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United States Department of Agriculture

Agricultural Research Service

Research Project: Developmental Determinants of Obesity in Infants and Children

Location: Children's Nutrition Research Center

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

Author
item Xu, Yuanzhong
item Wu, Zhaofei
item Sun, Hao
item Zhu, Yaming
item Kim, Eun Ran
item Lowell, Bradford
item Arenkiel, Benjamin
item Xu, Yong
item Tong, Qingchun

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.

Last Modified: 09/22/2017
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