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Bovine Milk Exosome and miRNA-2478 Enhances Insulin Sensitivity by Upregulating Insulin Receptor and Promotes Glycogen Synthesis in HepG2 Cells

Background: Milk and milk products are a sort of mandatory component of diet world-wide. Milk exosome and its bioactive content especially miRNA has been linked with several metabolic regulatory pathways and diseases. However, there is lack of convincing experimental validation. Recently, we have profiled cow milk exosomal miRNAs and in silico analysis identified insulin receptor (INSR) as potential target of miRNA-2478 which one of the candidate miRNA is encapsulated in cow milk exosomes. Down-regulation of insulin receptor (INSR) in peripheral tissues including liver results in the development of pathogenesis of Type II diabetes. However, role of miRNA-2478 in regulation of insulin signaling has not been studied so far. The main aim of the study was to decipher the role of milk exosomal miR-2478 on its target insulin receptor in HepG2 cells. 
 
Methods: The effect of miR-2478 mimic on INSR mRNA and protein expression, glycogen content and enrichment of RNA polymerase II at insulin gene promoter in HepG2 cells was analysed. 
 
Findings: Results of the current study showed that there was increased expression of insulin receptor gene at both mRNA and protein level with increased abundance of bta-miR-2478 in HepG2 cells. Similarly, glycogen content was also found to be increased in bta-miR-2478 transfected cells. Results of ChIP assay also showed enrichment of RNA polymerase on insulin receptor promoter in miR-2478 transfected cells as compared to control. 
 
Interpretation: In conclusion, bovine milk exosomes and miR-2478 enhanced insulin sensitivity through increased expression of insulin receptor and glycogen synthesis in HepG2 cells. 
 
Funding Statement: None. 
 
Declaration of Interests: All authors declare they have no conflict of interest. 
 
Ethics Approval Statement: Cow (Sahiwal) milk was collected from the healthy and early lactating animals of ICAR-National Dairy Research Institute, Karnal as per the Institute Animal Ethics Guidelines.