Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia
Longlong Tu, … , Yanlin He, Yong Xu
Longlong Tu, … , Yanlin He, Yong Xu
Published June 1, 2023
Citation Information: J Clin Invest. 2023;133(14):e163391. https://doi.org/10.1172/JCI163391.
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Research Article Neuroscience

Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia

Abstract

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Authors

Longlong Tu, Jonathan C. Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A. Scarcelli, Kristine M. Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

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Figure 4

Effects of VMHAno4 neurons on feeding and glycemic control.

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Effects of VMHAno4 neurons on feeding and glycemic control. (A) Schemati...
(A) Schematic diagram of injection of AAV8-hSyn-DIO-hM3D(Gq)-mCherry into the VMH in Ano4-P2A-Cre mice (male, 8–10 weeks of age). (B and C) Food intake in both satiated and fasted condition following activation of VMHAno4 neurons via CNO injection (n = 8 for WT, and n = 9 for Ano4-P2A-Cre). (D and E) Activation of VMHAno4 neurons elicits hyperglycemia (n = 8 for WT, and n = 9 for Ano4-P2A-Cre). (F–J) Circulating concentrations of insulin, glucagon, corticosterone, norepinephrine, and epinephrine levels after activation of VMHAno4 neurons (n = 8 for WT, and n = 9 for Ano4-P2A-Cre). (K and L) Glucose levels during GTT after CNO injection (n = 8 for WT, and n = 9 for Ano4-P2A-Cre). (M and N) Glucose levels during ITT after CNO injection (n = 8 for WT and n = 9 for Ano4-P2A-Cre). (O and P) Glucose levels during 2-DG-induced glucopenia after CNO injection (n = 8 for WT, and n = 9 for Ano4-P2A-Cre). (Q) Schematic diagram of injection of AAV-EF1a-DIO-Kir2.1-P2A-dTOMATO into the VMH in Ano4-P2A-Cre mice. (R and S) Weekly blood glucose and body weight in STZ-treated mice (n = 7 for control and n = 10 for Kir2.1). (T-W) Blood glucagon, insulin, corticosterone, and leptin levels 2 weeks after STZ treatment (n = 7 for control and n = 10 for Kir2.1). Data are expressed as mean ± SEM. Significant differences between control and Ano4-P2A-Cre groups are shown as *P < 0.05, **P < 0.01, and ***P < 0.001 (2-tailed Student’s t test for E, H, I, L, N, and W, and 2-way ANOVA followed by Bonferroni tests for B, C, D, K, M, O, R, and S).