Abstract
Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.
Highlights
Obesity is a complex multifactorial disease, with an incidence that has reached epidemic proportions
Adipocyte-specific proteins and mRNAs, such as adiponectin, leptin, fatty acid–binding protein 4 (FABP4), and PPARγ, were detected in both 3T3-L1 cells (Figure 1, E and G) and subcutaneous AT (SAT) (Figure 1, F and H) and, in lower amount, in their respective Extracellular vesicles (EVs), except PPARγ, which was absent in SAT-EVs
We show that EVs from 3T3-L1 adipocytes increase survival and proliferation, reduce apoptosis, and positively influence glucose-stimulated insulin secretion (GSIS) in INS-1E β cells and human pancreatic islets, both those untreated or exposed to diabetogenic stimuli
Summary
Obesity is a complex multifactorial disease, with an incidence that has reached epidemic proportions. Features of obesity-induced metabolic and inflammatory diseases include accumulation of ectopic fat in key insulin-sensitive organs, inflammation of white adipose tissue (AT), and infiltration of proinflammatory macrophages, all contributing to the development of insulin resistance, type 2 diabetes (T2D), cardiovascular and neurodegenerative diseases, and cancer [1].. AT is a complex and dynamic endocrine organ and a master regulator of whole-body homeostasis through release of adipokines, lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), which act on metabolic tissues to regulate lipid and glucose homeostasis. EVs are membrane-bound particles released from all types of cells and important mediators of intercellular communication among different organs and tissues. They deliver proteins, mRNAs, and noncoding RNAs, such as miRNAs, to recipient cells, thereby modulating their phenotype. The nature of their bioactive cargo is heavily dependent on the cell of origin, its physiopathological state, and the stimulus for release [8, 9]
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