Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
Joseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, Giles S.H. Yeo
Joseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, Giles S.H. Yeo
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Research Article Genetics Metabolism

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

Abstract

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 Snord116fl 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.

Authors

Joseph Polex-Wolf, Brian Y.H. Lam, Rachel Larder, John Tadross, Debra Rimmington, Fàtima Bosch, Verónica Jiménez Cenzano, Eduard Ayuso, Marcella K.L. Ma, Kara Rainbow, Anthony P. Coll, Stephen O’Rahilly, Giles S.H. Yeo

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Figure 5

Cre-targeted mice have unaltered hypothalamic leptin-melanocortin gene expression, but increased Socs3 expression in obese animals.

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Cre-targeted mice have unaltered hypothalamic leptin-melanocortin gene e...
Box plots of gene expression from laser-captured hypothalamic sections from AAV-Cre hits with less than 25% body-weight gain after surgery (AAV-Cre, n = 3); AAV-Cre hits with more than 40% body-weight gain after surgery (AAV-Cre obese, n = 3); and AAV-GFP controls (n = 3). (A–F) Expression of Pomc, Pcsk1, Npy, Nhlh2, Agrp, and LepR is unchanged between the AAV-Cre–treated groups and AAV-GFP controls. (G) Expression of hypothalamic Socs3 is increased in AAV-Cre obese mice (FDR = 0.08), and (H) expression of Cre (FDR = 2.37 × 10–45) and (I) GFP (FDR = 5.55 × 10-22) are only present within the respective treatment groups. Data shown are from mice at 10 weeks after surgery with expression as log2 counts per million. FDR values were generated using the Benjamini-Hochberg FDR procedure.