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New insights uncovered in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare genetic disease characterized by hyperphagia — a chronic feeling of hunger — coupled with a metabolism that uses drastically fewer calories than normal, leading to excessive eating/obesity in patients with the disease.


Prader-Willi affects approximately 1 in 25,000 births or about 400,000 individuals worldwide. It is recognized as the most common genetic cause of life-threatening childhood obesity.

A study published in the journal Human Molecular Genetics by researchers at Children's Hospital Los Angeles (CHLA) provides insights into the brain mechanisms underlying the insatiable hunger and subsequent obesity in patients with Prader-Willi syndrome.

Although much attention has been focused on the metabolic and behavioral outcomes of PWS, scientists knew relatively little about development of appetite-related pathways in the hypothalamus — that portion of the brain developing in neonatal life under the influence of both environment and gene factors.

It had been suggested that the importance of the hypothalamus in the control of eating and energy balance, might be affected by early impairment of its development, resulting in metabolic dysregulation.


"Our goal was to characterize the development of brain circuits involved in appetite regulation, using a mouse model for Prader-Willi syndrome. We specifically focused on the hypothalamus because it is the brain region critical for regulation of homeostatic processes such as feeding." [Homeostasis: tendency of the body to seek and maintain balance or equilibrium internally, even with varying external changes. Example: an ability to maintain internal temperature of 98.6 degrees Fahrenheit, despite outside temperature]

Sebastien Bouret PhD, Associate Professor, Pediatrics, Keck School of Medicine, University of Southern California (USC), member of The Saban Research Institute's Developmental Neuroscience Program, and lead author.


The Magel2 gene is located on chromosome 15. Bouret and colleagues found that in mice without the Magel2 gene — one of the genes responsible for PWS — displayed abnormal development of brain connections which normally trigger satiation. Thus, the mouse's body cannot tell when it has gotten enough to eat.


The research also revealed that Magel2 defects in neurodevelopment are unlikely to involve endocrines — the hormones that regulate growth, metabolism and development. Instead, they found the Magel2 gene appears to directly affect the growth of nerve axons — the long, slender projections off nerve cells that conduct electrical impulses.


Based on previous research which revealed a pivotal role for the metabolic hormones leptin and ghrelin in hypothalamus development, the scientists decided to measure levels of these two hormones in Magel2 knockout mice (mice without a Magel2 gene) and compare them to control mice which do have the gene.

They found that the knockout mice had normal levels of leptin and ghrelin, suggesting that the affect of the loss of Magel2 alone leads to disruption of feeding circuits in the hypothalamus, independent of the effects of both the leptin and ghrelin hormones.

Abstract
Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both peripheral and central systems. The arcuate nucleus of the hypothalamus (ARH) is critical for the regulation of homeostatic processes including feeding, and this nucleus develops during neonatal life under of the influence of both environmental and genetic factors. Although much attention has focused on the metabolic and behavioral outcomes of PWS, an understanding of its effects on the development of hypothalamic circuits remains elusive. Here, we show that mice lacking Magel2, one of the genes responsible for the etiology of PWS, display an abnormal development of ARH axonal projections. Notably, the density of anorexigenic α-melanocyte-stimulating hormone axons was reduced in adult Magel2-null mice, while the density of orexigenic agouti-related peptide fibers in the mutant mice appeared identical to that in control mice. Based on previous findings showing a pivotal role for metabolic hormones in hypothalamic development, we also measured leptin and ghrelin levels in Magel2-null and control neonates and found that mutant mice have normal leptin and ghrelin levels. In vitro experiments show that Magel2 directly promotes axon growth. Together, these findings suggest that a loss of Magel2 leads to the disruption of hypothalamic feeding circuits, an effect that appears to be independent of the neurodevelopmental effects of leptin and ghrelin and likely involves a direct neurotrophic effect of Magel2.

Additional contributors to the study include first author Julien Maillard, Children's Hospital Los Angeles and INSERM, Jean-Pierre Aubert Research Center, University Lille, France; Soyoung Park, Sophie Croizier and Joshua H. Cook, Children's Hospital Los Angeles; Charlotte Vanacker and Vincent Prevot, INSERM; and Maithé Tauber, INSERM and Children's Hospital, Toulouse, France.

This work was supported by the Foundation for Prader-Willi Research, the National Institutes of Health (Grants R01DK84142, R01DK102780, and P01ES022845), the United States Environment Protection Agency (Grant RD83544101), and the EU FP7 integrated project.

About Children's Hospital Los Angeles
Children's Hospital Los Angeles has been named the best children's hospital on the West Coast and among the top five in the nation for clinical excellence with its selection to the prestigious U.S. News & World Report Honor Roll. Children's Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States. Children's Hospital is also one of America's premier teaching hospitals through its affiliation since 1932 with the Keck School of Medicine of the University of Southern California. For more information, visit CHLA.org or visit our blog at ResearCHLAblog.org.

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Jun 20, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



The loss of the gene Magel2 leads to the disruption of hypothalamic feeding circuits,
causing insatiable hunger and obesity in patients with Prader-Willi syndrome.
Image Credit: Nov. 2015, Journal: Diseases


 


 

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