Abstract
BackgroundIt is generally accepted that obesity can lead to metabolic disorders such as NAFLD and insulin resistance. However, the underlying mechanism has been poorly understood. Moreover, there is evidence to support the possible role of exosomes in the metabolic homeostasis regulation. Accordingly, we aimed to determine the effect of plasma circulating exosomes derived from obese and normal-weight women on insulin signaling and the secretion of hepatokines in human liver cells.MethodsPlasma exosomes isolated from four obese (O-Exo) women and four normal-weight (N-Exo) female candidates were characterized for size, zeta potential, and CD63 protein expression and were used for stimulation of HepG2 cells. Then, cell viability, as well as levels of glycogen and triglyceride (TG), were evaluated. Levels of fetuin-A and FGF21 were measured using the ELISA kit. Expression of glucose 6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) genes were determined using qRT-PCR. Western blot analysis was carried out to evaluating the phosphorylation of GSK3β.ResultsThe TG levels increased significantly in the cells treated with O-Exo than the control (vehicle) group (P = 0.005) and normal-weight group (P = 0.018). Levels of p-GSK3β and glycogen were significantly reduced by O-Exo in comparison with control (P = 0.002, P = 0.018, respectively). The mRNA expression of G6pase and PEPCK enzymes increased in the cells treated with O-Exo in comparison with the vehicle group (P = 0.017, P = 0.010, respectively). The levels of FGF21 in the supernatant of cells treated with O-Exo and N-Exo were significantly lower than the control group (P = 0.007).ConclusionIt appears that obesity-related circulating exosomes can impair insulin signaling pathways and associated components, increase intracellular TG content, and decrease FGF21 secretion in the hepatocytes.
Highlights
It is generally accepted that obesity can lead to metabolic disorders such as nonalcoholic fatty liver disease (NAFLD) and insulin resist‐ ance
In an attempt to unravel the underlying mechanism in which obesity could result in metabolic disorders such as NAFLD and insulin resistance, we aimed to determine the effect of circulating exosomes derived from obese and normal-weight women on insulin signaling and the secretion of hepatokines in human liver cells
The levels of FGF21 in HepG2 cells treated with obese exosome (O-Exo) and normalweight exosome (N-Exo) were significantly lower than the control group (P = 0.007), no significant differences were observed between normal-weight and obese groups (P = 0.835, Fig. 6b)
Summary
It is generally accepted that obesity can lead to metabolic disorders such as NAFLD and insulin resist‐ ance. We aimed to determine the effect of plasma circulating exosomes derived from obese and normal-weight women on insulin signaling and the secretion of hepatokines in human liver cells. EVs are released by different cells into body fluids such as plasma, cerebrospinal fluid, amniotic fluid, urine, aqueous humor and breast milk [7]. These spherical particles are stable in plasma [8] and play a key role in cell–cell communication as well as in biological functions and pleiotropic cellular [9,10,11]. The unique pattern of EVs and their cargo associated with obesity points toward possible role of EVs in the initiation and development of obesity and its metabolic complications
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