High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome

Veronique Beauloye, Gwenaelle Diene, Renske Kuppens, Francis Zech, Coralie Winandy, Catherine Molinas, Sandy Faye, Isabelle Kieffer, Dominique Beckers, Ricard Nergårdh, Berthold Hauffa, Christine Derycke, Patrick Delhanty, Anita Hokken-Koelega, Maithé Tauber, Veronique Beauloye, Gwenaelle Diene, Renske Kuppens, Francis Zech, Coralie Winandy, Catherine Molinas, Sandy Faye, Isabelle Kieffer, Dominique Beckers, Ricard Nergårdh, Berthold Hauffa, Christine Derycke, Patrick Delhanty, Anita Hokken-Koelega, Maithé Tauber

Abstract

Background: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS.

Methods: Measurement of at least 4 h-fasting plasma acylated and unacylated ghrelin in 37 infants with a genetic diagnosis of PWS aged from 1 month to 4 years and in 100 age-matched controls without endocrine disorder recruited prior to minor surgery. One blood sampling was analysed for each patient/control and clinical data were recorded. Eleven PWS infants underwent repetitive blood samples at 3 or 6-month intervals during routine visits.

Results: In infants with PWS, AG is not elevated (p = 0.45), UAG is significantly higher (p = 0.0044; confidence interval 1.06;1.33) resulting in a low AG/UAG ratio (p = 0.0056; confidence interval 0.76;0.95) compared to controls.

Conclusion: Unlike children and adults with PWS that have high AG and AG/UAG ratio, infants with PWS have elevated UAG that supports the concept of anorexia in the early phases of the disease. The change in AG/UAG ratio possibly drives the switch from failure to thrive to obesity.

Clinical trial registration: NCT02529085 .

Keywords: Anorexia; Ghrelin; Infants; Nutrition; Obesity; Prader-Willi syndrome.

Figures

Fig. 1
Fig. 1
Plotted BMI of the PWS girls a and boys b. Open circles: PWS infants not treated with GH; dark circles: PWS infants treated with GH. When several measures had been taken for one individual, the circles are linked
Fig. 2
Fig. 2
Acylated (AG) a, unacylated (UAG) b ghrelin levels and AG/UAG ratio c according to age in both groups: red: PWS; blue: control children. Comparative analyses were conducted using linear generalized estimating equations with a common correlation between samples from the same patients, with p-value calculation according to Pan et al. and Chaganty et al. [18, 19]. PWS vs. Controls: p = 0.45 (A), p = 0.0044 (B), p = 0.0056 (C), see Additional file 1: Fig. S1
Fig. 3
Fig. 3
Unacylated (UAG) ghrelin levels according to age in GH-treated (open circles) and untreated (dark squares) PWS infants. Comparative analyses were conducted using linear generalized estimating equations with a common correlation between samples from the same patients, with p-value calculation according to Pan et al. and Chaganty et al. [18, 19]. UAG in function of age in GH (−) vs. GH (+): p = 0.0015

References

    1. Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, Dykens E, Butler MG, Shuster JJ, Driscoll DJ. Nutritional phases in prader-willi syndrome. Am J Med Genet A. 2011;155A:1040–9.
    1. Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY, Broglio F, et al. Ghrelin. Mol metab. 2015;4:437–60.
    1. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevated plasma ghrelin levels in prader willi syndrome. Nat Med. 2002;8:643–4.
    1. DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, Tataranni PA. High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome. J Clin Endocrinol Metab. 2002;87:5461–4.
    1. Feigerlova E, Diene G, Conte-Auriol F, Molinas C, Gennero I, Salles JP, Arnaud C, Tauber M. Hyperghrelinemia precedes obesity in prader-willi syndrome. J Clin Endocrinol Metab. 2008;93:2800–5.
    1. Kweh FA, Miller JL, Sulsona CR, Wasserfall C, Atkinson M, Shuster JJ, Goldstone AP, Driscoll DJ. Hyperghrelinemia in prader-willi syndrome begins in early infancy long before the onset of hyperphagia. Am J Med Genet A. 2015;167A:69–79.
    1. Asakawa A, Inui A, Fujimiya M, Sakamaki R, Shinfuku N, Ueta Y, Meguid MM, Kasuga M. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut. 2005;54:18–24.
    1. Delhanty PJ, Neggers SJ, van der Lely AJ. Mechanisms in endocrinology: ghrelin: the differences between acyl- and des-acyl ghrelin. Eur J Endocrinol Eur Fed Endocr Soc. 2012;167:601–608. doi: 10.1530/EJE-12-0456.
    1. Terashi M, Asakawa A, Harada T, Ushikai M, Coquerel Q, Sinno MH, Dechelotte P, Inui A, Fetissov SO. Ghrelin reactive autoantibodies in restrictive anorexia nervosa. Nutrition. 2011;27:407–13.
    1. Uehara M, Yasuhara D, Nakahara T, Nadkarni NA, Asakawa A, Inui A. Increase in energy intake leads to a decrease in obestatin in restricting-type of anorexia nervosa. Exp clin endocrinol diabetes : off j Ger Soc Endocrinol Ger Diabetes Assoc. 2011;119:536–539. doi: 10.1055/s-0031-1279703.
    1. Nakahara T, Harada T, Yasuhara D, Shimada N, Amitani H, Sakoguchi T, Kamiji MM, Asakawa A, Inui A. Plasma obestatin concentrations are negatively correlated with body mass index, insulin resistance index, and plasma leptin concentrations in obesity and anorexia nervosa. Biol Psychiatry. 2008;64:252–5.
    1. Harada T, Nakahara T, Yasuhara D, Kojima S, Sagiyama K, Amitani H, Laviano A, Naruo T, Inui A. Obestatin, acyl ghrelin, and des-acyl ghrelin responses to an oral glucose tolerance test in the restricting type of anorexia nervosa. Biol Psychiatry. 2008;63:245–7.
    1. Roelants M, Hauspie R, Hoppenbrouwers K. References for growth and pubertal development from birth to 21 years in Flanders, Belgium. Ann Hum Biol. 2009;36:680–694. doi: 10.3109/03014460903049074.
    1. Lawrence C, Fryer JG, Karlberg P, Niklasson A, Ericson A. Modelling of reference values for size at birth. Acta Paediatr Scand Suppl. 1989;350:55–69. doi: 10.1111/j.1651-2227.1989.tb11198.x.
    1. Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr. 1969;74:901–910. doi: 10.1016/S0022-3476(69)80224-6.
    1. Sempé M, Pédron G, Roy-Pernot M.P. Auxologie méthode et séquences. Théraplix. Paris; 1979.Réédition 1997 Méditions ISBN: 2-905839-2.
    1. Cole TJ, Bellizzi MC, Flegal KM, Dietz WH. Establishing a standard definition for child overweight and obesity worldwide: international survey. BMJ. 2000;320:1240–1243. doi: 10.1136/bmj.320.7244.1240.
    1. Pan W, Wall MM. Small-sample adjustments in using the sandwich variance estimator in generalized estimating equations. Stat Med. 2002;21:1429–1441. doi: 10.1002/sim.1142.
    1. Chaganty NR, Naik DN. Analysis of multivariate longitudinal data using quasi-least squares. J Stat Plann Inference. 2002;103:421–436. doi: 10.1016/S0378-3758(01)00235-X.
    1. Bachere N, Diene G, Delagnes V, Molinas C, Moulin P, Tauber M. Early diagnosis and multidisciplinary care reduce the hospitalization time and duration of tube feeding and prevent early obesity in PWS infants. Horm Res. 2008;69:45–52. doi: 10.1159/000111795.
    1. Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M. Speakers contributors at the second expert meeting of the comprehensive care of patients with PWS: recommendations for the diagnosis and management of prader-willi syndrome. J Clin Endocrinol Metab. 2008;93:4183–4197. doi: 10.1210/jc.2008-0649.
    1. Germain N, Galusca B, Grouselle D, Frere D, Tolle V, Zizzari P, Lang F, Epelbaum J, Estour B. Ghrelin/obestatin ratio in two populations with low bodyweight: constitutional thinness and anorexia nervosa. Psychoneuroendocrinology. 2009;34:413–9.
    1. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387–396. doi: 10.1016/j.cell.2008.01.017.
    1. Nishi Y, Yoh J, Hiejima H, Kojima M. Structures and molecular forms of the ghrelin-family peptides. Peptides. 2011;32:2175–2182. doi: 10.1016/j.peptides.2011.07.024.
    1. Goebel-Stengel M, Hofmann T, Elbelt U, Teuffel P, Ahnis A, Kobelt P, Lambrecht NW, Klapp BF, Stengel A. The ghrelin activating enzyme ghrelin-O-acyltransferase (GOAT) is present in human plasma and expressed dependent on body mass index. Peptides. 2013;43:13–9.
    1. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schurmann A, Joost HG, Jandacek RJ, Hale JE, et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med. 2009;15:741–5.
    1. Festen DA, de Lind van Wijngaarden R, van Eekelen M, Otten BJ, Wit JM, Duivenvoorden HJ, Hokken-Koelega AC. Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with prader-willi syndrome. Clin Endocrinol (Oxf). 2008;69:443–51.
    1. Eiholzer U, l’Allemand D, van der Sluis I, Steinert H, Gasser T, Ellis K. Body composition abnormalities in children with prader-willi syndrome and long-term effects of growth hormone therapy. Horm Res. 2000;53:200–206. doi: 10.1159/000023567.
    1. Haqq AM, Grambow SC, Muehlbauer M, Newgard CB, Svetkey LP, Carrel AL, Yanovski JA, Purnell JQ, Freemark M. Ghrelin concentrations in prader-willi syndrome (PWS) infants and children: changes during development. Clin Endocrinol (Oxf). 2008;69:911–20.
    1. Haqq AM, Muehlbauer M, Svetkey LP, Newgard CB, Purnell JQ, Grambow SC, Freemark MS. Altered distribution of adiponectin isoforms in children with prader-willi syndrome (PWS): association with insulin sensitivity and circulating satiety peptide hormones. Clin Endocrinol (Oxf). 2007;67:944–51.
    1. Bellone S, Prodam F, Savastio S, Avanzo D, Pagani A, Trovato L, Walker GE, Genoni G, Bona G. Acylated/unacylated ghrelin ratio in cord blood: correlation with anthropometric and metabolic parameters and pediatric lifespan comparison. Eur j endocrinol / Eur Fed Endocr Soc. 2012;166:115–20.
    1. Haqq AM, Farooqi IS, O’Rahilly S, Stadler DD, Rosenfeld RG, Pratt KL, LaFranchi SH, Purnell JQ. 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;88:174–8.
    1. Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, Frost G, Holland AJ, Grossman AB, Korbonits M, et al. Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance. J Clin Endocrinol Metab. 2004;89:1718–26.
    1. Kuppens RJ, Delhanty PJ, Huisman TM, van der Lely AJ, Hokken-Koelega AC. Acylated and unacylated ghrelin during OGTT in Prader-Willi syndrome: Support for normal response to food intake. Clin Endocrinol (Oxf) 2016. doi: 10.1111/cen.13072. [Epub ahead of print].
    1. Kuppens RJ, Diene G, Bakker NE, Molinas C, Faye S, Nicolino M, Bernoux D, Delhanty PJ, van der Lely AJ, Allas S, et al. Elevated ratio of acylated to unacylated ghrelin in children and young adults with prader-willi syndrome. Endocrine. 2015;50:633–42.
    1. Steculorum SM, Collden G, Coupe B, Croizier S, Lockie S, Andrews ZB, Jarosch F, Klussmann S, Bouret SG. Neonatal ghrelin programs development of hypothalamic feeding circuits. J Clin Invest. 2015;125:846–58.

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