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 3

Adult-onset deletion of Snord116 in the mediobasal hypothalamus results in hyperphagia with no alteration in energy expenditure.

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Adult-onset deletion of Snord116 in the mediobasal hypothalamus results ...
(A) Bilateral targeting of the mediobasal hypothalamus was performed with AAV-Cre injection and verified with Cre immunohistochemistry. 3V, third ventricle. Original magnification, ×200. (B) Micropunches of 3 brain regions revealed a selective decrease of Snord116 expression in the mediobasal hypothalamus in AAV-Cre–injected (n = 10) mice (28% decrease, P = 0.01, t test) compared with AAV-GFP controls (n = 9). Bars display mean ± SEM. (C) Ten-day average food intake measured from 2 weeks after stereotaxic surgery was not significantly different between AAV-GFP– and AAV-Cre–treated mice (P = 0.084, ANCOVA). (D) No differences in energy expenditure were observed over 72-hour indirect calorimetry commencing 6 weeks after viral delivery (P = 0.348, ANCOVA). (E) Significantly higher food intake (corrected for the covariate of body weight) was observed in AAV-Cre–treated mice versus AAV-GFP–treated controls (P = 0.001, ANCOVA) when measured over 5 days commencing 9 weeks after viral delivery. For C–E, top panels display scatter plots of body weight versus either food intake or energy expenditure and bottom panels display food intake/energy expenditure values that are ANCOVA-corrected for body weight (estimated marginal mean ± SEM). All data are reported for male mice, with surgery commencing at 10 to 12 weeks of age.