Cell Metabolism
Volume 18, Issue 6, 3 December 2013, Pages 860-870
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Article
Glutamate Mediates the Function of Melanocortin Receptor 4 on Sim1 Neurons in Body Weight Regulation

https://doi.org/10.1016/j.cmet.2013.11.003Get rights and content
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Highlights

  • Disruption of glutamate release from adult PVH neurons leads to obesity

  • Glutamate mediates MC4R function on Sim1 neurons for body weight control

  • MC4Rs on Sim1 neurons regulate both energy expenditure and feeding

  • PVH neuropeptides are not capable of compensating for loss of glutamate release

Summary

The melanocortin receptor 4 (MC4R) is a well-established mediator of body weight homeostasis. However, the neurotransmitter(s) that mediate MC4R function remain largely unknown; as a result, little is known about the second-order neurons of the MC4R neural pathway. Single-minded 1 (Sim1)-expressing brain regions, which include the paraventricular nucleus of hypothalamus (PVH), represent key brain sites that mediate melanocortin action. We conditionally restored MC4R expression in Sim1 neurons in the background of Mc4r-null mice. The restoration dramatically reduced obesity in Mc4r-null mice. The anti-obesity effect was completely reversed by selective disruption of glutamate release from those same Sim1 neurons. The reversal was caused by lower energy expenditure and hyperphagia. Corroboratively, selective disruption of glutamate release from adult PVH neurons led to rapid obesity development via reduced energy expenditure and hyperphagia. Thus, this study establishes glutamate as the primary neurotransmitter that mediates MC4Rs on Sim1 neurons in body weight regulation.

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