There are well-documented studies that lipid accumulation, inflammation, and defective insulin signaling have a central role in the pathogenesis of NAFLD [22]. Although there is ample evidence on the close association between obesity and impaired insulin signaling, to the best of our knowledge, no study has investigated the effects of plasma circulating exosomes derived from obese and normal-weight females on insulin signaling pathways (such as glycogenesis and gluconeogenesis), lipogenesis and the secretion of hepatokines in human liver cells in vitro. This evidence concerns the gene INS and metabolic dysfunction-associated steatotic liver disease.