Abstract
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, as 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 postnatal 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 the thermogenic activity in PWS-ICdel males, but failed to elevate the 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. Although 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.
Highlights
Prader–Willi syndrome (PWS) is caused by a lack of paternal gene expression from the 15q11–q13 imprinting cluster and results from large chromosomal deletions, chromosome 15 maternal uniparental disomy or imprinting-centre (IC) mutations
Loss of paternal gene expression from the imprinted gene cluster on human chromosome 15q11–q13 impairs neuroendocrine and metabolic function in PWS. Investigating these impairments in mouse models for PWS has been hampered by high postnatal lethality
With one notable exception, the metabolic phenotype of PWS is replicated in adult PWS-ICdel mice
Summary
Prader–Willi syndrome (PWS) is caused by a lack of paternal gene expression from the 15q11–q13 imprinting cluster and results from large chromosomal deletions, chromosome 15 maternal uniparental disomy or imprinting-centre (IC) mutations. This disorder is associated with significant metabolic impairment. Neonatal failure to thrive and early life metabolic impairment are seen in many models (Yang et al 1998, Ge et al 2002, Stefan et al 2005), including a number of single gene knock-out mice (Ding et al 2008, Schaller et al 2010). Despite being hypophagic (Kozlov et al 2007), mice null for Magel become obese (Bischof et al 2007), whereas mice carrying a deletion of the small nucleolar (sno)RNA Snord116 show mild hyperphagia, and impaired meal termination, coupled with leanness, even on a highfat diet (Ding et al 2008)
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