Leptin signaling defects in a mouse model of Prader-Willi syndrome

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.

Keywords: :

• childhood obesity
• hypothalamus
• POMC
• leptin
• Prader-Willi Syndrome
• electrophysiology
• neuropeptide Y
• mouse model

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Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.

Acknowledgments

Studies in the authors’ laboratories involving PWS mice were funded by grants from the CIHR (MT10520 and OTG 88592 to W.F.C.), the Prader-Willi Syndrome Association (Best Ideas Grant) and the Women and Children’s Health Research Institute at the University of Alberta. W.F.C. is an AHFMR Medical Scientist.