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

Authors: TU, LONGLONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); BEAN, JONATHAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HE, YANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIU, HAILAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); YU, MENG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIU, HESONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); ZHANG, NAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); YIN, NA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HAN, JUNYING - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); SCARCELLI, NIKOLAS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); CONDE, KRISTINE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); WANG, MENGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LI, YONGXIANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); FENG, BING - PENNINGTON BIOMEDICAL RESEARCH CENTER; GAO, PEIYU - PENNINGTON BIOMEDICAL RESEARCH CENTER; CAI, ZHAO-LIN - BAYLOR COLLEGE OF MEDICINE; FUKUDA, MAKOTO - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); XUE, MINGSHAN - BAYLOR COLLEGE OF MEDICINE; TONG, QINGCHUN - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER; YANG, YONGJIE - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); LIAO, LAN - BAYLOR COLLEGE OF MEDICINE; XU, JIANMING - BAYLOR COLLEGE OF MEDICINE; WANG, CHUNMEI - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC); HE, YANLIN - PENNINGTON BIOMEDICAL RESEARCH CENTER; XU, YONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/30/2023
Publication Date: 7/17/2023
Citation: Tu, L., Bean, J.C., He, Y., Liu, H., Yu, M., Liu, H., Zhang, N., Yin, N., Han, J., Scarcelli, N.A., Conde, K.M., Wang, M., Li, Y., Feng, B., Gao, P., Cai, Z., Fukuda, M., Xue, M., Tong, Q., Yang, Y., Liao, L., Xu, J., Wang, C., He, Y., Xu, Y. 2023. Anoctamin 4 channel currents activate glucose-inhibited neurons in the mouse ventromedial hypothalamus during hypoglycemia. Journal of Clinical Investigation. 133(14):Article e163391. https://doi.org/10.1172/JCI163391.
DOI: https://doi.org/10.1172/JCI163391

Interpretive Summary: Glucose is crucial for cellular viability, but the behavior of glucose-inhibited (GI) neurons, which paradoxically increase firing in low-glucose conditions, remains unclear. This study focused on ventromedial hypothalamic nucleus (VMH) neurons expressing the anoctamin 4 (Ano4) channel, demonstrating that Ano4-mediated currents are unique to GI neurons and essential for their activation in response to low glucose. Disrupting the Ano4 gene in VMH neurons led to lowered blood glucose and impaired responses during hypoglycemia in mice. Activating VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition improved hyperglycemia in a diabetic mouse model. Importantly, VMHAno4 neurons were identified as an orexigenic population transmitting positive valence, while neurons lacking Ano4 in the VMH suppressed feeding and conveyed a negative valence. These findings propose Ano4 channels and VMHAno4 neurons as potential therapeutic targets for conditions involving abnormal feeding or glucose imbalance.

Technical 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.