Abstract
<title>Abstract</title> <p>Tanycytes are specialized glial cells lining the third ventricle that sense metabolic cues and contribute to hypothalamic regulation of energy balance. Although their role in nutrient sensing is well established, their contribution to hypothalamic immune regulation remains unclear. Here, we identify tanycytes as key immunomodulatory cells that control thermoregulation by modulating microglial state in the hypothalamus. We show that tanycytes release the pro-resolving immune mediator Annexin A1 (ANXA1) via extracellular vesicles in a nutrient-dependent manner. Tanycyte-derived ANXA1 then modulates microglial morphology, phagocytic activity, and cytokine profiles, thereby influencing thermoregulatory responses. Notably, disruption of tanycytic ANXA1 signaling induces microglial activation and hyperthermia, whereas microglial depletion rescues temperature homeostasis, establishing microglia as essential mediators of this pathway. Together, our findings uncover an immune function for tanycytes and define a tanycyte-microglia axis that links metabolic sensing to hypothalamic thermoregulation.</p>