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 2

Expression of hypothalamic leptin/melanocortin pathway genes is unaltered in congenital Snord116 deletion compared with that in WT mice in both the ad libitum–fed and 24 hour–fasted states.

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Expression of hypothalamic leptin/melanocortin pathway genes is unaltere...
(A) Representative image of laser-captured nuclei from mouse hypothalamus (cresyl violet stained). Original magnification, ×50. (B) The nutritionally regulated expression pattern of Pomc, Npy, Lepr, and Agrp does not change in congenital Snord116 deletion mice in the ARC. Genotype by nutritional state interaction for the 3 genes is not significant. P > 0.6, FDR = 1, Benjamini-Hochberg FDR procedure. Expression of (C) Pcsk1 and (D) Nhlh2 does not significantly differ by genotype or nutritional state (ad libitum fed versus 24 hour fasted) across 4 different laser-captured hypothalamic nuclei. For B–D, expression is shown for male mice 16–19 weeks of age (n = 4–6 mice per condition) as log2 counts per million (CPM), with box plots showing the median, interquartile range, and extrema.