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.

Research Outcomes: Public Summary

Patients with Prader-Willi syndrome (PWS) have severe metabolic abnormalities that evolve throughout development. Newborns with PWS often exhibit inadequate weight gain and feeding difficulties. However, as they grow older, this pattern changes, and they gain weight progressively and develop an exaggerated interest in food, often leading to obesity. Although hypothalamic dysfunction may contribute to this altered metabolic phenotype, the specific hypothalamic targets and pathways that may be dysregulated in this context remain poorly understood. There is growing evidence that certain hypothalamic pathways involved in fat sensing play a role in regulating energy balance and food intake. However, their potential involvement in the metabolic alterations that arise throughout development in PWS patients remains unknown.
In this project, we have performed a comprehensive metabolic characterization of Magel2-null mice, an animal model of PWS, in both sexes and at different developmental stages. In addition, we have conducted a detailed analysis at the hypothalamic level of certain fatty acid (FA) sensors and lipid mediators in this context.
Magel2-null mice show a notable change in body weight pattern throughout development. Specifically, these mice have lower body weight than their respective controls before weaning and greater body weight gain after weaning, a pattern observed in both sexes and similar to that detected in PWS patients. In addition, sex- and age-specific metabolic alterations were identified, including significant changes in food intake patterns and energy efficiency, as well as moderate variations in certain body composition and metabolic hormone parameters. Of note, a significant subset of these alterations was associated with changes in the hypothalamic expression profiles of certain fat-sensing components and in the hypothalamic content of specific lipid mediators relevant to the control of energy balance, both of which were also dependent on the stage of development and sex.
Overall, our results support the view that hypothalamic alterations in specific fat-sensing pathways during defined developmental periods may contribute to the emergence of age-related metabolic alterations associated with PWS. Furthermore, they highlight sexual dimorphism in both the detected metabolic changes and the affected fat-sensing pathways, which may contribute to these alterations. These aspects not only suggest the relevance of certain hypothalamic lipid sensors and mediators in the development of metabolic disturbances associated with PWS but also underscore the importance of accounting for sex and developmental stage when designing efficient interventions targeting fat-sensing components to treat these alterations.