Format

Send to

Choose Destination
Hum Mol Genet. 2015 Aug 1;24(15):4276-83. doi: 10.1093/hmg/ddv159. Epub 2015 Apr 29.

Progressive postnatal decline in leptin sensitivity of arcuate hypothalamic neurons in the Magel2-null mouse model of Prader-Willi syndrome.

Author information

1
Department of Medical Genetics.
2
Department of Physiology, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.
3
Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.
4
Department of Medical Genetics, Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada rwevrick@ualberta.ca.

Abstract

Prader-Willi syndrome (PWS) is a multigene disorder associated with neonatal failure to thrive, developmental delay and endocrine abnormalities suggestive of hypothalamic dysfunction. Children with PWS typically develop overt hyperphagia and obesity ∼8 years of age, later than children with other genetic forms of obesity. This suggests a postnatal developmental or degenerative component to PWS-associated obesity. De novo inactivating mutations in one PWS candidate gene, MAGEL2, have been identified in children with features of PWS. Adult mice lacking Magel2 are insensitive to the anorexic effect of leptin treatment, and their hypothalamic pro-opiomelanocortin (POMC) neurons fail to depolarize in response to leptin. However, it is unclear whether this leptin insensitivity is congenital, or whether normal leptin sensitivity in neonatal Magel2-null mice is lost postnatally. We used in vitro cytosolic calcium imaging to follow the postnatal development of leptin responses in POMC neurons in these mice. Leptin caused an activation of POMC neurons in wild-type acute hypothalamic slice preparations at all ages, reflecting their normal leptin-invoked depolarization. Normal leptin responses were found in Magel2-null mice up to 4 weeks of age, but the proportion of leptin-responsive POMC neurons was reduced in 6-week-old Magel2-null mice. The number of α-melanocyte-stimulating hormone immunoreactive fibers in the paraventricular hypothalamic nucleus was also reduced in mutant mice at 6 weeks of age. A similar progressive loss of leptin sensitivity caused by loss of MAGEL2 in children with PWS could explain the delayed onset of increased appetite and weight gain in this complex disorder.

PMID:
25926624
DOI:
10.1093/hmg/ddv159
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center