Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome
Joseph Polex-Wolf, … , Stephen O’Rahilly, Giles S.H. Yeo
Joseph Polex-Wolf, … , Stephen O’Rahilly, Giles S.H. Yeo
Published January 29, 2018
Citation Information: J Clin Invest. 2018;128(3):960-969. https://doi.org/10.1172/JCI97007.
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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 1

Congenital Snord116 deletion mice display a growth phenotype, but do not transition to obesity or hyperphagia.

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Congenital Snord116 deletion mice display a growth phenotype, but do not...
(A) Postnatal body weight is lower in Snord116+/–P (n = 7) versus WT (n = 3) mice, measured to 20 days after birth. Significant weight differences were observed from day 16. **P < 0.01; ***P < 0.001, 2-way repeated-measures ANOVA. (B) Adult body weight in Snord116+/–P (n = 19) mice remains below that of WT (n = 18) mice, measured between 3 and 16 weeks of age, with significant effect of genotype on body weight observed throughout adulthood. P < 0.001, 2-factor mixed-design ANOVA. (C) All mass subcomponents are decreased in Snord116+/–P (n = 12) versus WT (n = 10) mice, as measured in adult males 13 to 16 weeks of age. ****P < 0.0001, t test. (D–F) Analysis of daily food intake (10-day average) in Snord116+/–P (n = 12) versus WT (n = 10) mice at 13–16 weeks of age reveals that, (D) when divided by body weight, food intake is significantly higher in Snord116+/–P mice (t test, P = 0.0026); however, when food intake is (E) plotted in relation to body weight as a covariate and (F) ANCOVA-corrected for differences in body weight, there is no evidence for altered food intake between WT and Snord116+/–P mice (ANCOVA, P = 0.378). Data are reported for male mice as mean ± SEM.