Orphan GPCRS and the Neurobiology of Hyperphagia in Prader-Willi Syndrome: Role of GPR160

Funding Summary

A protein called CART controls appetite and body weight in both lean and obese rodents and mutations in the CART gene have been linked to obesity in humans. The protein GPR160 helps CART signal brain cells to control appetite. However, CART and GPR160 have not been studied in PWS before. Therefore, this project will evaluate the role of CART in appetite regulation using a rat model of PWS. If this pathway shows promise in PWS, it opens new pathways for PWS treatment.

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

Lay Abstract

The goal of this proposal is to evaluate the potential role of a molecule called cocaine- and amphetamine-regulated transcript, or CART, in appetite regulation using a rat model of Prader Willi Syndrome. CART is a small protein made in the brain that has been shown to control appetite and body weight in both lean and obese rodents. Importantly, mutations in the CART gene have been linked to obesity in humans. Our lab recently discovered the way in which CART signals in brain cells to control appetite, through another protein called GPR160. This makes the development of drugs based on CART much more possible. However, the role of CART and GPR160 in Prader Willi Syndrome has not been established. Given the prominent role that CART plays in appetite regulation, and the potential “druggability” of CART, the lack of information of the role of CART in appetite regulation in the setting of Prader Willi Syndrome represents a major gap in the field of Prader Willi Syndrome research. We propose to investigate how CART affects food intake and meal patterning (i.e. when and how much at a time rats eat) using Magel2-deficient rats, a model of Prader Willi Syndrome. Because patients with Prader Willi Syndrome have reduced brain levels of the enzymes needed to make CART, it is possible that levels of CART could be reduced in the brains of patients with Prader Willi Syndrome as well. We will therefore measure levels of CART and GPR160 in the brains of Magel2-deficient rats as well. We anticipate that the rats will have very low levels of CART in their brains, but that they will respond to treatment with CART with a reduction in appetite. These data would suggest that individuals with Prader Willis Syndrome do not make enough CART to properly regulation appetite, and that replacing CART using drugs based off of the CART protein could at least partially correct the overeating and obesity associated with Prader Willi Syndrome. If this is what we observe, then our next steps would be to investigate whether CART deficiency is a cause of metabolic dysfunction associated with Prader Willi Syndrome by injecting Magel2-deficient rats with a synthetic gene so that they will begin making CART in their brains, and evaluating their appetite and body weight. The necessary first experimental steps presented in this research proposal will lay the groundwork for verification of CART and GPR160 as therapeutic targets for the treatment of overeating and obesity associated with Prader Willi Syndrome. Ultimately our goal is to use biochemical approaches to make drugs based off of the CART protein to alleviate the insatiable appetite (hyperphagia) and obesity experienced by patients with Prader Willi Syndrome.

Research Outcomes: Public Summary

The finding that CART peptide, through its receptor GPR160, demonstrates an increased anorexigenic effect in a rat model of Prader-Willi syndrome (PWS), specifically Magel2-deficient rats, holds great significance in the field of PWS research and potential therapeutic strategies. PWS is a complex genetic disorder characterized by hyperphagia, leading to severe obesity and various metabolic complications. Understanding the role of CART peptide and GPR160 in the context of PWS provides valuable insights into the mechanisms underlying appetite dysregulation in this syndrome. The enhanced anorexigenic effect observed suggests that targeting the CART-GPR160 signaling pathway could potentially be a promising approach for managing the excessive appetite and weight gain associated with PWS. Further investigations into the molecular interactions and downstream signaling pathways involved in CART peptide and GPR160 activation in Magel2-deficient rats will contribute to a deeper understanding of PWS pathophysiology and may lead to the development of novel therapeutic interventions to alleviate the devastating effects of this syndrome on affected individuals.