Type 2 diabetes, atherosclerosis, non-alcoholic steatohepatitis… Therapeutic approaches able to limit obesity-related comorbidities are still cruelly lacking in medicine. Extracellular vesicles are starting to emerge as major effectors in their early mechanisms. These could represent predictive biomarkers for cardiovascular complications of obesity, or even targets for their prevention.
Extracellular vesicles (EVs) are nanovesicles created from the cell membrane of numerous cells. These are found in the extracellular environment and in several types of body fluid. Long considered to transport cell waste, these units were recently described as being capable of transferring biological contents from one cell to another. This "shuttle" role has since been examined in numerous oncology and cardiology studies. It has, moreover, attracted growing interest in the field of obesity.
Hence, a team from Anjou, supervised by Soazig Le Lay*, has long been focusing on the role of EVs in obesity-related metabolic disorders. "Adipose tissue is not only a lipid storage reserve: it is also a real endocrine organ which secretes numerous substances, adipocytokines. Their secretion is considerably modified in overweight individuals, and contributes to the development of obesity-related metabolic disorders. It was interesting to determine whether EVs contributed to their secretion, transport and, consequently, their activity".
MIF, a pro-inflammatory passenger
The team therefore took a blood sample from approximately thirty subjects suffering from a metabolic disorder (originating from the Numevox cohort - Angers University Hospital) and from twenty or so healthy subjects, each classed according to their body mass index (BMI). The researchers assayed the different types of circulating EVs in the plasma, namely exosomes and microvesicles which are the most abundant: "The concentration of these two populations was seen to increase with BMI" Soazig Le Lay reports. They then analyzed different plasma molecules involved in inflammation before and after eliminating the EVs from the blood samples. "This step showed that, although most of these compounds circulate freely in the blood as their concentrations are equivalent before and after elimination of EVs, this is not the case for macrophage migration inhibitory factor (MIF): the concentration of this proinflammatory factor drops following elimination of microvesicles, indicating that it is predominantly transported to its site of action by these large EVs".
The final stage in the study involved examining the action mechanism of MIF after reaching the macrophages: "It was seen to act on its intracellular target after being internalized by the microvesicles. In the free state, it exerts its effects without penetrating the cells, activating a reaction cascade starting from the macrophage membrane, by interacting with specific receptors".
This specificity is of importance: the MIF intracellular action site could, in fact, constitute a therapeutic target, and inhibition thereof could limit the inflammatory phenomenon related to obesity. More generally, "microvesicles could also be used as shuttles allowing certain anti-inflammatory agents to act directly at intracellular level", explains the researcher. Furthermore, while this discovery is of interest in managing obesity, "it could also offer new prospects in research focusing on other chronic inflammatory diseases, particularly rheumatological disorders, in which the role of MIF has also been described".
*Inserm Unit 1063/University of Angers, Oxidative stress and metabolic diseases (SOPAM), Angers
Source : J Amosse et al. Phenotyping of circulating extracellular vesicles (EVs) in obesity identifies large EV as functional conveyors of Macrophage Migration Inhibitory Factor. Molecular Metabolism, online edition dated October 9, 2018. https://doi.org/10.1016/j.molmet.2018.10.001