Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome.
Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome.
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DOI：
10.1530/joe-16-0367
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发表时间：
2017-01
期刊：
影响因子：
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通讯作者：
Wells T
中科院分区：
文献类型：
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作者：
Golding DM;Rees DJ;Davies JR;Relkovic D;Furby HV;Guschina IA;Hopkins AL;Davies JS;Resnick JL;Isles AR;Wells T
Prader-Willi综合征(PWS)是一种由15q11-q13的父系基因表达缺失引起的神经发育障碍，以生长迟缓、吞噬功能亢进和肥胖为特征。然而，由于这种情况下的单基因突变小鼠模型显示的PWS表型谱不完整，我们已经确定了完全PWS小鼠模型的代谢损伤的特征，在该模型中，印记中心(IC)的缺失取消了整个PWS簇的父系基因表达。我们发现PWS-ICdel小鼠出生后表现出生长迟缓，体重减轻，高生长激素血症和明显的腹部消瘦；腹膜后、附睾部/大网膜和腹股沟白色脂肪组织(WAT)的重量分别减少了82%、84%和67%。PWS-ICdel小鼠还显示出比例肩峰间棕色脂肪组织(IsBAT)重量减少48%，腹部水分显著变浅，肩峰表面体温升高2摄氏度。PWS-ICdel小鼠在中温(30°C)条件下的维护抑制了PWS-ICdel雄性小鼠的生热活动，但未能提高腹水重量，这可能是由于卡路里摄入量正常化所致。有趣的是，PWS-ICdel小鼠在标准和高脂肪饮食中也表现出夸大的食物囤积行为，但尽管在切换到高脂肪饮食时变得吞噬过度，PWS-ICdel小鼠并没有增加体重。这一证据表明，与患有PWS的人类不同，小鼠PWS簇中父系基因表达的缺失会导致腹部消瘦。尽管皮下隔热能力的降低可能会导致热量损失和产热的夸大，但腹部消瘦很可能是因为脂肪储存能力的降低，而不是蝙蝠对能量的利用增加。
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.