Exosomes from Short-Term High-Fat or High-Sucrose Fed Mice Induce Hepatic Steatosis through Different Pathways

Obesity and other closely associated diseases, such as metabolic-associated fatty liver disease (MAFLD) and type 2 diabetes, give rise to a common biometric and metabolic phenotype resulting from a different etiopathogenesis. To characterize the first stages of metabolic dysfunction induced by either obesity or hepatic steatosis, we compared two animal models of short-term feeding with either high-fat (HFD) or high-sucrose (SAC) diets. Using transcriptomic, metabolic, and calorimetric analyses, we determined that a short-term HFD leads to obesity and then hepatic steatosis through lipid storage, whereas SAC increases gluconeogenesis and de novo lipogenesis, resulting in hepatic steatosis followed later by obesity. Plasma exosomal miRNA profiles differed between HFD and SAC mice, and the injection of exosomes from HFD or SAC mice reproduced some transcriptomic and metabolic features of the donor mice. Finally, we exploited our data to identify circulating miR-22-3p as a candidate biomarker for MAFLD patient stratification. In conclusion, dietary challenges affecting adipose or hepatic metabolism regulate the abundance of exosomal miRNAs in plasma, which in turn modulate gene expression, helping the organism to adapt.