Cellular and molecular basis for obesity in PWS (Year 2)

Funding Summary

This renewal application builds on excellent work to date from the Friedman lab, which has identified a new subset of neurons in the hypothalamus and a novel gene that may be driving hyperphagia in PWS.  They will explore how Magel2 impacts the function in these neurons and whether a pharmacological approach can impact their newly identified target gene and modify appetite.  

Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.

Lay Abstract

Individuals with Prader-Willi Syndrome (PWS) often experience uncontrollable overeating (hyperphagia), a distressing symptom for which there are currently no approved treatments. The hypothalamus, a vital brain region involved in regulating food intake and energy balance, is believed to play a role in PWS, but the specific changes in the brain contributing to these symptoms are not well understood due to the complexity of different types of nerve cells with distinct functions within the hypothalamus. In our research, we study mice with a specific genetic mutation (MAGEL2-null mice) that mimic PWS symptoms to better understand the underlying biology. Using an advanced technique called multiplexed single nuclear RNA sequencing (snRNA-seq), we comprehensively analyzed individual brain cells in the hypothalamus to identify specific changes linked to uncontrollable hunger and obesity in PWS. Our analysis highlighted significant alterations in the arcuate nucleus (ARC) and paraventricular nucleus of the hypothalamus (PVH) of PWS mice. Notably, despite no difference in cell types, PWS animals exhibited a five-fold increase in Lef1-expressing neurons in the ARC compared to normal mice. This suggests that these neurons may contribute to PWS symptoms, as the Lef1 gene is known to play key roles in the hypothalamus and feeding regulation. We plan to investigate the functions of Lef1-expressing neurons in feeding and body weight regulation using genetic tools and behavioral tasks. If confirmed, we aim to identify drug targets that could specifically target these Lef1-neurons for PWS treatment. Additionally, we observed elevated expression of the Nova1 gene in the PVH of PWS mice. Deleting Nova1 in this brain region resulted in leanness and reduced appetite, suggesting a potential role in PWS symptoms. Our next step is to explore whether suppressing Nova1 can reverse PWS symptoms, including hyperphagia and obesity, and identify potential drugs that target Nova1 for PWS therapy. In summary, our genetic analysis provides critical insights into the mechanisms underlying hyperphagia and obesity in PWS. By understanding these molecular changes, we aim to develop targeted and rational drug therapies to improve the lives of individuals affected by this challenging disorder. This research lays a solid foundation for identifying effective treatments that directly address the underlying causes of PWS. Furthermore, our focus on elucidating the functions of Lef1-neurons and the Nova1 gene represents an advanced step towards targeted therapy, with the potential to lead to novel treatments for PWS. 

Research Outcomes: Public Summary

 Prader-Willi Syndrome (PWS) is characterized by severe, persistent hunger (hyperphagia) that can lead to life-threatening obesity. Despite its major impact on patients and families, the brain mechanisms driving this uncontrolled appetite remain poorly understood, limiting the development of effective treatments.
In this project, we focused on identifying specific brain cells and molecular pathways that regulate feeding behavior and may be disrupted in PWS. Using a genetic mouse model of PWS, we identified a previously unrecognized population of neurons in the hypothalamus, a key brain region that controls hunger. We found that activating these neurons promotes feeding behavior, indicating that they play an important role in driving appetite. Notably, this neuronal population is increased in the PWS model, suggesting that its dysregulation may contribute to excessive hunger.
In parallel, we identified a key molecular regulator in the brain that plays a critical role in controlling food intake. By selectively manipulating this pathway, we showed that reducing its activity decreases food intake and body weight, while increasing its activity has the opposite effect. These findings demonstrate that this pathway acts as an important regulator of feeding behavior and energy balance.
Together, these results provide new insight into the brain circuits and molecular mechanisms that drive hyperphagia in PWS. By identifying both specific neuronal populations and key regulatory pathways that control appetite, this work highlights new potential targets for therapeutic intervention.
Ultimately, these discoveries lay the foundation for developing more precise, brain-based treatments aimed at reducing excessive hunger and improving quality of life for individuals with PWS.