Excessive eating (hyperphagia) is one of the most challenging features of Prader-Willi Syndrome (PWS) and currently there are no medications available for effective appetite regulation. Hyperphagia is most likely to be driven by elevated levels of the appetite-stimulating hormone ghrelin in patients with PWS. The underlying cause of this elevated ghrelin is poorly understood. Recently, antibodies that bind to ghrelin and protect it from being degraded in the blood have been discovered in obese and lean humans and mice. These antibodies help to increase the blood levels of ghrelin and thus increase delivery of ghrelin to the brain to stimulate appetite. We have exciting preliminary data demonstrating that these antibodies are elevated in children with PWS compared to their unaffected sibling controls. This innovative project will be the first to fully examine these antibodies in children with PWS and will help us to better understand why ghrelin is increased in PWS. We will also focus on how to disrupt these antibodies in order to reduce ghrelin levels and regulate appetite. This may lead to new approaches to the prevention of hyperphagia, a major challenge in the management of children with PWS, and a priority research area for the Foundation for Prader-Willi Syndrome Research.
This project was funded by the Foundation for Prader-Willi Research Canada.
Research Outcomes: Public Summary
Anti-ghrelin autoantibodies are significantly elevated in children with PWS when compared to age-matched unaffected controls (including first and second degree relatives), however, these autoantibodies did not differentially protect acyl ghrelin from degradation ex vivo.
Epitope mapping demonstrated that anti-ghrelin IgG in PWS are generated against unique epitopes compared to anti-ghrelin IgG from controls, suggesting that the ghrelin peptide circulating in children with PWS has a unique structure potentially due to aberrant processing. Unacylated ghrelin significantly reduced weight gain in mice with diet-induced obesity, however UAG did not modulate serum levels of anti-ghrelin autoantibody or ghrelin serum levels.
Research Outcomes: Publications
Ghrelin-Reactive Autoantibodies are elevated in Children with Prader-Willi Syndrome. Crisp G, Nyunt O, Chopin L, Harris M, Jeffery P. BIORXIV, 2016.
Lisa Chopin, DVM, PhD
Queensland University of Technology, Australia