SEX DIFFERENCES IN THE ACUTE EFFECT OF ASTROCYTE-DERIVED EXTRACELLULAR VESICLES ON THE HYPOTHALAMIC RESPONSE TO HIGH FAT DIET INTAKE

The melanocortin system plays a central role in regulating energy balance. In addition to proopiomelanocortin (POMC) and Agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons, hypothalamic astrocytes actively participate in the control of food intake and metabolic homeostasis. We have previously shown that the content of the extracellular vesicles (EVs) released by hypothalamic astrocytes depends on the nutritional environment and sex. Here, we investigated whether these EVs affect the response to a high-fat diet (HFD) and whether this effect differs between the sexes. Primary hypothalamic astrocyte cultures from male and female mice were treated with oleic acid (OA, 0.5 mM) or vehicle for 24 h, after which the EVs were subsequently isolated. EVs were theninjected into the third ventricle of sex-matched adult mice 2 h before exposure to either a control diet (CD) or a HFD. Metabolic parameters and hypothalamic signaling were assessed 24 h later. In male mice, EVs derived from OA-treated astrocytes enhanced hypothalamic POMC expression under HFD conditions and increased p-STAT3 levels, suggesting potentiation of central leptin signaling. In contrast, EV-OA administration reduced body weight in female mice under CD, with no significant changes in POMC expression. Although an HFD increased circulating leptin levels in both sexes, no effect of EV treatment was found. These findings indicate that astrocyte-derived EVs acutely modulate the hypothalamic response to high fat intake in a sex-dependent manner suggesting a role for astrocytic EVs in enhancing central leptin sensitivity during exposure to a HFD in males.