title: Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome.
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-ICdelmice 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-ICdelmice 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-ICdelmice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-ICdelmales, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-ICdelmice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdelmice 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.
authors: School of BiosciencesCardiff University, Cardiff, UK.
authors: David M
authors: DM
authors: Golding
authors: Institute of Life SciencesCollege of Medicine, Swansea University, Swansea, UK.
authors: Daniel J
authors: DJ
authors: Rees
authors: Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK.
authors: Jennifer R
authors: JR
authors: Davies
authors: Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK.
authors: Dinko
authors: D
authors: Relkovic
authors: Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK.
authors: Hannah V
authors: HV
authors: Furby
authors: School of BiosciencesCardiff University, Cardiff, UK.
authors: Irina A
authors: IA
authors: Guschina
authors: School of BiosciencesCardiff University, Cardiff, UK.
authors: Anna L
authors: AL
authors: Hopkins
authors: Institute of Life SciencesCollege of Medicine, Swansea University, Swansea, UK.
authors: Jeffrey S
authors: JS
authors: Davies
authors: Center for Mammalian GeneticsUniversity of Florida, College of Medicine, Gainesville, Florida, USA.
authors: James L
authors: JL
authors: Resnick
authors: Behavioural Genetics GroupMRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine & Psychology, Cardiff University, Cardiff, UK.
authors: Anthony R
authors: AR
authors: Isles
authors: School of BiosciencesCardiff University, Cardiff, UK wellst@cardiff.ac.uk.
authors: Timothy
authors: T
authors: Wells
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000502:physiology*; D019175:DNA Methylation; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics*; D017384:Sequence Deletion; D022722:Thermogenesis / Q000502:physiology; D013851:Thinness / Q000235:genetics*
keywords: Prader–Willi syndrome; fat mass; food hoarding; thermogenesis