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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Yuna Choi,
  • Min Woo Kim,
  • Gyeongyun Go,
  • Dongsheng Cai

摘要

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.