Journal
JOURNAL OF ENDOCRINOLOGY
Volume 232, Issue 1, Pages 123-135Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-16-0367
Keywords
Prader-Willi syndrome; fat mass; thermogenesis; food hoarding
Categories
Funding
- Research Council UK Dorothy Hodgkin Postgraduate Award
- GlaxoSmithKline
- Prader-Willi Syndrome Association UK
- Biotechnology and Biological Sciences Research Council [BB/J016756/1]
- Foundation for Prader-Willi Research
- Seed Corn Fund (Schools of Biosciences)
- Seed Corn Fund (MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University)
- BBSRC [BB/J016756/1] Funding Source: UKRI
- MRC [G0801418] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/J016756/1] Funding Source: researchfish
- Medical Research Council [G0801418, MR/L010305/1] Funding Source: researchfish
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Prader Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q1-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-IC mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant 'beiging' of abdominal WAT, and a 2 degrees C increase in interscapular surface body temperature. Maintenance of PWS-1C(del) mice under thermoneutral conditions (30 degrees 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.
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