Impaired Hypothalamic Regulation of Endocrine Function and Delayed Counterregulatory Response to Hypoglycemia in Magel2-Null Mice

Abstract

Hypothalamic dysfunction may underlie endocrine abnormalities in Prader-Willi syndrome (PWS), a genetic disorder that features GH deficiency, obesity, and infertility. One of the genes typically inactivated in PWS, MAGEL2, is highly expressed in the hypothalamus. Mice deficient for Magel2 are obese with increased fat mass and decreased lean mass and have blunted circadian rhythm. Here, we demonstrate that Magel2-null mice have abnormalities of hypothalamic endocrine axes that recapitulate phenotypes in PWS. Magel2-null mice had elevated basal corticosterone levels, and although male Magel2-null mice had an intact corticosterone response to restraint and to insulin-induced hypoglycemia, female Magel2-null mice failed to respond to hypoglycemia with increased corticosterone. After insulin-induced hypoglycemia, Magel2-null mice of both sexes became more profoundly hypoglycemic, and female mice were slower to recover euglycemia, suggesting an impaired hypothalamic counterregulatory response. GH insufficiency can produce abnormal body composition, such as that seen in PWS and in Magel2-null mice. Male Magel2-null mice had Igf-I levels similar to control littermates. Female Magel2-null mice had low Igf-I levels and reduced GH release in response to stimulation with ghrelin. Female Magel2-null mice did respond to GHRH, suggesting that their GH deficiency has a hypothalamic rather than pituitary origin. Female Magel2-null mice also had higher serum adiponectin than expected, considering their increased fat mass, and thyroid (T 4 ) levels were low. Together, these findings strongly suggest that loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS. (Endocrinology 152: 967-978, 2011) P rader-Willi syndrome (PWS) is a complex genetic disorder, whose clinical features suggest abnormalities of the hypothalamic-pituitary axis. These include GH deficiency with short stature, increased fat mass and reduced lean mass, hypogonadotropic hypogonadism, childhood-onset hyperphagia and obesity, and sleep disorders. Structural abnormalities of the brain documented in PWS include frequent ventriculomegaly and cortical abnormalities. Pituitary abnormalities are common, but structural abnormalities of the hypothalamus are not typically found (1-3). Children with PWS typically have decreased spontaneous GH secretion and low peak GH response in stimulation tests (4, 5), accompanied by reduced serum IGF-I and low IGF-binding protein 3 (6 -8). GH deficiency contributes to abnormal body composition consisting of increased body fat mass and reduced lean mass, and treatment with GH partially normalizes body composition and short stature (9 -11). In contrast, obesity in the general population is often associated with a relative GH deficiency but normal or high levels of IGF-I, suggesting defective feedback mechanisms in GH pathways that can resolve on weight loss.In normal adults, serum leptin levels increase with increasing adiposity, but levels of adiponectin, particularly in its multimeric high mole...

Histopathological and Biochemical Effects of Acute & Chronic Tramadol drug Toxicity on Liver, Kidney and Testicular Function in Adult Male Albino Rats

“…Tramadol influenced this activity where there was a reduction in the levels of LH, FSH and testosterone with induction of PRL and E2 levels. Previous studies concerned with gonadal activity during drugs abuse have been supported the present results where Tennese & Wevrick [30] reported decreased levels of LH and testosterone with increased prolactin hormone after morphine and methadone administration. Also El-Gaafarawi et al [21] observed the reduction of serum levels of LH, FSH and testosterone and the induction of prolactin hormone (PRL) and E2 secretions after cannabis use.…”

Global deficits in development, function, and gene expression in the endocrine pancreas in a deletion mouse model of Prader-Willi syndrome

“…These data imply that a similar signaling and/or secretory mechanism might be disturbed in both ␤-and ␣-cells in TgPWS mice. Recent studies have shown a delayed counterregulatory response to insulin-induced hypoglycemia in mice deficient for the PWS region Magel2 gene, although pancreatic hormones were not assessed (62). Loss of Magel2 in TgPWS deletion mice may contribute in part to the more severe neonatal hypoglycemia and complete lack of a counterregulatory response described here for TgPWS mice.…”

“…Indeed, mouse Necdin has been implicated both in GnRH gene expression and the development of GnRH neurons, providing a potential molecular basis for gonadotropin deficiency in PWS (45). Similarly, Magel2 has recently been implicated in sex-specific endocrine changes putatively of hypothalamic origin, including GH release in response to ghrelin, in Magel2-null mice (62). These observations, combined with the pancreatic data presented here for the TgPWS mouse model, are consistent with a hypothesis that similar mechanisms underlie abnormal pancreatic, pituitary, and hypothalamic hormone and peptide secretion in PWS.…”

USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

“…Furthermore, truncating mutations of MAGEL2 result in Schaaf-Yang syndrome (MIM 615547) with marked clinical overlap to PWS, highlighted by hypotonia, hypogonadism, intellectual disability, and autism spectrum disorder (Schaaf et al, 2013). The Magel2 knockout mice recapitulate several of these phenotypes (Bischof et al, 2007; Kozlov et al, 2007; Mercer et al, 2009; Mercer and Wevrick, 2009; Tennese and Wevrick, 2011). This suggests that the regulation of WASH-mediated endosomal actin assembly and protein recycling by the MAGE-L2-TRIM27 ubiquitin ligase plays an important role in neurodevelopment.…”