Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome

Golding, David M., Rees, Daniel J., Davies, Jennifer R., Relkovic, Dinko, Furby, Hannah V. ORCID: https://orcid.org/0000-0002-7279-1812, Guschina, Irina A., Hopkins, Anna L., Davies, Jeffrey S., Resnick, James L., Isles, Anthony R. ORCID: https://orcid.org/0000-0002-7587-5712 and Wells, Timothy ORCID: https://orcid.org/0000-0003-3618-0595 2017. Paradoxical leanness in the imprinting-centre deletion mouse model for Prader–Willi syndrome. Journal of Endocrinology 232 (1) , pp. 123-135. 10.1530/JOE-16-0367

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Abstract

Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 27 15q11-q13, is characterised by growth retardation, hyperphagia, and obesity. However, since single gene 28 mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have 29 characterised the metabolic impairment in a mouse model for “full” PWS, in which deletion of the imprinting 30 centre (IC) abolishes paternal gene expression from the entire PWS-cluster. 31 We show that PWS-ICdel mice displayed post-natal growth retardation, with reduced body weight, 32 hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and 33 inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67% respectively. PWS-ICdel 34 mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with 35 significant ‘beiging’ of abdominal WAT, and a 2°C increase in interscapular surface body temperature. 36 Maintenance of PWS-ICdel mice under thermoneutral conditions (30°C) suppressed thermogenic activity in 37 PWS-ICdel males, but failed to elevate abdominal WAT weight, possibly due to a normalisation of caloric intake. 38 Interestingly, PWS-ICdel mice also showed exaggerated food hoarding behaviour with standard and high-fat 39 diets, but, despite becoming hyperphagic when switched to a high-fat diet, PWS-ICdel mice failed to gain weight. 40 This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS-cluster 41 in mice results in abdominal leanness. While reduced subcutaneous insulation may lead to exaggerated heat 42 loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than 43 increased energy utilisation in BAT.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	Prader-Willi syndrome; fat mass; thermogenesis; food hoarding
Additional Information:	This is an open access article under the terms of the CC-BY license.
Publisher:	BioScientifica
ISSN:	0022-0795
Funders:	BBSRC
Date of First Compliant Deposit:	11 November 2016
Date of Acceptance:	31 October 2016
Last Modified:	19 Jan 2024 07:19
URI:	https://orca.cardiff.ac.uk/id/eprint/95817

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