7 substitution was analyzed separately in boys and girls due to reported gender differences in the body adiposity in children (17). Means ± SEM are presented. The impact of Leu7Pro polymorphism on repeated measurements of relative weight, nutrient intake as energy percentage, serum cholesterol, and serum triglycerides (log transformed) was analyzed using a mixed model procedure. Because dietary intervention had an effect on several of the parameters, the treatment group (intervention/control) was included in the model with age and Leu7Pro polymorphism. The impact of Pro7 substitution on relative weight and nutrient intake as energy percentage was also further investigated by calculating the frequency of the Pro7 substitution in the lowest and in the highest quartiles of the respective trait. Finally, because the investigated traits are complex and subjected to large variation, we also carried out analyses in the whole study population of all children (gender, intervention, and age as covariates) to increase statistical power to detect minor differences. All statistical analyses were conducted using SAS software (SAS Institute, Cary, NC).
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The frequency of the Pro7 substitution ranged from 9.7–12.7% in girls and from 11.2–12.2% in boys during the study. The frequency of obese children in the study population was low. In genotyped boys, 7.1% had 20–40% weight deviation (overweight) and only 0.8% had more than 40% deviation (overweight). In genotyped girls, 10.9% had 20–40% weight deviation and 0.8% had more than 40% deviation, respectively.
The association of the Leu7Pro polymorphism with birth weight in the boys of the study has been published (12). Leu7Pro polymorphism was not associated with relative weight in the two genders during the 9-yr follow-up (Fig. 1A
). The frequency of the Pro7 substitution was similar in the lowest and in the highest quartiles of relative weight (data not shown). The mixed model procedure revealed borderline significance to the association of NPY Leu7Pro polymorphism with the relative weight in boys (NPY Leu7Pro polymorphism F = 3.09, P = 0.0798; age F = 23.93, P < 0.0001; and dietary intervention F = 0.47, P = 0.49), but consistent difference in relative weight was not observed between the two groups of boys (Fig. 1A).
|
) or to any of the variables representing relative intake of energy from carbohydrates, protein, or fats in boys or in girls (data not shown). Pro7 substitution frequency did not differ between the lowest and the highest quartiles of energy intake or intake of energy nutrients (data not shown). In the whole study population analysis (gender groups combined), Pro7 substitution was not associated with relative weight, energy, or energy nutrient intake. Serum lipids
Pro7 substitution was significantly associated with serum triglycerides (log transformed) in boys but not in girls. Serum triglyceride concentrations at the ages of 5, 7, and 9 yr were 0.63 ± 0.01, 0.65 ± 0.02, and 0.66 ± 0.02 mmol/liter in the Leu7/Leu7 group, and in the carriers of the Pro7 substitution, 0.74 ± 0.05, 0.73 ± 0.08, and 0.80 ± 0.09 mmol/liter, respectively. The differences in the mean triglyceride concentrations between the two genotype groups were 0.11 mmol/liter (17%) at the age of 5 yr, 0.09 mmol/liter (14%) at the age of 7 yr, and 0.15 mmol/liter (22%) at the age of 9 yr (Fig. 2A). Leu7Pro polymorphism was not associated constantly with serum cholesterol concentrations in either gender (Fig. 2B). In the whole study population analysis, Pro7 substitution was not associated with serum cholesterol concentration.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
In healthy, unmedicated obese adults, the Leu7Pro polymorphism has been associated with high serum cholesterol and apolipoprotein B concentrations (7, 18). Pro7 substitution was not associated with serum cholesterol concentration in children, but the Pro7 substitution seems to have an impact on serum triglycerides in boys. The mean triglyceride concentrations in the carriers of the Pro7 substitution and in control subjects differ slightly from those we previously reported (12) because the number of study subjects differs between the two studies. However, the triglyceride data are essentially the same, and the difference in the mean fasting serum triglyceride value is even higher at the age of 9 yr than that of 5 or 7 yr of age (Fig. 2A). At the age of 9 yr, the mean serum triglyceride concentration of the subjects with the Pro7 substitution was in the mean 0.15 mmol/liter or 22% higher than that of the control children. If persistent, a difference of this magnitude might have a clinical impact on future cardiovascular disease risk. However, it is not known whether the difference in fasting triglycerides persists through adolescence or through to adulthood. Based on our previous study, it may appear that Pro7 substitution has an effect on the composition of the lipid particles mediated by the lipoprotein and hepatic lipase activity that affect lipid metabolism (19). The reason why this effect is observed only in boys is not known but may be related to gender differences in body fatness in childhood (17). Recently Nordman et al. (20) reported an association of Leu7Pro with impaired glucose tolerance and type 2 diabetes mellitus. It would be interesting to test whether elevated triglycerides could contribute to the reported association between Leu7Pro and impaired glucose tolerance and type 2 diabetes mellitus.
In conclusion, we have shown that the functional Leu7Pro polymorphism does not have a constant effect on relative weight or intake of major nutrients in childhood, but probably has an impact on serum triglycerides in boys. However, our study does not exclude the possibility that NPY may have some physiological role in the regulation of satiety in adults.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
First Published Online August 15, 2006
Abbreviation: NPY, Neuropeptide Y.
Received September 20, 2005.
Accepted August 3, 2006.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  J. Ma, S. Nordman, A. Mollsten, H. Falhammar, K. Brismar, G. Dahlquist, S. Efendic, and H. F Gu Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations Eur. J. Endocrinol., November 1, 2007; 157(5): 641 - 645. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
