Intermittent Fasting Alters Serum Exosomes in Middle-Aged Male Mice on Long-Term High-Fat Diet

Abstract

ObjectivesExtracellular vesicles (EVs), especially exosomes, have emerged as a critical regulator of intercellular and inter-organ communications. Dysregulation of exosome secretion and exosomal cargo composition has been associated with metabolic diseases. The objective of this study was to determine the effect of intermittent fasting (IF) on the size profile and cargoes of exosomes in diet-induced obesity. MethodsFemale and male mice (8–10 weeks old) were fed a high-fat diet (HFD) for 18 weeks prior to being placed either in an ad libitum feeding group (HFD-AL) or an IF feeding group (HFD-IF) for an additional 10 weeks. Mice on the normal chow ad libitum (NC-AL) for 28 weeks served as control. The IF group had food available for 10 hours and fasted for 14 hours daily. Serum EVs measured using Nanoparticle Tracking Analysis. ResultsHFD-AL mice had an increasing trend in mean diameter of serum EVs by 24 nm (P = 0.30) compared to the NC-AL mice. The IF caused a significant decrease in mean diameter of serum EVs by 47.9 nm (P < 0.03) when compared to the HFD-AL mice. However, neither HFD nor IF altered the overall particle amount per mL of serum when compared to NC-AL. The HFD-AL mice had a decreasing trend in the population of small-size EVs but an increase in large-size EVs compared to the NC-AL mice. Mice on long-term HFD with IF had a significant increase in the total amount of small EVs/exosomes (50–100 nm in size) per unit of serum, but a decrease in the amount of large EVs (250–500 nm in size). Moreover, the mean population (particles/ml) of small EVs/exosomes were increased in the HFD-IF mice by an average of 38% (P < 0.03), whereas the population of large-size micro-vesicles (250–300 nm in size) were decreased by an average of 4% (P < 0.01) when compared to the HFD-AL mice. In addition to exosome alterations, the weekly weigh-in differences were significantly higher in the HFD-IF mice compared to the HFD-AL mice (P < 0.02). Lastly, we found that IF could prevent the whitening of brown adipose tissue (BAT) and liver micro-vesicular steatosis induced by a long-term HFD. ConclusionsIF significantly alters the profile of serum EVs, which may serve as an important mechanism for the metabolic benefits of IF such as preventing the whitening of BAT and liver micro-vesicular steatosis in obesity. Funding SourcesThis work was supported by the General Mills Foundation Chair in Genomics for Healthful Foods to X.C.