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High Circulating Ghrelin: A Potential Cause for Hyperphagia and Obesity in Prader-Willi Syndrome

Clinical Diabetes and Nutrition Section (A.D.P., A.D.S., B.V., J.C.B., P.A.T.), National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona 85016; Endocrine Research and Statistics Department (M.T., M.L.H.), Eli Lilly \|[amp ]\| Co., Indianapolis, Indiana 46285; and Department of Nutrition Sciences (S.M.S.), University of Alabama at Birmingham, Birmingham, Alabama 35294

Address all correspondence to: Angelo DelParigi, M.D., National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Diabetes and Nutrition Section, 4212 North 16th Street, Room 5-41A, Phoenix, Arizona 85016. E-mail: adelpari{at}mail.nih.gov.

Abstract

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000–16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 ± 7 yr; body fat, 39 ± 11%, mean ± SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 ± 7 yr; body fat, 36 ± 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 ± 164 vs. 109 ± 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 ± 164 vs. 306 ± 205 vs. 260 ± 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.

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