Abstract
Ghrelin is a 28-amino acid peptide recently identified in the stomach as the endogenous
ligand for the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a potent
stimulator of GH secretion. It was recently shown that circulating ghrelin levels
in humans rise shortly before and fall shortly after every meal, and that ghrelin
administration increases voluntary food intake. The hypothesis that ghrelin hypersecretion
might contribute to genetic obesity has never been investigated. In this context,
Prader-Willi syndrome is the most common form of human syndromic obesity. As ghrelin
affects appetite as well as GH secretion and both are abnormal in PWS, it has been
surmised that these alterations might be due to ghrelin dysregulation. The aim of
the study was to investigate whether ghrelin is suppressed by the meals differently
in PWS children than in PWS adults. Overnight circulating fasting ghrelin levels and
ghrelin levels 120 min after breakfast were assayed in 7 PWS children (10.2 ± 1.7
yr), 7 subjects with morbid obesity (10.3 ± 1.3 yr), and 5 normal controls (8.4 ±
1.4 yr). Because of the data spread, no statistical difference was observed in fasting
ghrelin levels between PWS and control children (p = NS); anyway, fasting ghrelin
levels were significantly lower in obese children than in the other groups (p < 0.05
vs. control and PWS children). Ghrelin levels were slightly suppressed by the meal in
control subjects (mean fasting ghrelin: 160.2 ± 82 pg/ml; after the meal, 141.2 ±
57 pg/ml, p = NS); the meal failed to suppress ghrelin levels in obese children (mean
fasting ghrelin: 126.4 ± 8.5 pg/ml; after the meal, 119.1 ± 8.3 pg/ml, p = NS). Interestingly,
the meal markedly suppressed ghrelin levels in PWS children (mean fasting ghrelin:
229.5 ± 70.4 pg/ml; after the meal, 155.8 ± 34.2 pg/ml, p < 0.01). In conclusion,
since a lack of decrease in circulating ghrelin induced by the meal was previously
reported in PWS adults, the finding of a meal-induced decrease in ghrelin levels in
our population of young PWS would imply that the regulation of the ghrelin system
involved in the orexigenic effects of the peptide is operative during childhood, although
it progressively deteriorates and is absent in adulthood when hyperphagia and obesity
progressively worsen.
Key words
PWS - Ghrelin - Obesity - Children - Food intake
References
- 1
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K.
Ghrelin is a growth-hormone-releasing acylated peptide from stomach.
Nature.
1999;
402
656-660
- 2
Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal M S, Suganuma T, Matsukura S, Kangawa K,
Nakazato M.
Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct
endocrine cell type in the gastrointestinal tracts of rats and humans.
Endocrinology.
2000;
141
4255-4261
- 3
Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal M S, Hosoda H, Kojima M, Kangawa K,
Arima T, Matsuo H, Yada T, Matsukura S.
Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin
secretion.
Diabetes.
2002;
51
124-129
- 4
Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y,
Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K.
Ghrelin strongly stimulates growth hormone release in humans.
J Clin Endocrinol Metab.
2000;
85
4908-4911
- 5
Gnanapavan S, Kola B, Bustin S A, Morris D G, McGee P, Fairclough P, Bhattacharya S,
Carpenter R, Grossman A B, Korbonits M.
The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R,
in humans.
J Clin Endocrinol Metab.
2002;
87
2988
- 6
Tschop M, Wawarta R, Riepl R L, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C.
Post-prandial decrease of circulating human ghrelin levels.
J Endocrinol Invest.
2001;
24
RC19-21
- 7
Wren A M, Seal L J, Cohen M A, Brynes A E, Frost G S, Murphy K G, Dhillo W S, Ghatei M A,
Bloom S R.
Ghrelin enhances appetite and increases food intake in humans.
J Clin Endocrinol Metab.
2001;
86
5992
- 8
Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S.
A role for ghrelin in the central regulation of feeding.
Nature.
2001;
409
194-198
- 9
Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely A J, Deghenghi R,
Ghigo E.
Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia
and reduces insulin secretion in humans.
J Clin Endocrinol Metab.
2001;
86
5083-5086
- 10
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal M S, Tanaka M, Nozoe S, Hosoda H, Kangawa K,
Matsukura S.
Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin
secretion.
J Clin Endocrinol Metab.
2002;
87
240-244
- 11
Burman P, Ritzen E M, Lindgren A C.
Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to
GH.
Endocr Rev.
2001;
22
787-799
- 12
Holm V A, Cassidy S B, Butler M G, Hanchett J M, Greenswag L R, Whitman B Y, Greenberg F.
Prader-Willi syndrome: consensus diagnostic criteria.
Pediatrics.
1993;
91
398-402
- 13
Wharton R H, Loechner Wharton R H, Loechner K J.
Genetic and clinical advances in Prader-Willi syndrome.
Curr Opin Pediatr.
1996;
8
618-624
- 14
Cummings D E, Clement K, Purnell J Q, Vaisse C, Foster K E, Frayo R S, Schwartz M W,
Basdevant A, Weigle D S.
Elevated plasma ghrelin levels in Prader Willi syndrome.
Nat Med.
2002;
8
643-644
- 15
DelParigi A, Tschop M, Heiman M L, Salbe A D, Vozarova B, Sell S M, Bunt J C, Tataranni P A.
High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi
syndrome.
J Clin Endocrinol Metab.
2002;
87
5461-5464
- 16
Haqq A M, Farooqi I S, O'Rahilly S, Stadler D D, Rosenfeld R G, Pratt K L, LaFranchi S H,
Purnell J Q.
Serum ghrelin levels are inversely correlated with body mass index, age, and insulin
concentrations in normal children and are markedly increased in Prader-Willi syndrome.
J Clin Endocrinol Metab.
2003;
88
174-178
- 17
Ward O C.
Prader-Willi syndrome.
Lancet.
2000;
356
1856
- 18
English P J, Ghatei M A, Malik I A, Bloom S R, Wilding J P.
Food fails to suppress ghrelin levels in obese humans.
J Clin Endocrinol Metab.
2002;
87
2984
- 19
Cummings D E, Schwartz M W.
Genetics and pathophysiology of human obesity.
Annu Rev Med.
2003;
54
453-471
- 20 Bellone S, Rapa A, Vivenza D, Petri A, Me E, Bellone J, Radetti G, Gottero C, Broglio F,
Ghigo E, Bona G. Children show refractoriness to the inhibitory effect of feeding
on ghrelin secretion. 85th Annual Meeting of the Endocrine Society, June, 19th-23rd
2003, Philadelphia, PA, USA, Abstractbook P1 - 668.
- 21
Rittmaster R S, Loriaux D L, Merriam G R.
Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions
on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization
independent of GH pool depletion.
Neuroendocrinology.
1987;
45
118-122
- 22
Janssen J A, van der Toorn F M, Hofland L J, van Koetsveld P, Broglio F, Ghigo E,
Lamberts S W, Jan van der Lely A.
Systemic ghrelin levels in subjects with growth hormone deficiency are not modified
by one year of growth hormone replacement therapy.
Eur J Endocrinol.
2001;
145
711-716
- 23
Muller E E, Locatelli V, Cocchi D.
Neuroendocrine control of growth hormone secretion.
Physiol Rev.
1999;
79
511-607
- 24
Greenswag L R.
Adults with Prader-Willi syndrome: a survey of 232 cases.
Dev Med Child Neurol.
1987;
29
145-152
- 25
Ott V, Fasshauer M, Dalski A, Meier B, Perwitz N, Klein H H, Tschop M, Klein J.
Direct peripheral effects of ghrelin include suppression of adiponectin expression.
Horm Metab Res.
2002;
34
640-645
- 26
Schuster D P, Osei K, Zipf W B.
Characterization of alterations in glucose and insulin metabolism in Prader-Willi
subjects.
Metabolism.
1996;
45
1514-1520
- 27
Zipf W B.
Glucose homeostasis in Prader-Willi syndrome and potential implications of growth
hormone therapy.
Acta Paediatr Suppl..
1999;
88
115-117
- 28
Eiholzer U, Stutz K, Weinmann C, Torresani T, Molinari L, Prader A.
Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome.
Eur J Pediatr.
1998;
157
890-893
- 29
Hoybye C, Hilding A, Jacobsson H, Thoren M.
Metabolic profile and body composition in adults with Prader-Willi syndrome and severe
obesity.
J Clin Endocrinol Metab.
2002;
87
3590-3597
- 30
Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Targher G, Alberiche M, Bonadonna R C,
Muggeo M.
Prevalence of insulin resistance in metabolic disorders: the Bruneck Study.
Diabetes.
1998;
47
1643-1649
- 31
Cummings D E, Purnell J Q, Frayo R S, Schmidova K, Wisse B E, Weigle D S.
A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in
humans.
Diabetes.
2001;
50
1714-1719
- 32
Volante M, Allia E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E,
Papotti M.
Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells
and related endocrine tumors.
J Clin Endocrinol Metab.
2002;
87
1300-1308
- 33
McCowen K C, Maykel J A, Bistrian B R, Ling P R.
Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic
euglycemic conditions in rodents.
J Endocrinol.
2002;
175
R7-11
- 34
Caixas A, Bashore C, Nash W, Pi-Sunyer F, Laferrere B.
Insulin, unlike food intake, does not suppress ghrelin in human subjects.
J Clin Endocrinol Metab.
2002;
87
1902
- 35
Degerblad M, Bengtsson B A, Bramnert M, Johnell O, Manhem P, Rosen T, Thoren M.
Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased
bone turnover during 12 months of GH substitution therapy.
Eur J Endocrinol.
1995;
133
180-188
E. E. Müller
Department of Medical Pharmacology · University of Milan
via Vanvitelli 32 · 20129 Milan · Italy
Phone: +39(2)50317010-7012
Fax: +39(2)50317011
Email: eugenio.muller@unimi.it
