Genetic, endocrine, metabolic, immune and autonomic influences on energy homeostasis and cardiovascular risk in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity, caused by the loss of expression of an imprinted region on chromosome 15. PWS is characterised by muscular hypotonia and failure to thrive during infancy, followed by the development of hyperphagia. This has an onset at approximately 2-6 years and persists throughout life, and currently has no effective pharmaceutical treatment. Other features of the syndrome include short stature, hypogonadism, hypopigmentation, developmental delay and behavioural problems. A number of co-morbidities of PWS, including cardiopulmonary disease, type 2 diabetes and thrombophlebitis, are secondary to obesity. This project aimed to characterise the nature of the appetite dysregulation in PWS and to determine its association with endocrine, metabolic, immune and autonomic influences. In order to do this, we recruited a group of adults with PWS, matched obese controls and lean controls and conducted a meal study. Assessment of appetite and appetite-regulating hormones identified a defect in the postprandial hunger response (driven by elevated ghrelin), but not in the satiety response in PWS. Indirect calorimetry did not detect alterations in meal metabolism in PWS. Analysis of heart rate variability revealed that the PWS cohort had reduced sympathetic autonomic responsiveness compared to controls, which may be related to increased cardiovascular risk. Assessment of immune function showed that the PWS group had similar levels of low-grade inflammation to the obese group with the exception of IL-6, which was elevated. A second arm of the project investigated the role of Snord116, a snoRNA gene cluster implicated in the genetic aetiology of PWS. In order to do this, we assessed the metabolic effects of the deletion of Snord116 in mice at two different time points: in the germline and in adult mice. We found a critical role for Snord116 in the regulation of growth and food intake, with each model mimicking a different nutritional stage of PWS. In conclusion, this project found that the mechanisms behind appetite dysregulation and cardiovascular risk in PWS have a complex and interdependent basis, and identified potential roles for ghrelin, sympathetic nervous system activity, IL-6 and Snord116 in future pharmaceutical treatments of PWS hyperphagia