Prader-Willi Syndrome is the most common syndromic form of human
obesity and is caused by the loss of function of several genes, including MAGEL2. Mice lacking Magel2 display increased
weight gain with excess adiposity and other defects suggestive of hypothalamic deficiency. We demonstrate Magel2-null mice are insensitive to the anorexic effect of peripherally administered
leptin. Although their excessive adiposity and hyperleptinemia likely contribute to this physiological
leptin resistance, we hypothesized that Magel2 may also have an essential role in intracellular
leptin responses in hypothalamic neurons. We therefore measured neuronal activation by immunohistochemistry on brain sections from
leptin-injected mice and found a reduced number of arcuate nucleus neurons activated after
leptin injection in the Magel2-null animals, suggesting that most but not all
leptin receptor-expressing neurons retain
leptin sensitivity despite hyperleptinemia. Electrophysiological measurements of arcuate nucleus neurons expressing the
leptin receptor demonstrated that although neurons exhibiting hyperpolarizing responses to
leptin are present in normal numbers, there were no neurons exhibiting depolarizing responses to
leptin in the mutant mice. Additional studies demonstrate that arcuate nucleus
pro-opiomelanocortin (
POMC) expressing neurons are unresponsive to
leptin. Interestingly, Magel2-null mice are hypersensitive to the anorexigenic effects of the
melanocortin receptor agonist MT-II. In
Prader-Willi Syndrome, loss of MAGEL2 may likewise abolish
leptin responses in
POMC hypothalamic neurons. This neural defect, together with increased fat mass, blunted circadian rhythm, and
growth hormone response pathway defects that are also linked to loss of MAGEL2, could contribute to the
hyperphagia and
obesity that are hallmarks of this disorder.