RT Journal Article SR Electronic T1 Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201502 DO 10.26508/lsa.202201502 VO 5 IS 11 A1 Choi, Yuna A1 Min, Hyeon-Young A1 Hwang, Jiyeon A1 Jo, Young-Hwan YR 2022 UL https://www.life-science-alliance.org/content/5/11/e202201502.abstract AB Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene 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 the Magel2 gene disrupts POMC neuronal circuits and functions. Here, we report that loss of the Magel2 gene exclusively in ARCPOMC neurons 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 the Magel2 gene in ARCPOMC neurons 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 the Magel2 gene in ARCPOMC neurons innervating the MeA reduces susceptibility to diet-induced obesity with increased locomotor activity through activation of central GPER.