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This review explores the central role of connexin-mediated signalling in hypothalamic regulation of nutrient metabolism and energy homeostasis, together with the function of connexins in peripheral metabolic organs. Focusing on connexins Cx43 and Cx30, we discuss their specific expression within hypothalamic neuroglial populations, including astrocytes and tanycytes, and their involvement in glucose sensing, metabolic signalling, and neuroendocrine regulation. Functional studies demonstrate that hypothalamic Cx43 is dynamically regulated by metabolic status, while its knockdown impairs glucose-stimulated insulin secretion and systemic energy balance. Tanycytes, interconnected into a Cx43-dependent network, play a critical role in relaying metabolic cues from cerebrospinal fluid and blood to hypothalamic neurons, thereby orchestrating adaptive responses to glycaemic changes. The review further details how the disruption of connexin-mediated coupling in tanycytes leads to impaired glucose sensing, altered neuronal activity, and systemic metabolic disorders. Beyond the hypothalamus, this review also summarizes how connexins in peripheral metabolic organs contribute to metabolic homeostasis, inflammatory regulation, and disease progression. Collectively, these discoveries highlight the fundamental importance of connexins in integrating metabolic signals and maintaining systemic homeostasis.<\/jats:p>","DOI":"10.1093\/lifemedi\/lnag018","type":"journal-article","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T11:47:15Z","timestamp":1778240835000},"source":"Crossref","is-referenced-by-count":1,"title":["Connexins in metabolic control: linking brain cellular communication to systemic homeostasis"],"prefix":"10.1093","volume":"5","author":[{"given":"Yiyi","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen 518107,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6883-3752","authenticated-orcid":false,"given":"Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney , Sydney NSW 2007,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pathology, The First Affiliated Hospital of Gannan Medical University , Ganzhou 341000,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Verkhratsky","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen 518107,","place":["China"]},{"name":"Faculty of Biology, Medicine and Health, The University of Manchester , Manchester M13 9PT,","place":["United Kingdom"]},{"name":"Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University , Shenyang 110122,","place":["China"]},{"name":"International Joint Research Centre on Purinergic Signalling of Sichuan Province Chengdu University of Traditional Chinese Medicine , Chengdu 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