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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1357
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 12 6386-6391
Copyright © 2005 by The Endocrine Society

Peptide YY Is a Regulator of Energy Homeostasis in Obese Children before and after Weight Loss

Christian L. Roth, Pablo J. Enriori, Katia Harz, Joachim Woelfle, Michael A. Cowley and Thomas Reinehr

Department of Pediatrics, University of Bonn (C.L.R., K.H., J.W.), Bonn 53113, Germany; Division of Neurosciences, Oregon National Primate Research Center, Oregon Health and Science University (P.J.E., M.A.C.), Beaverton, Oregon 97006; and Vestische Children Hospital Datteln, University of Witten/Herdecke (T.R.), Witten/Herdecke 45711, Germany

Address all correspondence and requests for reprints to: PD Dr. Med. Christian L. Roth, Department of Pediatrics, University of Bonn, Adenauerallee 119, 53113 Bonn, Germany. E-mail: croth{at}uni-bonn.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The gut hormone peptide YY3–36 (PYY) reduces food intake via hypothalamic Y2 receptors in the brain. There is not much known about PYY in obese children.

Objective: The objective of this study was to investigate the role of PYY in the metabolic changes in obese children and its change during weight loss.

Setting: The study was performed at a university medical center.

Participants: We studied 73 obese children and 45 age-matched normal-weight children.

Interventions: We determined fasting serum total PYY and leptin by RIA in obese and normal-weight children. Fasting PYY was also measured in 28 obese children before and after completion of a 1-yr outpatient weight reduction program.

Main Outcome Measures: PYY, insulin, and body mass index were the main outcome measures.

Results: Obese children demonstrated significantly lower PYY levels than lean children (median, 67 vs. 124 pg/ml; P < 0.001). Fasting PYY correlated negatively to the degree of overweight. PYY levels did not differ significantly between boys and girls, nor between prepubertal and pubertal children. The group of patients participating in the outpatient weight reduction program was divided into four quartiles according to their changes in body mass index SD score over a 1-yr period. PYY increased significantly in patients with the most effective weight loss, but decreased in the subgroup of children with weight gain.

Conclusions: PYY is negatively correlated to the degree of overweight, with reduced values in obese compared with normal-weight children. Decreased PYY levels could predispose subjects to develop obesity. Our results indicate that low pretreatment PYY levels that increase during weight loss may be a predictor of maintained weight loss.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
SATIETY SIGNALS GENERATED by the gastrointestinal tract include pancreatic polypeptide, glucagon-like peptide 1, oxyntomodulin, cholecystokinin, as well as peptide YY3–36 (PYY) (1). These hormones are known as short-term regulators of food intake, in contrast to the long-term satiety regulators, leptin and insulin (1, 2, 3). Neurons within the arcuate nucleus of the hypothalamus (ARH) are primary targets for a variety of peripheral metabolic signals that regulate energy homeostasis. Specifically, the orexigenic neuropeptide Y (NPY) and anorexigenic proopiomelanocortin neurons in the ARH (4) transduce hormonal signals into neuronal signals, transmitting feeding and satiety information to the paraventricular hypothalamus. The paraventricular hypothalamus integrates signals from feeding circuits and regulates hypothalamic hormone production as well as autonomic sympathetic outflow to regulate energy expenditure (4, 5, 6). The gut-derived hormone PYY is postprandially released by the L cells of the lower intestine and inhibits gastric acid and motility through neural pathways (7, 8, 9). PYY has agonistic properties on Y2 receptors, which are highly expressed on NPY neurons in the ARH, leading to inhibition of food intake (10, 11, 12). Two endogenous forms of PYY are abundant in humans: PYY1–36 and PYY3–36 (13). Both forms decrease food intake in rodents, with PYY3–36 having a more potent effect than PYY1–36 (14).

In recent food intake studies, it was found that human caloric intake was decreased by 30% in obese subjects and by 31% in lean subjects 2 h after iv infusion of PYY3–36 (12, 15). Moreover, in cross-sectional studies, fasting PYY concentrations correlated negatively with body mass index (BMI) (15, 16). To date, there are no long-term weight reduction studies assessing the effects of endogenous PYY in the regulation of energy homeostasis. The main purpose of this study was to investigate the role of PYY in the metabolic changes in obese children and its potential role as a long-term regulator of body weight.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We examined 73 obese children (32 girls and 41 boys) treated for obesity either at the Department of Pediatrics, University of Bonn, or Vestische Kinderklinik, Datteln, Germany. The majority of patients developed obesity before 6.0 yr of age. None of the children changed their weight status in the 3 months before the study. Forty-five normal-weight children (23 girls and 22 boys) served as controls. The mean age of the children was 11 yr (Table 1Go). Children with endocrine disorders, premature adrenarche, or syndromal obesity were excluded from the study. Obesity was defined as a 97th percentile BMI using population-specific data (17) and the definition of the International Task Force of Obesity (18). Pubertal developmental stage was assessed using the standards from Marshall and Tanner. The study was approved by the local ethics committee of the University of Witten/Herdecke and the University of Bonn. Written informed consent was obtained from all subjects or their parents before participation.


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  		TABLE 1. Age, gender, pubertal stage, BMI, and serum levels of leptin and PYY in lean and obese children

 
To augment core cohort data, PYY, insulin, and blood glucose were measured before and after the 1-yr weight reduction treatment of 28 obese children (16 girls and 12 boys) all attending the Obeldicks intervention program in Datteln (19). Changes in weight status [SD score (SDS)-BMI] over the 1-yr period were correlated to baseline PYY levels adjusted for baseline SDS-BMI using partial correlation.

In core cohort subjects, PYY, leptin, insulin, and blood glucose were measured in the fasting state between 0800 and 1000 h. The children (and parents) were precisely instructed to fast over a period of at least 14 h.

The serum total PYY concentration was measured by RIA in duplicate using an iodine-labeled tracer ([125I]PYY3–36; University of Mississippi, Human American Peptide, Sunnyvale, CA) and a specific PYY antibody (Peninsula Laboratories, San Carlos, CA; T-4090.05000P, lot 031934-1) that detects both the cleaved form (PYY3–36) and full-length hormone (PYY1–36). The intra- and interassay coefficients of variation were less than 8%. The minimal detectable concentration was 9.2 pg/ml. Serum leptin levels were measured by a commercially available RIA (Human Leptin RIA, Mediagnost, Reutlingen, Germany); the intra- and interassay coefficients of variation were defined at 5% and 8%, respectively. The sensitivity was 0.1 ng/ml. Plasma glucose and serum insulin levels were determined by automated standard methods. Homeostasis model assessment (HOMA) was used to determine the degree of insulin resistance using fasting glucose and insulin concentrations by the formula: resistance (HOMA) = [insulin (mU/liter) x glucose (mmol/liter)]/22.5 (20).

Weight status was recorded as BMI as well as an SDS-BMI. Because BMI is not normally distributed, we used the LMS method for calculating SDS-BMI (17, 18). M and S curves correspond to the median (M) and coefficient of variation (S) for BMI for German children at each age and gender. The L curve allows for the substantial age-dependent skewness in the distribution of BMI. The assumption underlying the LMS method is that after Box-Cox power transformation, the data at each age are normally distributed. Additionally, triceps and subscapularis skinfold thicknesses were measured in duplicate using a caliper and were averaged to calculate the percentage of body fat using skinfold thickness with the following equations formulated by Slaughter et al. (41): boys: body fat % = 0.783 x (skinfold thickness subscapularis + triceps in mm) + 1.6; girls: body fat % = 0.546 x (skinfold thickness subscapularis + triceps in mm) + 9.7.

The 1-yr outpatient training Obeldicks is based on a program of physical exercise, nutrition education, and behavior therapy, including individual psychological care of the child and immediate family (19). An interdisciplinary team of pediatricians, diet assistants, psychologists, and exercise physiologists perform the training. The children are grouped according to sex and age. The training program takes place over the period of 1 yr and is divided into three phases. During the first 3 months (intensive phase), the children take part in a nutrition and the eating behavior course in six group sessions, each lasting 1.5 h. At the same time, the parents are invited to attend six parents’ evenings involving similar nutrition and eating behavior education along with medical information regarding what can exacerbate obesity and what they can expect from their children both medically and behaviorally during and after the program. After the intensive phase is a 6-month establishing phase during which individual psychological family therapy is provided. The final 3-month phase of the program offers additional individual care, when and if necessary, and is designed to accompany the families back to their everyday lives.

Exercise therapy takes place once a week throughout the year, and the nutrition course is based on the prevention concept applied by the optimized mixed diet. Current scientific recommendations are translated into dietary guidelines, which take into consideration the dietary habits of children and families in Germany (21). In contrast to the present day diet of children in Germany with a fat content of 38% of energy intake (E%), 13 E% proteins, and 49 E% carbohydrates, including 14 E% sugar (22), the optimized mixed diet contains 30 E% fat, 15 E% proteins, and 55 E% carbohydrates, including 5 E% sugar. Both fat and especially sugar are reduced. The children follow a "traffic light-system" when selecting their food, which introduces elements of fun, thought, and self-control over what they eat.

Statistical analyses were performed using Winstat for Excel (Microsoft Corp., Redmond, WA). Correlations were calculated by Pearson correlations. Normal distribution was tested for all continuous variables using the Kolmogorov-Smirnov test. Normally distributed variables in obese and normal-weight children were compared by Student’s t test for unpaired observations; non-Gaussian variables were compared by Mann-Whitney U test. Direct multiple linear regression analysis was performed with PYY as the dependent variable, and age, gender, pubertal stage, BMI, and leptin as independent variables. Gender and pubertal stage were used as classification variables. In longitudinal analyses, the children were separated into quartiles according to their changes in SDS-BMI over the 1-yr period. Baseline characteristics were compared in these four groups by the Kruskal-Wallis test. Quantitative items were compared between baseline and 1-yr follow-up using the nonparametric Wilcoxon test for paired observations in non-Gaussian variables and by Student’s t test for paired observations in normally distributed variables. Values in tables are expressed as both the median and the interquartile range, and in figures as the mean ± SEM. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Obese children did not significantly differ from normal-weight children with respect to gender distribution (P = 0.744), age (P = 0.272), and pubertal development (P = 0.933; see Table 1Go and Fig. 1AGo). Obese children demonstrated significantly lower PYY (Fig. 1BGo) and higher leptin levels than lean children (Table 1Go). PYY was negatively correlated to BMI (r = –0.46; P < 0.001) and SDS-BMI (r = –0.52; P < 0.001; see Fig. 2Go) and was weakly negatively correlated to leptin (r = –0.15; P = 0.006). In the cross-sectional study, in obese children the mothers were 35% obese (BMI, >30 kg/m2) and 28% overweight (BMI, >25–30 kg/m2), whereas the fathers were 51% obese and 12% overweight. In lean children, the mothers were 8% obese and 23% overweight, and fathers were 8% obese and 15% overweight. Obviously, tendencies toward parental overweight or obesity were more common in obese children compared with lean children. In the longitudinal study (1-yr outpatient weight reduction training in 28 patients), both maternal and paternal obesity was present in 43% of each of the four groups, and overweight tendencies were found in 43% (group 1) and 29% (groups 2–4). In other words, the groups were comparable according to parental weight distribution.



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  		FIG. 1. Serum PYY levels of all prepubertal and pubertal patients (A). PYY levels in lean vs. obese girls and boys. ***, P < 0.001 vs. lean group of same gender (B).

 


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  		FIG. 2. Negative correlation between {Delta}BMI [SDS] (BMI-SDS after 1 yr minus BMI-SDS at baseline) and PYY in 118 children ({diamond}, 45 normal weight; {diamondsuit}, 73 obese patients; r = –0.52; P = 0.001).

 
In 28 patients who participated in the 1-yr outpatient weight reduction training, the change in BMI (the difference between BMI-SDS at baseline and BMI-SDS after 1 yr) correlated significantly with baseline PYY. Lower baseline PYY levels were associated with a greater degree of weight reduction (Fig. 3Go). Changes in weight status (SDS) over the 1-yr period were significantly negatively correlated to baseline PYY levels adjusted for baseline SDS-BMI (r = –0.43; P = 0.012). The group of patients in the outpatient weight reduction program was divided into four quartiles according to changes in SDS-BMI over a 1-yr period. Quartile 1 was defined as the quartile with the least success in BMI reduction [i.e. BMI after 1-yr treatment ({Delta}SDS-BMI), 0.11; Fig. 4AGo]. Quartile 2 had no change in SDS-BMI. Quartiles 3 and 4 had significant reduction in BMI-SDS ({Delta}SDS-BMI, –0.25 and –0.67, respectively). In quartile 4, BMI reduction was associated with a significant increase in PYY 1 yr after treatment compared with the baseline level (Fig. 4BGo). In addition, quartile 4 demonstrated the largest loss in body fat percentage (Table 2Go). Although insulin resistance did not significantly improve in quartile 4, the trend was toward a decrease in the insulin resistance index (HOMA) after the 1-yr treatment.



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  		FIG. 3. Correlation between {Delta}BMI [SDS] (BMI-SDS after 1 yr minus BMI-SDS at baseline) and baseline PYY in 28 patients before and after 1 yr of treatment. Lower baseline PYY levels were associated with a greater degree of weight reduction (r = 0.39; P = 0.02).

 


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  		FIG. 4. Changes in BMI (A) and PYY (B) in 28 patients before and after 1 yr of treatment. Four groups (quartiles of seven patients each) were formed; group 1 had the least success, and group 4 had the greatest success in weight reduction. Significant weight reduction in group 4 was associated with a significant increase in PYY levels after 1 yr of treatment. a, P < 0.01 vs. groups 1 and 2. b, P < 0.01 vs. group 1.

 

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  		TABLE 2. BMI-SDS, BMI, body weight, leptin, percentage of body fat, insulin resistance index (HOMA), and serum PYY levels at baseline and 1 yr after weight reduction treatment in 28 patients

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This is the first study investigating PYY in obese children before and after weight reduction. We found significantly lower PYY levels in obese children compared with normal-weight children, which is in concordance with comparable studies in adults (15, 16). We found no difference in PYY levels between boys and girls, or between prepubertal and pubertal children. The most interesting finding in this study was that 1 yr after weight loss, the low pretreatment PYY levels of obese children had increased significantly, indicating that weight loss restored physiological PYY serum levels.

Body weight homeostasis is maintained by the balance between energy intake and energy expenditure. In humans, the highest concentration of PYY is in the terminal ileum (9). PYY has been proposed to participate in the ileal brake (23). It has been shown to induce vasoconstriction, inhibit intestinal motility, and inhibit pancreatic and gastric secretions (24). In addition to these peripheral effects, PYY is a known short-term central satiety signal via binding to Y2 receptors in the ARH, resulting in inhibition of orexigenic NPY neurons and stimulation of anorexigenic proopiomelanocortin neurons (12, 25). Although the acute effects of peripherally administered PYY3–36 on satiety in rodents have been controversial (26), it is reasonably accepted that peripheral administration of PYY3–36 reduces food intake in a dose-dependent manner within hours in rodents (12, 14, 27, 28, 29). It also bears mentioning that central infusion of PYY3–36 into the lateral ventricle of mice induces hyperphagia (30). In humans, Batterham et al. (12) first reported that single iv infusion of PYY3–36 significantly decreased appetite and food intake for up to 12 h, and some of us have recently demonstrated that chronic infusion of PYY3–36 into monkeys can cause modest weight loss (31). Although the role of PYY in the long-term regulation of body weight and its possible role in the etiology of obesity are relatively unexplored, recent studies have shown that variations in PYY and Y2 receptor genes are associated with severe obesity (32, 33). Increased PYY levels could support weight loss by decreasing appetite, as has been shown in humans and rodents. However, the changes in PYY3–36 levels that modify food intake are much larger than the changes observed in this study. This is probably because exercise affects many systems, whereas the PYY intervention studies only alter PYY levels, and many factors influence food intake. It is also possible that sustained small changes in food intake can have a large cumulative effect on body weight.

This study does not discriminate PYY1–36 from PYY3–36, and the data need to be interpreted carefully; however, it is likely that PYY1–36 only exists transiently, because it is cleaved to PYY3–36 by the dipeptidyl peptidase IV (34). If PYY1–36 is present at significant concentrations in the blood, it would probably exert actions similar to PYY3–36, because the hyperphagic effects of the NPY family peptides are only seen when these peptides reach deep within the brain. Indeed, peripheral infusion of NPY (which will activate all NPY receptors) inhibits food intake (35).

The effects of nutrients on PYY secretion have been extensively studied in vivo and in vitro (23, 36). PYY is produced in proportion to the amount of calories ingested (37). PYY secretion is also controlled by humoral and neural stimuli as well as local factors, such as intestinal peristalsis and intraluminal nutrients (1, 9). Batterham et al. (15) demonstrated that PYY levels increase shortly after a meal and remain stimulated several hours thereafter. Published data suggest that the PYY response to a meal may be more important than the absolute baseline values (38). It has also been demonstrated that isocaloric meals of fat stimulate PYY more potently than meals containing primarily protein or carbohydrate (39). In rats, intraduodenal injection of hyperosmolar glucose solution stimulates PYY release more than hyperosmolar saline, indicating that glucose is a short-term PYY stimulant in this species (36). In contrast, some of us have recently shown that iv glucose tolerance tests do not change PYY3–36 levels in rhesus monkeys (31).

It is noteworthy that low pretreatment PYY levels increased significantly after effective weight loss, although insulin resistance did not differ between the quartiles and did not change significantly after treatment. This indicates that the restoration of physiological PYY levels after weight loss is not primarily dependent upon changes in glucose metabolism. It is possible that the quartiles in this study are too small to detect significant changes in the HOMA index after weight loss, because in a previous study we found significant reduction in the HOMA index in a group of subjects who had effective weight loss (40). Furthermore, the change in BMI might also be influenced by the lower percentage of pubertal patients in group 4.

In conclusion, PYY is negatively correlated to degree of overweight, with reduced values in obese compared with normal-weight children. Besides its known effects as a short-term regulator of energy homeostasis, PYY levels also reflect long-term changes in body composition. Low PYY levels could predispose subjects to develop obesity. Considering the size and age group limitations of our study along with the small number of patients showing effective weight loss, we can only speculate that low pretreatment PYY levels and/or a strong increase in PYY levels might serve as a predictor of effective weight loss. Long-term effects of PYY and the maintenance of weight loss should be verified in larger studies. Once effective weight loss has been achieved, the anorectic effect of PYY may help to stabilize weight and thereby prevent later weight gain in patients whose PYY levels increased to normal levels. In this respect, it is possible that PYY is also a long-term regulator of body weight.


   Acknowledgments
 
We thank Erin E. Jobst, Ph.D. (OHSU Beaverton, OR), and M. Neff-Heinrich, Göttingen, for their kind help in editing the manuscript. Furthermore, we thank R. Maslak (Children’s Hospital University of Bonn) for her support in the laboratory.


   Footnotes
 
This work has been supported by the Bonfor Research Foundation, University of Bonn, Germany (Grant O-119.0010), and by National Institutes of Health Grants RR0163 and DK 62202.

First Published Online October 4, 2005

Abbreviations: ARH, Arcuate nucleus of the hypothalamus; BMI, body mass index; E%, percentage of energy intake; HOMA, homeostasis model assessment; NPY, neuropeptide Y; PYY, peptide YY3–36; SDS, SD score; {Delta}SDS-BMI, BMI after 1-yr treatment.

Received June 20, 2005.

Accepted September 27, 2005.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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  38. Stock S, Leichner P, Wong AC, Ghatei MA, Kieffer TJ, Bloom SR, Chanoine JP 2005 Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J Clin Endocrinol Metab 90:2161–2168[Abstract/Free Full Text]
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