ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Invest 2018;128:960-969

Mouse models for PWS are urgently needed to facilitate drug development for treatment of hyperphagia and obesity in PWS patients. Here, the authors set out to create a mouse model that better recapitulates human PWS; they chose Snord116 as the target. Snord116 comprises a cluster of noncoding RNAs (ncRNAs) on paternal chromosome 15q11.2. Deletions that include SNORD116 and 2 neighboring ncRNAs result in hyperphagia and other features of PWS in humans (1). SNORD116 is therefore a candidate for the hyperphagia in humans with PWS. Expression of Snord116 snoRNAs increases within hypothalamic nuclei by weaning age in mice, in line with the characteristic appearance of hyperphagia in humans after initial feeding difficulties. All Snord116 deletion mouse models reported so far (whether the deletion is monoallelic, biallelic, NPY specific or inducible) are smaller than controls, in line with the failure to thrive in PWS infants. However, they do not transition to obesity, as seen in humans with PWS, and therefore those models provided limited insights.

Therefore, these authors set out to generate a mouse with adult-onset Snord116 deficiency, by use of hypothalamic injections of (adenovirus associated) Cre with Lox-P flanked Snord116 to reduce hypothalamic Snord116 expression in 10-week old mice. No difference in food intake was found 2 weeks after Cre delivery, but after 9 weeks the mice were heavier, and food intake corrected for body weight was ~25% higher without a change in energy expenditure. No significant changes were detected in the expression of Pomc, Lepr, Npy, Agrp, Pcksk1, or Nhlh2 but there was an increase in the expression of Socs3, one of the genes of the family of suppressors of cytokine signaling, which is a target gene for Stat3 and a negative regulator of leptin signaling (2) amongst other cytokine signaling pathways. Indeed, overexpression of Socs3 in POMC neurons results in increased body weight and adiposity (3) therefore supporting involvement of SOCS3 in the hyperphagia and obesity of PWS.

Thus, a mouse model mimicking the obesity and hyperphagia in PWS is now available. This will be useful for further research into PWS, although unfortunately currently the model requires individual stereotaxic hypothalamic injection with viral Cre to generate the necessary Snord116 deletion, and this may preclude the model to be used widely. The involvement of Socs3 in the hyperphagia requires further study, since this may be a novel target for pharmacological intervention.

1. Duker AL, et al. Paternally inherited micro- deletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome. Eur J Hum Genet. 2010;18(11):1196–1201.


2. Buettner C et al. Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanism. Nat Med 2008;14(6):667-675.

3. Rooks, C.R. et al. Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R92–R102 (2005).