Background: Prader-Willi Syndrome (PWS) is a complex genetic disorder characterised by developmental and growth abnormalities, insatiable appetite, and excessive eating (hyperphagia). Hyperphagia is thought to be driven by supraphysiological levels of the appetite stimulating hormone ghrelin; however, the underlying causes of hyperghrelinaemia in PWS are currently unknown. Recently, ghrelin-reactive autoantibodies (isotype IgG) were identified in non-genetic obesity and were found to reversibly bind circulating ghrelin and, acting as carrier proteins, protect ghrelin from degradation thereby potentiating its orexigenic effects.
Objectives: This project aimed to measure ghrelin-reactive autoantibodies in children with PWS. We hypothesised that patients possess higher levels of ghrelin-reactive autoantibodies compared to their unaffected sibling controls. We also tested whether the inactive ghrelin isoform, unacylated ghrelin (UAG), outcompetes ghrelin and sequesters autoantibodies ex vivo.
Methods: Blood samples were taken from patients and controls after an overnight fast and 10, 20, 30, 60 and 120 minutes after a standardised mixed meal. Plasma was extracted and ghrelin-reactive autoantibodies were measured using ELISA. To test specificity of the ELISA and to determine if the autoantibodies bind to UAG, the samples were also pre-absorbed with exogenous ghrelin and UAG (10−6 M) prior to being subjected to separate ELISAs.
Results: We have demonstrated that children with PWS have significantly higher levels of plasma ghrelin-reactive autoantibodies compared to controls after an overnight fast (P<0.0001, unpaired t test). Food intake did not affect autoantibody levels in patients or controls. Both ghrelin and UAG pre-absorbed controls showed significant reduction of ghrelin-reactive autoantibody detection in the PWS and control groups (P<0.001, unpaired t test), suggesting that the autoantibodies complex with both isoforms.
Conclusions: Increased levels of ghrelin-reactive autoantibodies in children with PWS may contribute to the hyperghrelinaemia and hyperphagia that characterises PWS. Targeting these autoantibodies may be a future therapeutic avenue for this incurable condition.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology