Connexins in metabolic control: linking brain cellular communication to systemic homeostasis

Connexins, a family of transmembrane proteins, are essential for intercellular communication in the mammalian central nervous system, particularly through their assembly into gap junction channels. This review explores the central role of connexin-mediated signalling in hypothalamic regulation of nutrient metabolism and energy homeostasis, together with connexin functions 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 expressed 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.