Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia
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
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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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 3

Electrical responses of VMHAno4 neurons to glucose fluctuation.

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Electrical responses of VMHAno4 neurons to glucose fluctuation. (A) Expe...
(A) Experimental illustration of a recorded VMHAno4 neuron. (B–D) Firing frequency, resting membrane potential, and percentages of GI and NGS neurons in VMHAno4 neurons under glucose exposure from 5 → 1 mM (n = 0 for GE, n = 21 for GI, and n = 6 for NGS). (E) Ano current was detected in GI VMHAno4 neurons and was minimal in NGS VMHAno4 neurons (n = 6 for GI and NGS). (F and G) Firing frequency and resting membrane potential of VMHAno4 neurons under glucose exposure from 5 mM → 2.5 mM → 1 mM (n = 13). (H) Ano current detected in VMHAno4 neurons under different glucose fluctuations from 5 mM → 2.5 mM → 1 mM (n = 5). (I) Ano current detected in VMHAno4 neurons under different glucose fluctuation was blocked by Compound C (n = 5). (J and K) Firing frequency and resting membrane potential of VMHAno4 neurons in response to low glucose in the presence of AMPK blocker Compound C (10 μM) (n = 11). Data are expressed as mean ± SEM. Significant differences between 5 mM glucose and 1 mM glucose are shown as ****P < 0.0001 determined by a 2-tailed paired Student’s t test for B, C, F, G, J, and K and 2-way ANOVA followed by Bonferroni tests for E and H.