Role of fat sensing in the altered feeding behavior and metabolic phenotype of Prader-Willi syndrome

Funding Summary

Our project aims to test the hypothesis that alterations in certain specific lipid sensors and mediators in the hypothalamus may contribute to the disrupted feeding behavior and the altered metabolic phenotype associated with PWS at different stages of postnatal development. These studies will try to reverse the metabolic alterations observed before and after weaning in the Magel2-null mouse model of PWS by manipulating specific lipid sensors and mediators. If our proposal is successful, we will unveil the contribution of specific lipid signaling pathways to the metabolic alterations associated with PWS throughout development and lay the groundwork for designing tools to treat them in the future.

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

Lay Abstract

PWS patients show severe metabolic disturbances that vary throughout development. Interestingly, newborns with PWS show no interest in food. However, this eating behavior changes as they grow, resulting in a disturbing interest in food and a considerable increase in food intake, which is associated with a loss of satiety and can lead to morbid obesity. Numerous studies suggest that a region of the brain known as the hypothalamus could be relevant in these metabolic alterations since this brain region contains neurons capable of controlling metabolism and food intake. The elements or factors that could be altered in the hypothalamus of PWS patients and contribute to the alterations described above are not yet fully understood. Recent evidence suggests that the hypothalamus is sensitive to specific nutrients and lipid mediators and that these could play a relevant role in the control of metabolism and food intake. However, this role has not yet been explored in Prader-Willi syndrome, nor has its contribution to the metabolic disorders associated with this syndrome at different stages of development. Our project aims to test the hypothesis that alterations in certain specific lipid sensors and mediators in the hypothalamus may contribute to the disrupted feeding behavior and the altered metabolic phenotype associated with PWS at different stages of postnatal development. To this end, we will conduct a series of studies in an animal model of PWS, Magel2-null mice, which partially represents some of the metabolic alterations described above, i.e., a slight decrease in body weight before weaning and an increase in adiposity and weight gain in the adulthood. These studies will try to reverse the metabolic alterations observed before and after weaning by manipulating specific lipid sensors and mediators. If our proposal is successful, we will unveil the contribution of specific lipid signaling pathways to the metabolic alterations associated with PWS throughout development and lay the groundwork for designing tools to treat them in the future. The next step of our project would be to raise the possibility of developing specific nutritional interventions based on the fatty acid composition of the diet in order to improve the metabolic phenotype of PWS patients.