Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
Polex-Wolf, Joseph (Medical Research Council (MRC) Metabolic Diseases Unit)
Lam, Brian Y. H. (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Larder, Rachel (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Tadross, John (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Rimmington, Debra (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Cenzano, Verónica Jiménez (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Ayuso, Eduard (Universitat Autònoma de Barcelona. Centre de Biotecnologia Animal i de Teràpia Gènica (CBATEG))
Ma, Marcella K. L. (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Rainbow, Kara (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Coll, Anthony P. (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
O'Rahilly, Stephen (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)
Yeo, Giles S. H. (Medical Research Council (MRC) Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories)

Fecha:	2018
Resumen:	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.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Genetics ; Metabolism ; Obesity
Publicado en:	The journal of clinical investigation, Vol. 128 (january 2018) , p. 960-969, ISSN 1558-8238

DOI: 10.1172/JCI97007
PMID: 29376887

10 p, 3.3 MB

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