Tanycyte-derived lactate activates astrocytic HCAR1 to modulate glutamatergic signaling and POMC neuron excitability

Astrocytes and tanycytes play essential roles in hypothalamic metabolic sensing, yet how glial-glial communication translates metabolic cues into neuronal activity remains poorly understood. We previously demonstrated that tanycytes release lactate and that this metabolite modulates the activity of arcuate pro-opiomelanocortin (POMC) neurons. Here, we identify the lactate receptor, HCAR1, as a key mediator of tanycytes-astrocyte-neuron signaling in the arcuate nucleus. We show that HCAR1 is highly expressed in hypothalamic astrocytes and present in a subset of NPY neurons. In primary hypothalamic cultures, L-lactate, the endogenous agonist of HCAR1, elicited increases in astrocytic cytosolic Ca2+ and stimulated glutamate release; both effects were abolished by HCAR1 silencing using siRNA. In parallel, L-lactate and 3Cl-HBA increased connexin hemichannel activity, and hemichannel inhibition reduced glutamate release. Consistent with these in vitro observations, focal intracellular glucose delivery to a single tanycyte in acute hypothalamic slices triggered rapid Ca2+ elevations in neighboring astrocytes, revealing functional glial-glial communication in situ. Importantly, activation of astrocytic HCAR1 enhanced NMDA receptor-dependent slow inward currents and excitability in POMC neurons, an effect reproduced by pharmacological HCAR1 agonists and abolished by astrocytic HCAR1 silencing. Together, these findings uncover a glial metabolic relay in which tanycyte-derived lactate activates astrocytic HCAR1, promotes glutamate release, and enhances POMC neuron excitability, providing a mechanistic link between cerebrospinal fluid-borne glucose fluctuations and hypothalamic control of feeding.