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Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 clu...

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Autores principales: Polex-Wolf, Joseph, Lam, Brian Y.H., Larder, Rachel, Tadross, John, Rimmington, Debra, Bosch, Fàtima, Cenzano, Verónica Jiménez, Ayuso, Eduard, Ma, Marcella K.L., Rainbow, Kara, Coll, Anthony P., O’Rahilly, Stephen, Yeo, Giles S.H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824864/
https://www.ncbi.nlm.nih.gov/pubmed/29376887
http://dx.doi.org/10.1172/JCI97007
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author Polex-Wolf, Joseph
Lam, Brian Y.H.
Larder, Rachel
Tadross, John
Rimmington, Debra
Bosch, Fàtima
Cenzano, Verónica Jiménez
Ayuso, Eduard
Ma, Marcella K.L.
Rainbow, Kara
Coll, Anthony P.
O’Rahilly, Stephen
Yeo, Giles S.H.
author_facet Polex-Wolf, Joseph
Lam, Brian Y.H.
Larder, Rachel
Tadross, John
Rimmington, Debra
Bosch, Fàtima
Cenzano, Verónica Jiménez
Ayuso, Eduard
Ma, Marcella K.L.
Rainbow, Kara
Coll, Anthony P.
O’Rahilly, Stephen
Yeo, Giles S.H.
author_sort Polex-Wolf, Joseph
collection PubMed
description Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116(+/–P) mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116(fl) mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.
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spelling pubmed-58248642018-03-08 Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome Polex-Wolf, Joseph Lam, Brian Y.H. Larder, Rachel Tadross, John Rimmington, Debra Bosch, Fàtima Cenzano, Verónica Jiménez Ayuso, Eduard Ma, Marcella K.L. Rainbow, Kara Coll, Anthony P. O’Rahilly, Stephen Yeo, Giles S.H. J Clin Invest Research Article Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116(+/–P) mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116(fl) mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS. American Society for Clinical Investigation 2018-01-29 2018-03-01 /pmc/articles/PMC5824864/ /pubmed/29376887 http://dx.doi.org/10.1172/JCI97007 Text en Copyright © 2018 Polex-Wolf et al. http://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Research Article
Polex-Wolf, Joseph
Lam, Brian Y.H.
Larder, Rachel
Tadross, John
Rimmington, Debra
Bosch, Fàtima
Cenzano, Verónica Jiménez
Ayuso, Eduard
Ma, Marcella K.L.
Rainbow, Kara
Coll, Anthony P.
O’Rahilly, Stephen
Yeo, Giles S.H.
Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title_full Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title_fullStr Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title_full_unstemmed Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title_short Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
title_sort hypothalamic loss of snord116 recapitulates the hyperphagia of prader-willi syndrome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824864/
https://www.ncbi.nlm.nih.gov/pubmed/29376887
http://dx.doi.org/10.1172/JCI97007
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