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The Journal of Clinical Endocrinology & Metabolism 90(12):6386 – 6391
Copyright © 2005 by The Endocrine Society
doi: 10.1210/jc.2005-1357
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
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.
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. (J Clin Endocrinol Metab 90: 6386 – 6391, 2005)
Main Outcome Measures: PYY, insulin, and body mass index were
the main outcome measures.
S
ATIETY 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 shortterm regulators of food intake, in contrast to the long-term
satiety regulators, leptin and insulin (1–3). 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 – 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 (7–9). PYY
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; ⌬SDS-BMI, BMI after 1-yr treatment.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.
has agonistic properties on Y2 receptors, which are highly
expressed on NPY neurons in the ARH, leading to inhibition
of food intake (10 –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
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 1). 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
6386
Roth et al. • Changes in PYY in Obese Children
J Clin Endocrinol Metab, December 2005, 90(12):6386 – 6391
TABLE 1. Age, gender, pubertal stage, BMI, and serum levels of
leptin and PYY in lean and obese children
No.
Age (yr)
Gender
Pubertal stage
BMI
BMI-SDS
Leptin (ng/ml)
PYY (pg/ml)
Normal weight
Obese patients
P value
45
11 (9 to 13)
49% boys
60% pubertal
18.8 (17.1 to 20.5)
0.38 (⫺0.27 to 0.84)
5.4 (2.3 to 9.9)
124 (99 to 180)
73
11 (9 to 13)
56% boys
59% pubertal
28.8 (26.2 to 32.1)
2.53 (2.17 to 2.85)
23.9 (15.5 to 45.6)
67 (49 to 88)
0.714
0.744
0.933
⬍0.001
⬍0.001
⬍0.0001
⬍0.0001
Values for median and interquartile range are shown.
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.
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) ⫻ 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 ⫻ (skinfold thickness subscapularis ⫹ triceps in mm)
⫹ 1.6; girls: body fat % ⫽ 0.546 ⫻ (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
6387
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
Obese children did not significantly differ from normalweight children with respect to gender distribution (P ⫽
0.744), age (P ⫽ 0.272), and pubertal development (P ⫽ 0.933;
see Table 1 and Fig. 1A). Obese children demonstrated significantly lower PYY (Fig. 1B) and higher leptin levels than
lean children (Table 1). PYY was negatively correlated to BMI
(r ⫽ ⫺0.46; P ⬍ 0.001) and SDS-BMI (r ⫽ ⫺0.52; P ⬍ 0.001;
see Fig. 2) 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.
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. 3). Changes in weight status (SDS) over the 1-yr
6388
J Clin Endocrinol Metab, December 2005, 90(12):6386 – 6391
Roth et al. • Changes in PYY in Obese Children
FIG. 3. Correlation between ⌬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).
Discussion
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).
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 (⌬SDS-BMI), 0.11; Fig. 4A].
Quartile 2 had no change in SDS-BMI. Quartiles 3 and 4 had
significant reduction in BMI-SDS (⌬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. 4B). In addition, quartile 4 demonstrated the largest loss in body fat percentage
(Table 2). 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.
FIG. 2. Negative correlation between ⌬BMI [SDS] (BMI-SDS after 1
yr minus BMI-SDS at baseline) and PYY in 118 children (〫, 45
normal weight; ⽧, 73 obese patients; r ⫽ ⫺0.52; P ⫽ 0.001).
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 normalweight 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
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.
J Clin Endocrinol Metab, December 2005, 90(12):6386 – 6391
Four quartiles were formed (seven patients each) according to degree of change in BMI-SDS. Values for median and interquartile range are shown. Age differed among the four
quartiles, but not significantly (by Kruskal-Wallis test).
a
P ⬍ 0.05 vs. baseline group 4.
b
P ⬍ 0.05 vs. baseline groups 1 and 2.
c
P ⬍ 0.05 vs. baseline group 4.
1.99 (1.72–2.40)a
23.1 (21.9 –26.7)
51.9 (43.3–75.6)
34% (29 – 41%)b
2.4 (1.4 –7.3)
106 (63–183)d
2.59 (2.31–3.04)
25.5 (23.5–29.4)
51.1 (40.5–77.2)
41% (37– 46%)
3.5 (1.9 – 4.5)
42 (38 – 68)c
2.11 (1.85–2.39)
26.8 (24.5–28.2)
56.7 (54.8 –79.7)
41% (40 – 44%)
3.2 (2.8 – 6.3)
81 (37–93)
2.35 (2.10 –2.62)
27.6 (23.4 –28.9)
55.1 (48.6 –75.0)
54% (44 –55%)
3.5 (3.0 – 4.4)
85 (67–96)
2.15 (2.02–2.72)
27.7 (26.8 –32.7)
78.5 (71.3– 88.4)
44% (36 – 49%)
3.3 (2.7–5.6)
70 (60 –98)
2.14 (2.03–2.71)
27.4 (26.0 –32.1)
70.9 (63.7– 81.5)
49% (47–52%)
5.1 (4.2–7.5)
92 (69 –154)
2.43 (2.25–2.88)
30.0 (28.6 –33.3)
76.5 (74.2–98.7)
53% (44 –56%)
4.5 (3.9 – 6.8)
54 (47–108)
2.19 (2.12–2.76)
28.4 (27.5–31.4)
71.2 (67.7– 88.3)
48% (41–54%)
3.8 (3.3–5.3)
125 (70 –134)
BMI-SDS
BMI
Body weight
% Body fat
HOMA
PYY (pg/ml)
1 yr later
At baseline
1 yr later
At baseline
1 yr later
At baseline
1 yr later
At baseline
7
8.7 (6.0 to 10.9)
43
14
⫺0.67 (⫺0.74 to ⫺0.54)
7
10.2 (8.5 to 12.5)
43
57
⫺0.25 (⫺0.42 to 0.20)
7
12.0 (11.0 to 12.9)
43
71
0.0 (⫺0.02 to 0.02)
7
12.9 (11.9 to 13.8)
43
71
0.11 (0.05 to 0.14)
No.
Age (yr)
% Male
% Pubertal stage
⌬BMI-SDS
Fourth quartile (group 4)
Third quartile (group 3)
Second quartile (group 2)
First quartile (group 1)
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
Roth et al. • Changes in PYY in Obese Children
6389
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, 27–29). 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
6390
J Clin Endocrinol Metab, December 2005, 90(12):6386 – 6391
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 shortterm 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.
Roth et al. • Changes in PYY in Obese Children
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Acknowledgments
We thank Erin E. Jobst, Ph.D. (OHSU Beaverton, OR), and M. NeffHeinrich, 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.
Received June 20, 2005. Accepted September 27, 2005.
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: [email protected].
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.
22.
23.
24.
25.
26.
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