Abstract
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.
Highlights
Energy balance is regulated in part by the coordinated action of specialized neurons within the hypothalamus of the brain, which sense circulating signals of energy stores such as the adipocyte derived hormone, leptin [1]
We report that Magel2-null mice display physiological leptin resistance, that leptin resistance precedes the development of increased adiposity, and that leptin-mediated electrophysiological responses in POMC neurons are conspicuously absent in these animals
This leptin resistance is accompanied by a 39% reduction in the number of POMC neurons in the arcuate nucleus (ARC), and by a complete absence of leptin-induced depolarization responses in the remaining POMC neurons
Summary
Energy balance is regulated in part by the coordinated action of specialized neurons within the hypothalamus of the brain, which sense circulating signals of energy stores such as the adipocyte derived hormone, leptin [1]. The arcuate nucleus (ARC) is a key hypothalamic region involved in energy balance regulation, and is a major site for leptin action. Two distinct populations of ARC neurons, expressing either Neuropeptide Y (NPY) and Agoutirelated peptide (AgRP) or pro-opiomelanocortin (POMC), have opposing effects on energy balance. NPY and AgRP, via different mechanisms, stimulate food intake and reduce energy expenditure, with the overexpression of either leading to obesity [2,3,4]. POMC is processed into several shorter peptides including a-MSH, which reduces food intake and stimulates energy expenditure through melanocortin-responsive neurons in the paraventricular nucleus and elsewhere [5]. Mutations that affect processing or lead to loss of expression of the POMC gene cause obesity in mice and humans [6,7,8]
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