Fatty Acids Modify the MicroRNA Content of Exosomes Released by Hypothalamic Astrocytes and the Response of POMC Neurons to These Exosomes

Abstract

It is now clear that hypothalamic astrocytes participate in maintaining metabolic homeostasis. Both nutrients and metabolic hormones can directly impact on these glial cells to modify their release of gliotransmitters, metabolic factors, growth factors, etc, as well as their physical interaction with neighboring neurons. Another mechanism by which astrocytes could communicate with neurons is through their release of exosomes. We have previously shown (by RNAseq analysis) that exposure to palmitic acid (PA) dramatically modifies the miRNA content of exosomes released by hypothalamic astrocytes. Here our objectives were: 1) To determine if the miRNA changes in hypothalamic astrocyte-derived exosomes in response to oleic acid (OA) differ from those seen in response to PA and 2) Analyze the response of POMC neurons to exosomes derived from astrocytes exposed to either PA or OA. Primary hypothalamic astrocyte cultures were treated with PA (0.5 mM), OA (0.5 mM) or vehicle (V) for 24 hours. Exosomes were purified from the media and used for miRNA analysis and to treat a POMC neuronal cell line (mHypoA-POMC/GFP-1). Both OA and PA modified miRNA levels in exosomes compared to those detected in V exosomes, but these modifications differed between the two fatty acids. Furthermore, the response of POMC neurons to exosomes from vehicle (E-V), OA (E-OA) and PA (E-PA) treated astrocytes for 24 hours differed significantly. The expression of POMC mRNA was significantly decreased in response to E-V and increased in response to both E-OA and E-PA, although the increase in POMC mRNA was significantly greater in E-PA treated neurons. These results suggest that hypothalamic astrocytes can directly communicate with neurons involved in metabolic control through exosomes and that the messages contained within these exosomes are modulated by the nutrient environment.