A recent study published in The Journal of Clinical Investigation has unravelled the role of hypothalamic Snord116 in the hyperphagia that is characteristic of Prada–Willi syndrome (PWS) using a new mouse model of the disease. Previous studies have implicated the deletion of SNORD116 in PWS in humans, but the functional link between SNORD116 and hyperphagia in PWS has remained unclear, until now.

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“We wanted to understand how SNORD116 was functionally linked to the dysregulated energy homeostasis evident in PWS and so set out to study the neural mechanisms in the mouse,” says co-corresponding author Giles Yeo. “However, while humans with a deletion of SNORD116 become obese and hyperphagic, these phenotypes do not arise in mice with a congenital Snord116 deletion; these mice are small, similar to the early failure to thrive in human patients with PWS, but they never transition to obesity.”

The authors hypothesized that by deleting Snord116 in the mediobasal hypothalamus of adult mice that did not have an early growth phenotype they would be able to uncover a metabolic or food intake phenotype. They created an adult-onset hypothalamic deletion of Snord116 mouse model by injecting adeno-associated virus (AAV)–Cre into the mediobasal hypothalamus using a stereotaxic frame. This approach enabled Yeo and colleagues to study the functional consequences of Snord116 deletion, thus linking loss of Snord116 to hyperphagia.

the authors hope that ... this model will be useful as a preclinical model

“Mice with an adult-onset hypothalamic deletion of Snord116 were demonstrably hyperphagic and some also developed obesity, which highlights the role of hypothalamic Snord116 in the hyperphagia of PWS,” adds Yeo. “Interestingly, we did not observe changes in the expression of genes that control hypothalamic melanocortin or prohormone processing after deleting Snord116, which suggests that these hypothalamic energy homeostasis pathways remain intact in our mouse model.”

The authors now plan to refine their mouse model to avoid the need for stereotaxic surgery. As hyperphagia in PWS is without effective pharmacological therapies, the authors hope that in the future this model will be useful as a preclinical model that can be used to test interventions.