Circulating adipocyte-derived extracellular vesicles are novel markers of metabolic stress

Abstract

We recently reported that stressed adipocytes release extracellular vesicles (EVs) that act as “find me” signals to promote macrophage migration and activation. In this study we performed a comprehensive characterization of stressed adipocyte-derived EVs, assessing their antigenic composition, lipidomics, and RNA profiles. Perilipin A was identified as one of the adipose-specific proteins and studied as a potential novel biomarker to detect adipocyte-derived EVs in circulation. Circulating EVs were significantly increased in mice with diet-induced obesity (DIO) and in obese humans with Metabolic Syndrome compared to lean controls. This increase was associated with decreased glucose tolerance in the DIO mice and metabolic dysfunction, elevated insulin and homeostatic model assessment of insulin resistance (HOMA-IR), in the obese humans. EVs from both DIO mice and obese humans were enriched in perilipin A, a central gatekeeper of the adipocyte lipid storehouse and a marker of adipocyte differentiation. In obese humans, circulating levels of EVs enriched in perilipin A were dynamic, decreasing 35% (p<0.05) after a 3-month reduced calorie diet intervention. This translational study provides an extensive characterization of adipocyte-derived EVs. The findings identify perilipin A as a novel biomarker of circulating EVs of adipocyte origin and support the development of circulating perilipin A-positive EVs as indicators of adipose tissue health.

miR-450a-5p within rat adipose tissue exosome-like vesicles promotes adipogenic differentiation by targeting WISP2

“…miR-93-5p and miR-203-3p) had been reported to negatively regulate osteogenesis (Table S3) (Kennell et al, 2008;Hamam et al, 2014;Yang et al, 2012;. Eguchi et al also analyzed the miRNAs in adipocytes derived from EVs and detected several adipogenic miRNAs (including miR-148a-3p, miR-181a-5p, miR30a-5p, miR-125b-5p) (Eguchi et al, 2016), which is consistent with our results (Table S3).…”

“…Inhibition of miR-450a-5p does not arrest Exo-AT-mediated adipogenesis completely. Eguchi et al performed a comprehensive protein content characterization of EVs derived from stressed adipocytes using tandem mass spectroscopy (LC-MS/MS) and found that the functions of proteins in EVs were mainly involved in translation, carbohydrate and lipid metabolism, cytoskeleton, extracellular matrix, ribonucleoproteins and nucleosomes (Eguchi et al, 2016). Connolly et al have reported that EVs from adipocytes are enriched in markers of adipogenesis (such as PREF-1, also known as DLK1, and PPARγ).…”

Extracellular Vesicles from Hypoxic Adipocytes and Obese Subjects Reduce Insulin‐Stimulated Glucose Uptake

“…Previous reports found that obesity leads to an increase in EV release in rodent animal models . However, we did not detect any differences in the concentration of circulating EVs found in subjects with obesity (not shown).…”

“…[24] Previous reports found that obesity leads to an increase in EV release in rodent animal models. [15,25] However, we did not detect any differences in the concentration of circulating EVs found in subjects with obesity (not shown). However, in agreement with [26] the model of hypoxic 3T3-L1 adipocytes produced more EVs compared to normoxic cells, a phenomena seen in other hypoxic cell types.…”

A Combination of Proteomic Approaches Identifies A Panel of Circulating Extracellular Vesicle Proteins Related to the Risk of Suffering Cardiovascular Disease in Obese Patients

“…It is noteworthy that increased levels of different EVs subpopulations are well associated with metabolic syndrome and obesity . Recent studies demonstrate that obese patients show higher levels of plasma EVs compared with normal weight healthy individuals . Furthermore, chronic inflammation, metabolic stress, and prothrombotic state of obese individuals may be factors triggering the release of EVs or EVs‐related proteins released from circulating cells .…”