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-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.

Circulating microRNA Associated to Different Stages of Liver Steatosis in Prader–Willi Syndrome and Non-Syndromic Obesity

“…Mir-92a-3p, which is reported to be inversely correlated with the human brown adipose tissue (BAT) activity [27], has been suggested as a potential serum biomarker for BAT in mice and humans. A mouse model with a deletion of the imprinting center (PWS-IC del mouse), shows an increased lipid utilization in BAT [28], however this experimental model is characterized by an incomplete phenotype of the syndrome, with reduced body weight. On the other hand, no data about BAT are currently available in patients with PWS.…”

“…This difference could involve not only lipid profiles but also lipid accumulation in the liver. Indeed, Golding et al [28] showed that the hepatic lipid storage in a PWS-IC del mice was disrupted with a fewer but larger lipid droplets compared to the wild type. It is worth noting the finding of major differences in PWS compared to OB when considering the presence of steatosis grade 1.…”

Caralluma fimbriata extract activity involves the 5‐HT2c receptor in PWS Snord116 deletion mouse model

“…This genetic deletion in the mouse’ chromosome 7C creates a hyperphagic phenotype (Duker et al, ; Kantor, Shemer, & Razin, ) which is relatively homologous with the human PWS paternally deleted chromosome 15. However, the animal does not become obese as is the case with all mouse models replicating genetic deletions from the PWS critical region (Bervini & Herzog, ; Golding, et al, ).…”

“…It is reported that hyperphagic feeding in the Snord116del mice is due to enhanced NPY activity (Bervini & Herzog, 2013;Zhang, Bouma, McClellan, & Tobet, 2012); we therefore targeted the melanocortin appetite pathway (Komarnytsky et al, 2013) via the 5-HT2c receptor to firstly determine homeostatic balance with NPY (Heisler et al, 2006;Zhou et al, 2005) and to discover whether CFE signaling involved this receptor. As this receptor has been reported to be disrupted in humans with PWS (Angulo, Butler, & Cataletto, 2015;Isles, 2017;Kishore & Stamm, 2006;Stamm, Gruber, Rabchevsky, & Emeson, 2017), it is important to understand whether CFE's action involves this pathway.…”

Thermoneutrality improves skeletal impairment in adult Prader–Willi syndrome mice

“…Such studies have revealed features of PWS not commonly reported in humans. For example, our study of metabolic homeostasis in the PWS-IC del mouse, in which paternal inheritance of an imprinting centre (IC) deletion results in a complete lack of gene expression from the entire PWS interval (Chamberlain et al, 2004), revealed overactive brown fat and excess heat production (Golding et al, 2017). Unlike humans with PWS (Kahn et al, 2018), PWS-IC del mice display profound abdominal leanness, probably resulting from a compromised capacity of PWS adipocytes to import lipid (Golding et al, 2017), a phenomenon reported in isolated human PWS adipocytes (Cadoudal et al, 2014).…”