Astrocyte-derived extracellular vesicles regulate proopiomelanocortin neurons and modify food intake and glucose metabolism

Background Astrocytes actively regulate hypothalamic circuits involved in energy balance, yet the mechanisms are not completely understood. Here we analyzed whether extracellular vesicles (EVs) released by hypothalamic astrocytes carry nutritionally sensitive signals that modulate metabolism, focusing on the potential role of proopiomelanocortin (POMC) neurons in this response and whether miRNAs carried in these EVs are involved.Methods EVs were isolated from primary hypothalamic astrocyte cultures exposed to palmitic acid (PA), oleic acid, or vehicle and their effects assessed in vitro on proopiomelanocortin (POMC) neurons and in vivo. Changes in miRNA content in these EVs in response to PA were determined by miRNAseq and the effects of selected miRNAs on POMC neurons were tested.Results EVs were internalized by POMC neurons in vitro and increased Pomc expression. When infused into the lateral ventricle or directly into the arcuate nucleus, astrocytic EVs were internalized by POMC neurons, as well as other cells, and altered mitochondrial density and mitochondria-endoplasmic reticulum interactions in POMC neurons, food intake, eating patterns and glucose metabolism in male mice. All in vivo and in vitro responses varied depending on the previous fatty acid (FA) environment of the EV-releasing astrocytes. Indeed, the miRNA content of astrocytic EVs was modified by exposure to PA, and this response differed between EVs released from astrocytes from male or female mice.Conclusion These findings indicate that astrocyte-derived EVs act as metabolic messengers by transmitting nutrient-specific information to hypothalamic neurons, influencing energy homeostasis through structural and functional remodeling.