Mechanism of hyperphagia and therapeutic interventions in mouse models for Prader-Willi syndrome

The overall goals of our research are to elucidate the pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS, and to evaluate two types of treatments for persistent hunger and food seeking behavior. We have focused on the role of a special type of RNA, called Snord116 (formally PWCR1/HBII-85) small nucleolar RNA (snoRNA). Studies of rare cases of PWS with smaller deletions and chromosome rearrangements have narrowed the minimal critical region from 4 million DNA building blocks (nucleotides) to only 121,000, which contains many similar copies of Snord116. Also, recently there were 2 cases of PWS who harbor the microdeletions encompassing only the Snord116 cluster, indicating the major role of Snord116 in Prader-Willi symptoms. We made a mouse model in which the Snord116 cluster is deleted, and the mutant mice manifested major symptoms of Prader-Willi syndrome, including delayed development and short statue, deficiency in motor learning, overeating behavior, and high levels of ghrelin. Ghrelin is a peptide hormone that promotes feeding, whose level is high during fasting as a signal for hunger. In well-fed Snord116 mutant mice, ghrelin level is dramatically elevated. We hypothesize that the high ghrelin level is likely to be the cause of persistent hunger and food-seeking behavior in PWS individuals. In this study, we will use the mouse model to study the underlying mechanism of high levels of ghrelin, and to evaluate treatment options.

Firstly, we will study if the ghrelin secretion cells and nerve endings for mechanical sensing in the stomach of the Snord116del mouse model are abnormal. Secondly, we will treat mutant mice with commonly used medicines that target parasympathetic and sympathetic nervous system, which were shown to modulate ghrelin secretion. We will test whether the mutant mice have abnormal response to these drugs, as an initial step toward the identification of more specific medicines to reduce ghrelin levels. Thirdly, we will treat the mutant mice with a drug that specifically blocks the action of ghrelin, and measure if the over-eating behavior in the mutant mice can be normalized.

Research Outcomes: Project Summary

In this study, candidate drugs was tested to treat hyperphagia in a mouse model for Prader-Willi syndrome. The first two drug candidates are designed to inhibit signaling through ghrelin receptor GHSR. Antagonists for ghrelin receptor GHSR had been proposed as potential treatment options for PWS a decade ago (Akasawa 2003).  We tested for the first time the effect of these substances on hyperphagia of Snord116 deletion mice.  In contrast to the long-held optimism, both competitive antagonist [D-Lys3]-GHRP6 and reverse agonist SPA are ineffective in suppressing food intake in either wild-type or Snord116 deletion mice in the long term experiments. The mice became adapted to these inhibitors after a few days of treatment. Increased dose of either [D-Lys3]-GHRP6 or SPA resulted in severe toxicity.  These results suggest that [D-Lys3]-GHRP6 and SPA could not be used for treating hyperphagia of PWS. Encouragingly, exendin-4 showed long-term efficacy in suppressing food intake of both wild-type and Snord116 deletion mice. However, its effect on Snord116 deletion mice was less prominent. Detailed analysis of hourly food intake showed that the deletion mice recovered more quickly from the suppression effect of exendin-4. Hence, we suggest that increase dose and/or injection frequency is required in treating hyperphagia of PWS. With the additional benefit of normalizing glucose levels after meals, exendin-4 is a promising therapeutic option for PWS.     

Research Outcomes: Publications           

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome. Lin D, Wang Q, Ran H, Liu K, Wang Y, Wang J, Liu Y, Chen R, Sun Y, Liu R, Ding F. Endocrinology, 2014 Jul;155(7):2355-62.

Funded Year:


Awarded to:

Feng Ding, PhD




Xiamen University

Search Projects

Donate for PWS Research