The role of ghrelin in the hyperphagia of the Prader-Willi syndrome

Ghrelin, postnatally expressed in the gastric fundus (X/A cells) and in the hypothalamus, increases before meals to concentrations sufficient to stimulate hunger and food intake. Ghrelin is regulated by the state of energy homeostasis and involved in long-term body weight regulation. It circulates in relation to energy stores and shows compensatory changes in response to body weight alterations. Exogenous application of ghrelin increases hunger and calories eaten, and stimulates GH release. Fasting levels of plasma ghrelin, the orexigenic, stomach-derived hormone, are grossly elevated in children with Prader-Willi syndrome (PWS). This could contribute to the hyperphagia characteristic for this disorder. The cause of the ghrelin elevation, the regulation and the source of ghrelin in PWS is largely unknown. However, the capacity of a mixed meal and individual nutritional components as glucose to suppress ghrelin is maintained in patients. This appears to be at least partially explained by the preserved insulin sensitivity and hypoinsulinemia, compared to normal obese subjects. Although somatostatin suppresses plasma ghrelin concentrations in PWS patients, appetite is not reduced. Ongoing studies are looking at the possible benefit of chronic administration of long acting somatostatin analogues in PWS. GH treatment, known to change body weight and composition favorably in PWS has been found to lower total, but not acylated ghrelin in one study (1). Pharmacological agents that specifically abolish ghrelin action, as the spiegelmers, may be useful to further elucidate the role of ghrelin in PWS. It appears that in addition to hormonal abnormalities, there are overriding brain defects, including hypothalamic defects, which lead to resistance in peripheral satiety signals. Better knowledge of these hormonal and structural defects is a prerequisite for the development of new therapies targeting hypothalamic and extrahypohalamic brain structures to reduce hyperphagia in PWS. (1.) Hauffa BP et al., JCEM 92:834–40 (2007)