Metabolic regulation by tanycyte-derived extracellular vesicles through insulin precursor-mediated neuronal recognition and mTORC component delivery.

The hypothalamus regulates feeding and metabolic balance in response to metabolic cues. Here we report that extracellular vesicles (EVs) are secreted from the mediobasal hypothalamus in a diurnal manner that is influenced by daily feeding. Sox2-positive tanycytes have a critical role in maintaining the diurnal pattern of hypothalamic EV release. Inhibition of tanycyte EV release leads to a loss of feeding diurnality, weight control and blood glucose homoeostasis, whereas supplementation with tanycytic EVs confers metabolic benefits. We show that a subset of tanycytic EVs carries surface prepro-insulin (ppIns), which mediates recognition and uptake by insulin-receptor-positive hypothalamic neurons. These EVs are loaded with mTORC components, including Rictor in a low-phosphorylation state, and support hypothalamic neuronal signalling. Both ppIns and Rictor are important for the EV-mediated preservation of feeding rhythmicity and resistance to diet-induced metabolic dysfunction. Collectively, these findings identify tanycyte-derived EVs as regulators of feeding diurnality through insulin precursor-directed targeting and delivery of mTORC components to hypothalamic neurons.