Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a lack of muscle tone at birth, a failure to thrive in infancy, and mild learning disabilities. On emerging from infancy, children with PWS show reduced skeletal growth and an insatiable appetite, which, when combined with an obsession with food, results in obesity. Individuals with PWS also show a chronic elevation in circulating ghrelin. We have shown that many of these symptoms are reproduced in a novel PWS mouse model (PWS-IC). These mice display increased food intake, exaggerated food hoarding and alterations in food reactivity and food reward motivation. In a new collaboration, we have generated unpublished data demonstrating that PWS-IC mice also display reduced skeletal growth, with reduced fat mass, accompanied by a reduction in overall surface body temperature and a 3-fold elevation in circulating ghrelin.
Since ghrelin is the only hormone known to stimulate appetite and regulate growth and metabolism, we will determine which of the characteristics of PWS result from the elevation in circulating ghrelin. To address this issue, we will generate a novel ghrelin-null PWC-IC mouse model by crossing mice with a deletion of the ghrelin gene with PWS-IC animals to establish a stable line. These mice will subsequently be used to determine the importance of elevated circulating ghrelin in skeletal growth, feeding behavior (including food hoarding and motivation), metabolism (including the storage of fat in white and brown adipose tissue), temperature profile and the regulation of heat generation, insulin secretion, the metabolic consequences of maintenance on a high fat or highly palatable diet and reproductive performance in PWS. Thus, the new ghrelin-null PWS model generated in this project will ultimately reveal which of the characteristics of PWS are due to elevated circulating ghrelin. This will not only establish potential benefits of medicines that block the ghrelin receptor in the treatment of PWS, but may also result in the description of novel actions of this gut hormone.
Paradoxical leanness in the imprinting centre deletion mouse model for Prader-Willi syndrome. Golding DM, Rees DJ, Davies JR, Relkovic D, Furby HV, Guschina IA, Hopkins AL, Davies JS, Resnick JL, Isles AR, Wells T. Journal of Endocrinology. 2017 Jan;232(1):123-135.
Timothy Wells, PhD