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Title: Estrogen receptor-a expressing neurons in the ventrolateral VMH regulate glucose balance

Author
item HE, YANLIN - Children'S Nutrition Research Center (CNRC)
item XU, PINGWEN - Children'S Nutrition Research Center (CNRC)
item WANG, CHUNMEI - Children'S Nutrition Research Center (CNRC)
item YAN, XIA - Children'S Nutrition Research Center (CNRC)
item YU, MENG - Children'S Nutrition Research Center (CNRC)
item YANG, YONGJIE - Children'S Nutrition Research Center (CNRC)
item YU, KAIFAN - Children'S Nutrition Research Center (CNRC)
item CAI, XING - Children'S Nutrition Research Center (CNRC)
item QU, NA - Children'S Nutrition Research Center (CNRC)
item SAITO, KENJI - Children'S Nutrition Research Center (CNRC)
item WANG, JULIA - Children'S Nutrition Research Center (CNRC)
item HYSENI, LLIRJANA - Children'S Nutrition Research Center (CNRC)
item ROBERTSON, MATTHEW - Baylor College Of Medicine
item PIYARATHNA, BADRAJEE - Baylor College Of Medicine
item GAO, MIN - Baylor College Of Medicine
item KHAN, SOHAIB - University Of Cincinnati
item LIU, FENG - University Of Texas At San Antonio
item CHEN, RUI - Baylor College Of Medicine
item COARFA, CRISTIAN - Baylor College Of Medicine
item ZHAO, ZHONGMING - University Of Texas Health Science Center
item TONG, QINGCHUN - University Of Texas Health Science Center
item SUN, ZHENG - Baylor College Of Medicine
item XU, YONG - Children'S Nutrition Research Center (CNRC)

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/6/2020
Publication Date: 5/1/2020
Citation: He, Y., Xu, P., Wang, C., Yan, X., Yu, M., Yang, Y., Yu, K., Cai, X., Qu, N., Saito, K., Wang, J., Hyseni, L., Robertson, M., Piyarathna, B., Gao, M., Khan, S., Liu, F., Chen, R., Coarfa, C., Zhao, Z., Tong, Q., Sun, Z., Xu, Y. 2020. Estrogen receptor-a expressing neurons in the ventrolateral VMH regulate glucose balance. Nature Communications. 11:2165. https://doi.org/10.1038/s41467-020-15982-7
DOI: https://doi.org/10.1038/s41467-020-15982-7

Interpretive Summary: Severe hypoglycemia is a life-threatening problem for diabetic patients with intensive insulin therapy. While normal individuals can correct isolated hypoglycemic events through a defending mechanism, this protection is often impaired in diabetic patients. Blood glucose balance is essential for survival, but how it is regulated is not fully understood. Here we showed that a small group cells in the brain can sense fluctuations in glucose levels and then trigger a series of neural responses to regulate blood glucose levels. These findings identify novel brain mechanisms for the regulation of blood glucose balance.

Technical Abstract: Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-a (ERa)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERavlVMH) or glucose-excited neurons (GE-ERa^vlVMH). Hypoglycemia activates GI-ERa^vlVMH neurons via the anoctamin 4 channel, and inhibits GEERa^vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERavlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERa^vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERa^vlVMH to mpARH circuit and inhibition of ERa^vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERa^vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.