PWS is the most common syndromic form of obesity, characterized by excessive weight gain, obesity and hyperphagia. Dr Andrea Haqq‘s previous work suggests that PWS serves as a unique model of ghrelin excess, potentially explaining the ravenous appetite and progressive weight gain that characterize the condition. Her group has investigated the role of a number of additional hormones (peptide YY (PYY), GLP-1, insulin) and metabolites (amino acids, fatty acids) in the obesity associated with PWS. In 2014 Haqq conducted a collaborative study (with Dr Mike Freemark, Duke University), that compared the effects of a high carbohydrate versus a high fat meal on ghrelin, insulin and PYY in PWS children (n=14) and obese control (n=14) children. They found that children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ratio of ghrelin/PYY. Ultimately, they discovered that the ratio of Ghrelin/PYY appears to be a novel marker of orexigenic drive. This work is important because it forms the foundation for the development of therapies targeting these appetite-stimulating hormones, with the aim to ameliorate the difficult-to-treat obesity associated with PWS. Details of their research were published in the Journal of Clinical Endocrinology & Metabolism (100:3822-31, 2015). Their collaborative group has also shown that PWS children have reduced levels of branched chain amino acids (BCAA, Leu/Ile/Val), including interesting gender-based effects. Further, their results suggest that the hyperghrelinemia and increased insulin sensitivity of PWS may be related to these reduced levels of BCAAs. This data suggests increased proteolysis in PWS as a potential explanation for the reduced muscle mass, sarcopenia and decreased energy expenditure in PWS. Along with increasing the understanding of the endocrinology of PWS, her group (in collaboration with Dr Lonnie Zwaigenbaum) published a recent systematic review detailing the social-communication impairments present in PWS and evaluating the association between Autism Spectrum Disorder (ASD) and PWS. Meanwhile, fellow Alberta Diabetes Institute member Dr Rachel Wevrick continues her groundbreaking research into the genetic basis of PWS, including the MAGEL2 (MAGE Family Member L2) gene that is known to be inactivated in PWS children. Adult mice lacking MAGEL2 are insensitive to the typical anorexic effects of leptin treatment while exhibiting a lack of neuronal depolarization in hypothalamic pro-opiomelanocortin (POMC) neurons. With the hypothalamus playing a major role in development and endocrine functions, Wevrick and her co-investigators explored the question of whether the mutation inactivation of MAGEL2 was congenital or post-natal. In vitro experimentation using POMC neurons from hypothalamic slices of MAGEL2 mice of various ages revealed a progressive decline in leptin-invoked depolarization. Therefore it is possible that a similar, progressive loss of leptin sensitivity and loss of MAGEL2 in children could explain the delayed onset of hyperphagia and obesity (Human Molecular Genetics, 24:4276-4283, 2015).