From Metabolic Sensing to Intercellular Signaling: The Emerging Biology of Tanykines

Hypothalamic tanycytes have traditionally been viewed as metabolic sensors, structural components of hypothalamic barriers, and transporters of circulating signals. However, accumulating evidence indicates that they also translate metabolic, hormonal, and inflammatory inputs into bioactive signals that coordinate communication with neurons, glia, blood vessels, and cerebrospinal fluid. Here, we introduce the term tanykines to describe bioactive molecules whose extracellular availability depends on their regulated generation, release, processing, or bioactivation by tanycytes and that modify tanycyte function or other target cells. We propose a mechanism-based taxonomy comprising: (i) primary tanykines, directly generated and released by tanycytes, including ATP, lactate, β-hydroxybutyrate, prostaglandin E₂, and VEGF-A; (ii) secondary processed tanykines, generated extracellularly from a primary tanykine, exemplified by ATP-derived adenosine; and (iii) bioactivated tanykines, produced through tanycyte-dependent transformation of a transported precursor, exemplified by T4-to-T3 conversion. We further distinguish established, probable, and candidate or disputed tanykines according to tanycytic origin, regulated extracellular availability, target-cell identity, mechanism of action, and physiological causality. This framework separates tanykines from molecules merely sensed, transported, or expressed by tanycytes and reframes these cells as context-dependent signal generators coordinating metabolic and neuroendocrine homeostasis.