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

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.

In adults with Prader–Willi syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and GLP-1 levels

“…The present study confirms previous reports (DelParigi et al, 2002, Haqq et al, 2003, Goldstone et al, 2004and Tauber et al, 2004) that fasting and postprandial ghrelin levels are significantly higher in PWS subjects compared to obese and lean subjects. However, in contrast to previous reports , Goldstone et al, 2004, Goldstone et al, 2005and McLaughlin et al, 2004, our data suggest that the observed increase in ghrelin in PWS is not due to altered fat distribution or hypoinsulinemia because PWS and obese subjects were matched for total and central adiposity and showed similar insulin secretion and insulin resistance.…”

Neural representations of hunger and satiety in Prader–Willi syndrome

“…In contrast to the imaging results, the blood plasma levels of glucose, insulin, ghrelin and PYY were found in accordance with the predictions: levels of all of the above were significantly different between the fasting and high-energy meal conditions. While ghrelin levels were elevated in comparison to controls in previously published literature, 35,[41][42][43] recent work has shown that even when ghrelin levels are reduced to a normal level, using somatostatin or a somatostatin agonist, there is no effect on appetite or food intake in individuals with PWS. 44,45 This suggests that the dysfunction in PWS is central in origin, rather than as a result of abnormalities in the periphery, at least in terms of the measures in this study.…”

Prader-Willi syndrome

“…[8][9][10][11][12] Ghrelin is a potent circulating orexigenic hormone that is produced mainly in the stomach. Circulating ghrelin levels rise after fasting and are suppressed by food intake.…”