Journal
CELL METABOLISM
Volume 18, Issue 6, Pages 860-870Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2013.11.003
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Funding
- NIH [R01DK092605, R01DK093587, R00DK085330, P30 DK079638-03, R01 NS078294, R01 DK075632, R01 DK07105, R01 DK089044, P30 DK046200, P30 DK057521]
- Scientist Development Award from American Heart Association
- American Diabetes Association
- Klarman Family Foundation
- Naman Family Fund for Basic Research
- Curtis Hankamer Basic Research Fund
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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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