Home > Research Publications > 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

Scientific Notation:

J Endocrinol. 2016 Oct 31. pii: JOE-16-0367




Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11-q13, is characterised by growth retardation, hyperphagia, and obesity. However, since single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for “full” PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS-cluster. We show that PWS-ICdel mice displayed post-natal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67% respectively. PWS-ICdel mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant ‘beiging’ of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-ICdel mice under thermoneutral conditions (30°C) suppressed thermogenic activity in PWS-ICdel males, but failed to elevate abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-ICdel mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but, despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdel mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS-cluster in mice results in abdominal leanness. While reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT.

FPWR Grant:

Generating a novel model of ghrelin-null Prader-Willi syndrome