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Updated: Aug 31, 2025
Body Composition and Metabolic Caging Analysis in High Fat Fed Mice
Published on: May 24, 2018
Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced
Yuna Choi1,2, Hyeon-Young Min1,2, Jiyeon Hwang1,2
1Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York City, NY, USA.
Insights
Loss of the Magel2 gene in specific brain neurons reduces diet-induced obesity and increases activity. This finding offers new insights into Prader-Willi syndrome (PWS) and obesity, potentially through GPER activation.
Area of Science:
- Neuroscience
- Genetics
- Endocrinology
Background:
- Prader-Willi syndrome (PWS) is characterized by hyperphagia and obesity.
- The Magel2 gene, located in the PWS deletion region, is crucial for proopiomelanocortin (POMC) neuron function in the hypothalamus.
- Disruption of Magel2 impacts POMC neuronal circuits, contributing to metabolic dysregulation.
Purpose of the Study:
- To investigate the role of Magel2 specifically in ARC POMC neurons that innervate the medial amygdala (MeA) in diet-induced obesity.
- To explore the mechanisms underlying the anti-obesity effects, including locomotor activity and hormonal changes.
Main Methods:
- Generated mice with Magel2 gene knockout exclusively in ARC POMC neurons innervating the MeA.
- Assessed body weight, locomotor activity, glucose tolerance, and insulin tolerance in mice on a high-fat diet.
- Measured plasma estrogen levels and evaluated the role of estrogen receptors (GPER, ER-α) in observed effects.
Main Results:
- Loss of Magel2 in ARC POMC neurons led to reduced body weight and increased locomotor activity in mice on a high-fat diet.
- No significant differences in glucose or insulin tolerance were observed.
- Female mutant mice exhibited higher plasma estrogen levels, and GPER blockade reduced their locomotor activity.
Conclusions:
- Knockdown of Magel2 in ARC POMC neurons projecting to the MeA confers resistance to diet-induced obesity.
- Increased locomotor activity is a key factor in this anti-obesity effect, mediated by central GPER activation in females.
- This research elucidates a novel pathway involving Magel2, POMC neurons, and GPER in regulating body weight and activity.
Abstract:
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.
