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 2

Knockout of Ano4 in VMHSF1 neurons induces hypoglycemia and blunts counterregulatory response.

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Knockout of Ano4 in VMHSF1 neurons induces hypoglycemia and blunts count...
(A) Schematic representation of CRISPR-mediated knockout of Ano4 in both sides of VMHSF1 neurons in SF1-Cre mice. (B–D) Body weight, food intake, and blood glucose in male mice (n = 10 for control, and n = 7 for Ano4 KOSF1). (E–G) Body weight, food intake, and blood glucose in female mice (n = 10 for control, and n = 7 for Ano4 KOSF1). (H–K) Blood glucose levels and respective AUC after treatment with 2-DG (300 mg/kg, i.p.) or saline (10 mL/kg, i.p.) in male mice (H and I, n = 10 for control, and n = 7 for Ano4 KOSF1) and female mice (J and K, n = 7 for control, and n = 6 for Ano4 KOSF1). (L–N) Response to repeated treatment with 2-DG (300 mg/kg, i.p.) with glucose measurement on day 1 and day 4 in female mice (n = 7 for Control, and n = 6 for Ano4 KOSF1). (O–R) Blood glucose levels (O) and glucose infusion rate (P) throughout the recording of hyperinsulinemic-hypoglycemic clamp in male mice (n = 5 for control and Ano4 KOSF1). Blood glucagon and corticosterone levels at the fixed hypoglycemic status (Q–R, n = 5 for control and Ano4 KOSF1). Data are expressed as mean ± SEM. Significant differences between control and Ano4 KOSF1 groups are shown as *P < 0.05, **P < 0.01, and ***P < 0.01 (2-tailed Student’s t test for D, G, Q and R; 2-way ANOVA followed by Bonferroni tests for E, H, J, M, and P; 1-way ANOVA with Bonferroni’s adjustment for multiple comparisons for I, K, and N.).