Role of MAGEL2 in melanocortinergic circuits and feeding regulation

Funding Summary

Dr. Jo and his team are working on appetite-controlling pathways in the brain. Research has shown that mice lacking the Magel2 gene have fewer and less functional proopiomelanocortin (POMC) neurons, which are important in regulating appetite. These neurons appear to work through the amygdala, which is a part of the brain that is important in emotions and motivation. This study will investigate how loss of the Magel2 gene impairs the ability of POMC neurons to control appetite through the amygdala, leading to an understanding of the cellular mechanisms underlying weight gain in PWS.

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

Watch the full webinar describing all 7 research projects funded in this grant cycle here. 

Lay Abstract

Prader-Willi Syndrome (PWS) is a genetic disorder exhibiting hyperphagia, intellectual disability, and social and behavioral difficulties. Eating disorder is one of the factors that most affects individuals with PWS. Constant hunger, obsession with food, and obesity in PWS appear to be due to the disruption of appetite-controlling pathways in the brain and the neural circuitry known as the central melanocortin system, in particular. In fact, setmelanotide (RM-493), a melanocortin-4 receptor agonist has been developed for the treatment of PWS and is currently in clinical trials. Patients with PWS show inactivation of the Magel2 gene. Mice lacking the Magel2 gene have fewer proopiomelanocortin (POMC) neurons that produce melanocortins and have selective loss of function in POMC neurons. These specific neurons appear to express estrogen receptor-? (ER-?) and also regulate ER-?-expressing neurons located in the amygdala, the integrative center for emotions, emotional behavior, and motivation. Individuals with PWS show greater activation in the amygdala to food stimuli than obese people, suggesting a potential role of the amygdala in food-seeking behavior and hyperphagia in PWS. Therefore, we propose that impaired POMC projection to ER-?-expressing neurons due to a loss of the Magel2 gene in POMC neurons induces hyperphagia, resulting in obesity in individuals with PWS. Thus, we believe that this application has great potential to find out how the MC4R agonist efficiently reduces appetite and body weight in individuals with PWS. As low to low-normal estrogen levels have been reported in almost all pubertal females with PWS, it is also possible that reduced estrogen levels impair this melanocortin tone, leading to hyperphagia in females with PWS, in particular. Hence, our proposed study will build a strong foundation for the development of better strategies to control feeding behavior and body weight in people with PWS.

Research Outcomes: Public Summary

During high-fat feeding for 10 weeks, I found that females without the Magel2 gene exclusively in POMC neurons projecting to the MeA gain less body weight compared to the control group. This anti-obesity effect is associated with reduced fat mass. As a result, there are reduced levels of plasma leptin and insulin in these animals compared with the control group. Importantly, plasma estradiol levels are higher in female mice without the Magel2 gene in POMC neurons than in control. In contrast, male mice without the Magel2 gene in POMC neurons projecting to the MeA show no difference in body weight during high-fat feeding. Interestingly, although the body weight between the groups is similar, the relative fat mass is higher in the experimental groups than in the control group.
I also found that females with or without the Magel2 gene in POMC neurons projecting to the MeA fed a low-fat diet for 10 weeks display no difference in body weight. No metabolic dysregulation in food intake, energy expenditure (i.e., oxygen consumption), physical activity, and glucose tolerance has been observed. Additionally, the control and experimental male groups fed a low-fat diet show no significant differences in body weight, energy expenditure, glucose tolerance, and insulin resistance. However, the experimental group exhibits higher levels of fasting blood glucose compared with the control. Physical activity also significantly increases in the experimental group.

Research Outcomes: Publications

Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity. Choi Y, Min H-Y, Hwang J, Jo Y-H.  Life Science Alliance. 2022;5(11): e202201502.