Prader-Willi Syndrome as a Model of Human Hyperphagia

Abstract

Prader-Willi syndrome (PWS), first described in 1956, is considered as a paradigm of a neurodevelopmental disorder with severe and early obesity with hyperphagia and impaired satiety. The improved knowledge in the natural history and recent data on genetics offer new perspectives for understanding the metabolic and endocrine dysfunctions and possibly for treatment. Natural history of the disease has been described due to the early diagnosis performed in the first months of life and various nutritional phases have been described. In addition, there is clear evidence that the abnormal feeding behavior is included in the behavioral problems. Brain imaging studies have shown that some brain regions may be important in PWS. The role of SNORD116 gene cluster is detailed and its links with circadian rhythm and brain and hypothalamus development. Pathophysiology of the abnormal ghrelin levels and of OT dysfunction is documented. While no effect on appetite and weight regulation has been reported with ghrelin antagonists, OT has been shown to improve some of the behavioral problems in adults. We discuss our hypothesis of an abnormal ghrelin/OT/dopamine pathway which may explain the switch of nutritional phases and behavior. These new aspects offer an opportunity for therapeutic use and possible early intervention.

Anomalous basal ganglia connectivity and obsessive–compulsive behaviour in patients with Prader Willi syndrome

“…Altered eating behaviour in patients with Prader Willi syndrome is considered to be a failure of satiety 51,52 potentially related to hypothalamic dysfunction. 53 Our results may provide direct evidence of the abnormal association between very basic limbic structures governing internal homeostasis (i.e., hypothalamus and amygdala) and the ventral frontostriatal system related to motivation, reward and satiety.…”

Ontogenesis of oxytocin pathways in the mammalian brain: late maturation and psychosocial disorders

“…After 2 years, it is characterized by a true hyperphagia with obesity. In fact, PWS children initially display anorexia as neonates and then switch to hyperphagia with obesity (Tauber et al, 2014). …”

Apo-Ghrelin Receptor (apo-GHSR1a) Regulates Dopamine Signaling in the Brain

“…A recent report on the Snord116 ± mouse model of PWS showed that different inhibitors of GHSR1a failed to inhibit food intake (78) and that the involvement of some new pathway is linked to changes in feeding and psychiatric behavior (79). The authors concluded that ghrelin signaling is not involved in PWS and perhaps the elevated plasma ghrelin concentration is playing a compensatory role in PWS subjects.…”