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Title: Glutamate mediates the function of melanocortin receptor 4 on sim1 neurons in body weight regulation

Author
item XU, YUANZHONG - University Of Texas Health Science Center
item WU, ZHAOFEI - University Of Texas Health Science Center
item SUN, HAO - University Of Texas Health Science Center
item ZHU, YAMING - University Of Texas Health Science Center
item KIM, EUN RAN - University Of Texas Health Science Center
item LOWELL, BRADFORD - Harvard Medical School
item ARENKIEL, BENJAMIN - Texas Children'S Hospital
item XU, YONG - Children'S Nutrition Research Center (CNRC)
item TONG, QINGCHUN - University Of Texas Health Science Center

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/25/2013
Publication Date: 12/3/2013
Citation: Xu, Y., Wu, Z., Sun, H., Zhu, Y., Kim, E., Lowell, B.B., Arenkiel, B.R., Xu, Y., Tong, Q. 2013. Glutamate mediates the function of melanocortin receptor 4 on sim1 neurons in body weight regulation. Cell Metabolism. 18:860-870.

Interpretive Summary: Obesity is a serious global health problem. The melanocortin receptor 4 (MC4R) is essential for the maintenance of normal body weight. However, how MC4R-expressing neurons regulate body weight remains unknown. We showed that glutamate release from MC4R-expressing neurons is required for normal body weight in mice. These results reveal novel mechanisms by which the brain integrates multiple signals to regulate body weight balance. This aids the field of science and additional studies can occur.

Technical Abstract: 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.