Exosomes are lipid bilayer encased extracellular vesicles with a diameter in the 50-200 nm range that are secreted by cells with contents of various bioactive molecules, such as mRNAs, miRNAs, proteins, or various lipids, including adipokines and cytokines (Ahn et al., 2022). In metabolic syndrome, various types of cells communicate with their surrounding by releasing exosomes into the extracellular spaces and, subsequently, into the bloodstream (Kita et al., 2019). Metabolic syndrome is linked to adipocyte dysfunction, macrophage infiltration, and low-grade inflammation, which probably contributes to insulin resistance, but also to the altered lipid composition and the dysregulation of secretion of exosomes which are attracting attention (Jafari et al., 2022; Wu and Ballantyne, 2020). In fact, it has been recently proposed that changes in exosomes can induce metabolic syndrome (Mei et al., 2022). Specifically, fatty exosomes, i.e., exosomes with lipid contents of high concentration and modified composition, may induce lipid accumulation and alter the metabolism in recipient cells (Van den Bossche, 2020). Below, we review recent studies that investigated fatty exosomes to determine the mechanisms by which they induced metabolic syndrome.

Zhang et al. (2021) performed a gene set enrichment analysis of the gene expression omnibus database and found that the expression of the damage-regulated autophagy modulator (DRAM) gene, a mediator of autophagy, was upregulated in nonalcoholic fatty liver (NAFLD) patients. The same study also identified DRAM as one of the genes linked to exosome secretion by increasing the expression of the RAB27B, VAMP3, and YKT6 genes in hepatocytes of patients with NAFLD. Moreover, in vitro study using human liver carcinoma cell line (HepG2) cells confirmed that palmitic acid (PA) increased DRAM expression and induced the accumulation of lipids through the recruitment of stomatin (STOM) to the lysosomes, which promoted lysosomal membrane permeabilization (LMP). Furthermore, silencing DRAM inhibited PA-induced exosome secretion from HepG2 cells, suggesting that knocking down of DRAM could prevent upregulation of exosome secretion in hepatocytes in response to fatty acids (FAs) by suppressing STOM-mediated LMP.

As mentioned above, the composition of lipids in exosomes along with exosome secretion reportedly changes in patients with metabolic disorders (Jafari et al., 2022; Wu and Ballantyne, 2020). In a study on the lipid composition in exosomes extracted from the feces of obese mice fed high fat diet (HFD), Kumar et al. (2021b) identified the phosphatidylethanolamine methyltransferase (PEMT)–mediated conversion of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) as a cause of inducing insulin resistance. Furthermore, their analysis of exosome characteristics revealed that the secretion and size of exosomes increased in HFD mice over those in lean mice, and the ratio of PC to PE in the exosomes was elevated by a PEMT-dependent manner. Surprisingly, fecal CD63+A33+ exosomes isolated from HFD mice were orally administered to lean mice and they induced insulin resistance and glucose intolerance, as well as raised their plasma concentration of free FA, suggesting that the fatty exosome of HFD mice promoted metabolic disorder. A related finding is that HFD-induced transcriptional activity of aryl hydrocarbon receptor (AhR), which is related to insulin resistance, and targets AhR signaling to prevent HFD-induced insulin resistance (Kumar et al., 2021a; Roh et al., 2015). Absorption of exosomes derived from HFD mice or supplementation of PC by liver macrophages promoted macrophage activation and the subsequent production of TNF-α and IL-6, thereby contributing to insulin resistance and hepatic glucose uptake inhibition. Consistent with the findings in the mouse study, human-derived exosomes from patients with type II diabetes were larger than in healthy subjects and had increased concentrations. The PC to PE ratio was remarkably increased in patients with diabetes. Together, these results suggest that AhR activation could be induced by exosomes secreted by diabetic or obese patients, as follows: PC binds directly to AhR in hepatocytes, which in turn induces dyslipidemia and liver dysfunction. These results add to the evidence that the increased FA contents and altered lipid composition (especially the PC fraction) of exosomes are critical for the complications, from diabetes and liver damage, caused by exosome uptake by hepatocytes.

Lipid droplet formation and metabolic shift to glycolysis is associated with immune reaction of dendritic cells (DC) (Choi et al., 2020). In a related study on metabolic shift of DC by FA-carrying exosomes, Yin et al. (2020) reported that delivering FAs via exosomes to DC induced the activation of peroxisome proliferator-activated receptor alpha (PPARα). FA-induced PPARα activation induced metabolic conversion, from glycolytic state to oxidative phosphorylation, thereby downregulating immune function of DC, but it could be restored through inhibiting FA oxidation and lipid droplet formation-related enzymes, such as long-chain acyl-CoA synthetases (ACSL) and carnitine palmitoyltransferase I (CPT1). Furthermore, inhibiting PPARα signaling alleviated the exosomal FA induced DC dysfunction and restored the anti-tumor immunotherapeutic efficacy of DC.

In addition to the above FA-mediated influence on surrounding cells, obesity induced changes in the biomolecule composition of exosomes could be a critical inducer of metabolic disorders. For example, Castano et al. (2018) showed that plasma exosomes in obese mice had an altered miRNA profile, containing miR-122, miR-192, miR-27a-3p, and miR-27b-3p at higher levels. When exosomes obtained from obese mice were given to lean mice, the recipient animals developed glucose intolerance and insulin resistance. The authors hypothesized that the overexpressed miRNA could inhibit the expression of PPARα in epididymal white adipose tissue and the reduction of PPARα could lead to the increase of delivery of FAs by defective FA oxidation. To determine if the candidate miRNAs had an effect causing glucose intolerance and insulin resistance, the authors transfected exosomes with either negative control or a cocktail of synthetic miRNA mimics, including miR-122, miR-192, miR-27a-3p, and miR-27b-3p, and injected the transfected exosomes into lean mice. The miRNA mimics-treated lean mice exhibited dyslipidemia with elevated FA plasma levels associated with reduced PPARα-dependent transcriptional activity. These results are significant because they suggest the possibility of cellular function dependent strategic targeting of PPARα for reversing the exosomal FA-mediated dysfunction of recipient cells.

As we discussed above, the secretion processes and the composition of secreted lipids and biomolecules, are altered in fatty exosomes. These altered exosomes can induce changes in the metabolic and transcriptional activity in the recipient cells. Since fatty exosomes were shown to have a pathophysiological impact on the surrounding tissues, many researchers are discovering a target for reversing effects of fatty exosomes and developing a strategy for priming exosomes in patients with metabolic disorders has become a priority in the field. Accordingly, elucidating the function of exosomes and their controllers in patients with metabolic disorders will be crucial for developing therapies for limiting the adverse effects of exosomes and associated metabolic complications.

This research was supported by National R&D Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2020R1A2B5B02002442) and BK21 Four Future Veterinary Medicine Leading Education & Research Center.

Y.H.J. and H.J.H. wrote the manuscript.

The authors have no potential conflicts of interest to disclose.