Abstract
Extracellular vesicles (EVs) have recently emerged as a relevant way of cell to cell communication, and its analysis has become an indirect approach to assess the cell/tissue of origin status. However, the knowledge about their nature and role on metabolic diseases is still very scarce. We have established an insulin resistant (IR) and two lipid (palmitic/oleic) hypertrophied adipocyte cell models to isolate EVs to perform a protein cargo qualitative and quantitative Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH) analysis by mass spectrometry. Our results show a high proportion of obesity and IR-related proteins in pathological EVs; thus, we propose a panel of potential obese adipose tissue EV-biomarkers. Among those, lipid hypertrophied vesicles are characterized by ceruloplasmin, mimecan, and perilipin 1 adipokines, and those from the IR by the striking presence of the adiposity and IR related transforming growth factor-beta-induced protein ig-h3 (TFGBI). Interestingly, functional assays show that IR and hypertrophied adipocytes induce differentiation/hypertrophy and IR in healthy adipocytes through secreted EVs. Finally, we demonstrate that lipid atrophied adipocytes shed EVs promote macrophage inflammation by stimulating IL-6 and TNFα expression. Thus, we conclude that pathological adipocytes release vesicles containing representative protein cargo of the cell of origin that are able to induce metabolic alterations on healthy cells probably exacerbating the disease once established.
Highlights
Extracellular vesicles (EVs), and exosomes in particular, have recently arisen as a very specialized mechanism for cell to cell communication at a local and distant level [1]
Confirming the SWATH analysis, we show a striking elevation of transforming growth factor-beta-induced protein ig-h3 (TFGBI) exclusively on those vesicles liberated by insulin resistant adipocytes (HGHI) compared to control, and especially in relation to hypertrophied vesicles (Figure 3G,I)
We showed the elevated presence of Glut4 on hypertrophied vesicles; we might speculate that secretion of this glucose transporter through EVs might be a way of participating in insulin resistance; this protein was not identified in those vesicles from the high insulin (HGHI) cell model, this will require further analysis
Summary
Extracellular vesicles (EVs), and exosomes in particular, have recently arisen as a very specialized mechanism for cell to cell communication at a local and distant level [1]. Depending on the size and biogenesis, EVs comprise: microvesicles (100 nm–1 μm) originated by blebbing of the plasma membrane, exosomes (30–100 nm) assembled in multivesicular endosomes (MVEs) that are secreted by exocytosis, and larger vesicles (50–5000 nm) that include apoptotic bodies released by cells prior to apoptosis [3,4]. Since the molecular cargo of the exosomes mirrors physiological and pathophysiological changes of the cell or tissue of origin, the exosomes have arisen as potential biomarkers for the diagnosis of the disease [7]. These characteristics have generated great expectations around EVs and exosomes in particular, making the study of these vesicles a hot topic in many fields of research
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