Loss of Magel2 impairs the development of hypothalamic Anorexigenic circuits

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. On the basis of 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.

Prader‐Willi syndrome: A model for understanding the ghrelin system

“…We therefore propose that the poor feeding skills of neonates with PWS are related to the low AG/UAG ratio, which may drive anorexia and poor sucking and swallowing skills . Of interest, the elevated total ghrelin levels with normal AG levels were also found in Magel2 knockout (KO) mice at P8, which supports our findings. Interestingly, Magel2 mutations reproduce in mice, as in men, the post‐natal phase observed in PWS with the same findings in circulating ghrelin.…”

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader–Willi syndrome

“…Indeed, the significant reductions in body weight, food intake, fat mass, and leptin levels in Magel2 -null mice were as prominent as in their littermate, wild-type control animals, if not more. However, these findings are not in full agreement with the recent reports indicating that Magel2 -null mice display central leptin resistance [58], [59]. On the other hand, Pravdivyi and colleagues have recently shown that young Magel2 -null mice exhibit a normal hypothalamic response to leptin [60].…”

MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity

“…For example, in PWS, abnormalities of the appetitesuppressing pathways, due to proconvertase 1 (PC1) deficiency and activation of the orexigenic Agouti-related protein (AgRP) neurons, have been described (40,41). Moreover, inactivation of the MAGEL2 gene, located in the genomic region classically deleted in PWS (15q11-13), has been shown to be responsible for a decrease in the density of axons of aMSH neurons in a mouse model (42). In BBS, considered to be a ciliopathy, the transport of LEPR is altered and therefore its localization at the ciliary membrane of POMC neurons is affected (43,44).…”