Magel2knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity

Abstract

Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). TheMagel2gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of theMagel2gene disrupts POMC neuronal circuits and functions. Here, we report that loss of theMagel2gene exclusively in ARCPOMCneurons innervating the medial amygdala (MeA) causes a reduction in body weight in both male and female mice fed with a high-fat diet. This anti-obesity effect is associated with an increased locomotor activity. There are no significant differences in glucose and insulin tolerance in mice without theMagel2gene in ARCPOMCneurons innervating the MeA. Plasma estrogen levels are higher in female mutant mice than in controls. Blockade of the G protein–coupled estrogen receptor (GPER), but not estrogen receptor-α (ER-α), reduces locomotor activity in female mutant mice. Hence, our study provides evidence that knockdown of theMagel2gene in ARCPOMCneurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.