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Leptin signaling defects in a mouse model of Prader-Willi syndrome: An orphan genetic obesity syndrome no more?

Colmers WF, Wevrick R - Rare Dis (2013)

Bottom Line: Children with PWS not only rapidly gain weight and become severely obese because of reduced voluntary activity and increased food intake, but also exhibit growth hormone deficiency, excessive daytime sleepiness, endocrine dysregulation and infertility.The physiological basis for obesity in children with PWS has eluded researchers for decades.Most interestingly, disruptions of other components of this pathway cause obesity in both mice and humans, suggesting a mechanistic link between PWS and other rare genetic forms of severe childhood-onset obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology; University of Alberta; Edmonton, AB Canada.

ABSTRACT
Prader-Willi syndrome (PWS) is a rare (~1 in 12,000) genetic disorder that involves at least six genes on chromosome 15q11-q13. Children with PWS not only rapidly gain weight and become severely obese because of reduced voluntary activity and increased food intake, but also exhibit growth hormone deficiency, excessive daytime sleepiness, endocrine dysregulation and infertility. These phenotypes suggest dysfunction of the hypothalamus, the brain region that regulates short- and long-term energy balance and other body functions. The physiological basis for obesity in children with PWS has eluded researchers for decades. Mercer et al. now demonstrate that Magel2, the murine ortholog of one of the PWS genes, is a component of the hypothalamic leptin-melanocortin pathway that is critical for energy balance. Most interestingly, disruptions of other components of this pathway cause obesity in both mice and humans, suggesting a mechanistic link between PWS and other rare genetic forms of severe childhood-onset obesity.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Genes mutated in childhood obesity act in the hypothalamus to regulate energy balance. Mutations that cause rare monogenic or syndromic forms of childhood obesity have been identified in at least 10 different genes, listed on the right. The proteins encoded by these genes act in the hypothalamus (gray) and participate in the leptin - melanocortin pathway that regulates appetite and body weight. MAGEL2 is one of the genes inactivated in Prader-Willi syndrome, a rare genetic disorder that causes childhood-onset severe obesity. Mercer et al. showed that Magel2, the murine ortholog of MAGEL2, is essential for the leptin-mediated responses of a specific set of neurons, those that express POMC in the arcuate nucleus of the hypothalamus.
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Figure 1: Figure 1. Genes mutated in childhood obesity act in the hypothalamus to regulate energy balance. Mutations that cause rare monogenic or syndromic forms of childhood obesity have been identified in at least 10 different genes, listed on the right. The proteins encoded by these genes act in the hypothalamus (gray) and participate in the leptin - melanocortin pathway that regulates appetite and body weight. MAGEL2 is one of the genes inactivated in Prader-Willi syndrome, a rare genetic disorder that causes childhood-onset severe obesity. Mercer et al. showed that Magel2, the murine ortholog of MAGEL2, is essential for the leptin-mediated responses of a specific set of neurons, those that express POMC in the arcuate nucleus of the hypothalamus.

Mentions: Most childhood-onset, severe, syndromic or heritable forms of obesity are caused by rare mutations in genes important in energy balance control circuits in the hypothalamus (Fig. 1).7-12 This small region of the brain coordinates the nervous and endocrine systems to regulate energy balance and other homeostatic activities.13 Both rare mutations and common variants have been found in genes encoding proteins that are involved in the neural responses to leptin, a key hormone produced by adipose tissue. Mutations in these genes profoundly affect body weight and are not compensated for by other genes or pathways, highlighting their physiological importance. Further, leptin resistance is a hallmark of diet-induced obesity.14 The recent report by Mercer et al. demonstrating that loss of a protein named Magel2 impairs leptin signaling in the hypothalamus introduces a new member to the cast of characters essential for energy homeostasis.15Magel2 is the murine ortholog of MAGEL2,16-23 one of the genes that is inactivated in the orphan genetic obesity disorder Prader-Willi syndrome (PWS).21,24-26 This raises a question about this rare and poorly understood disease: is PWS still an orphan genetic obesity disorder or is it too caused by a defect in hypothalamic leptin signaling?


Leptin signaling defects in a mouse model of Prader-Willi syndrome: An orphan genetic obesity syndrome no more?

Colmers WF, Wevrick R - Rare Dis (2013)

Figure 1. Genes mutated in childhood obesity act in the hypothalamus to regulate energy balance. Mutations that cause rare monogenic or syndromic forms of childhood obesity have been identified in at least 10 different genes, listed on the right. The proteins encoded by these genes act in the hypothalamus (gray) and participate in the leptin - melanocortin pathway that regulates appetite and body weight. MAGEL2 is one of the genes inactivated in Prader-Willi syndrome, a rare genetic disorder that causes childhood-onset severe obesity. Mercer et al. showed that Magel2, the murine ortholog of MAGEL2, is essential for the leptin-mediated responses of a specific set of neurons, those that express POMC in the arcuate nucleus of the hypothalamus.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927482&req=5

Figure 1: Figure 1. Genes mutated in childhood obesity act in the hypothalamus to regulate energy balance. Mutations that cause rare monogenic or syndromic forms of childhood obesity have been identified in at least 10 different genes, listed on the right. The proteins encoded by these genes act in the hypothalamus (gray) and participate in the leptin - melanocortin pathway that regulates appetite and body weight. MAGEL2 is one of the genes inactivated in Prader-Willi syndrome, a rare genetic disorder that causes childhood-onset severe obesity. Mercer et al. showed that Magel2, the murine ortholog of MAGEL2, is essential for the leptin-mediated responses of a specific set of neurons, those that express POMC in the arcuate nucleus of the hypothalamus.
Mentions: Most childhood-onset, severe, syndromic or heritable forms of obesity are caused by rare mutations in genes important in energy balance control circuits in the hypothalamus (Fig. 1).7-12 This small region of the brain coordinates the nervous and endocrine systems to regulate energy balance and other homeostatic activities.13 Both rare mutations and common variants have been found in genes encoding proteins that are involved in the neural responses to leptin, a key hormone produced by adipose tissue. Mutations in these genes profoundly affect body weight and are not compensated for by other genes or pathways, highlighting their physiological importance. Further, leptin resistance is a hallmark of diet-induced obesity.14 The recent report by Mercer et al. demonstrating that loss of a protein named Magel2 impairs leptin signaling in the hypothalamus introduces a new member to the cast of characters essential for energy homeostasis.15Magel2 is the murine ortholog of MAGEL2,16-23 one of the genes that is inactivated in the orphan genetic obesity disorder Prader-Willi syndrome (PWS).21,24-26 This raises a question about this rare and poorly understood disease: is PWS still an orphan genetic obesity disorder or is it too caused by a defect in hypothalamic leptin signaling?

Bottom Line: Children with PWS not only rapidly gain weight and become severely obese because of reduced voluntary activity and increased food intake, but also exhibit growth hormone deficiency, excessive daytime sleepiness, endocrine dysregulation and infertility.The physiological basis for obesity in children with PWS has eluded researchers for decades.Most interestingly, disruptions of other components of this pathway cause obesity in both mice and humans, suggesting a mechanistic link between PWS and other rare genetic forms of severe childhood-onset obesity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology; University of Alberta; Edmonton, AB Canada.

ABSTRACT
Prader-Willi syndrome (PWS) is a rare (~1 in 12,000) genetic disorder that involves at least six genes on chromosome 15q11-q13. Children with PWS not only rapidly gain weight and become severely obese because of reduced voluntary activity and increased food intake, but also exhibit growth hormone deficiency, excessive daytime sleepiness, endocrine dysregulation and infertility. These phenotypes suggest dysfunction of the hypothalamus, the brain region that regulates short- and long-term energy balance and other body functions. The physiological basis for obesity in children with PWS has eluded researchers for decades. Mercer et al. now demonstrate that Magel2, the murine ortholog of one of the PWS genes, is a component of the hypothalamic leptin-melanocortin pathway that is critical for energy balance. Most interestingly, disruptions of other components of this pathway cause obesity in both mice and humans, suggesting a mechanistic link between PWS and other rare genetic forms of severe childhood-onset obesity.

No MeSH data available.


Related in: MedlinePlus