Neurohormonal Controls of Energy Balance in the MAGEL2-Deficient Rat

Funding Summary

Dr. Mietlicki-Baase and her team will investigate neural/neurohormonal control of energy balance in a rat model that lacks Magel2, a gene that is lost or mutated in Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS). They will test feeding motivation behaviors and examine the brain areas that control energy balance. They will also evaluate neural responses to satiation signals focusing on a part of the brain (NTS) that is an energy-balance controlling hub and examine key appetite hormones to gain new insights into the physiology and neurobiology of 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 complex disorder characterized by striking changes in energy balance (EB) control. Individuals with PWS develop extreme increases in food intake and body weight gain during childhood. The physiological causes of the EB phenotype of PWS are not fully understood but are thought to involve loss of function of the MAGEL2 gene. Because the brain controls EB, animal models are invaluable to researching PWS neurobiology. To date, animal models of MAGEL2 loss of function have not fully captured the PWS phenotype, making it crucial to develop models that more completely express the EB characteristics of PWS. FPWR has developed a novel MAGEL2-deficient rat; although this may be useful to evaluate mechanisms underlying the EB phenotype of PWS in humans, many aspects of the physiology and behavior of this model remain underinvestigated. The proposed studies investigate neural/neurohormonal controls of EB in MAGEL2-deficient rats, including testing feeding responses to satiation signals and motivational aspects of feeding, and begin to evaluate distributed brain areas underlying the EB phenotype of PWS. Behavioral mechanisms of feeding, including intake and meal patterns, will be evaluated in MAGEL2-deficient rats vs wild-type controls at baseline and in response to challenges to EB. Motivational aspects of feeding will be tested in MAGEL2-deficient rats via lever pressing for palatable food access and preference for different palatable foods (sucrose vs fat). We will evaluate hypothalamic and hindbrain neural responses to a satiation signal in this model, including examination of the nucleus tractus solitarius (NTS), a critical hindbrain integrative hub for EB control that has not been tested for its possible role in the EB phenotype of PWS. Finally, we will investigate how MAGEL2 deficiency impacts levels of key feeding-relevant hormones such as ghrelin, insulin, and leptin that have previously been shown to be altered in humans with PWS and/or the Magel2-null mouse, allowing us to understand whether these effects are exhibited in the MAGEL2-deficient rat. The outcomes of these studies are vital to future PWS research. If the MAGEL2-deficient rat more fully recapitulates the symptoms of PWS in humans, it will be useful in a variety of future studies aimed at understanding the physiology and neurobiology of PWS. Moreover, identifying whether NTS function is impacted by MAGEL2 deficiency paves the way for a deeper understanding of the distributed neural controls of EB in PWS, and lays a foundation for follow-up studies to fully elucidate the brain regions and neurotransmitters underlying the PWS phenotype. Collectively, these studies will provide urgently needed insight into a potential new model of PWS. This will generate evidence for the utility of the model in developing a more complete understanding of the physiological and neurobiological underpinnings of PWS, potentially leading to improved treatments or a cure for PWS.

 

Funded Year:

2020

Awarded to:

Elizabeth Mietlicki-Baase, PhD

Amount:

$102,600

Institution:

The Research Foundation for The SUNY on behalf of University at Buffalo

Researcher:

Elizabeth Mietlicki-Baase, PhD

Search Projects

Donate for PWS Research