Adipocyte-derived extracellular vesicles increase insulin secretion through transport of insulinotropic protein cargo

Abstract

Adipocyte-derived extracellular vesicles (AdEVs) are membranous nanoparticles that convey communication from adipose tissue to other organs. Here, to delineate their role as messengers with glucoregulatory nature, we paired fluorescence AdEV-tracing and SILAC-labeling with (phospho)proteomics, and revealed that AdEVs transfer functional insulinotropic protein cargo into pancreatic β-cells. Upon transfer, AdEV proteins were subjects for phosphorylation, augmented insulinotropic GPCR/cAMP/PKA signaling by increasing total protein abundances and phosphosite dynamics, and ultimately enhanced 1st-phase glucose-stimulated insulin secretion (GSIS) in murine islets. Notably, insulinotropic effects were restricted to AdEVs isolated from obese and insulin resistant, but not lean mice, which was consistent with differential protein loads and AdEV luminal morphologies. Likewise, in vivo pre-treatment with AdEVs from obese but not lean mice amplified insulin secretion and glucose tolerance in mice. This data suggests that secreted AdEVs can inform pancreatic β-cells about insulin resistance in adipose tissue in order to amplify GSIS in times of increased insulin demand.

A Panorama of Extracellular Vesicle Applications: From Biomarker Detection to Therapeutics

“…EVs can directly or indirectly influence insulin resistance by promoting these proinflammatory responses, or dysregulating insulin signaling and down-regulating glucose transporter expression . Conversely, treatment with MSC-derived EVs can increase glucose tolerance in the T2DM animal model, and recent evidence suggests that adipocyte-derived EVs secreted during excess weight gain can promote glucose secreted insulin secretion to attenuate the development of insulin resistance . Thus, EV therapeutics may have the potential to attenuate or reverse the underlying mechanisms responsible for T1DM and T1DM.…”

Vitamin D Modulates Lipid Composition of Adipocyte‐Derived Extracellular Vesicles Under Inflammatory Conditions

“…[17][18][19][20][21] In this context, several studies have shown that the proteins contained in AdEVs, as well as miRNAs, can be transferred to target cells to modulate their activity. [22][23][24] For example, EVs released by adipocytes of mice under high fat diet (HFD) modulate insulin metabolism in target cells through their proteinaceous cargo. [24] In addition, AdEVs also modulate macrophage polarization using miRNAs.…”

“…[22][23][24] For example, EVs released by adipocytes of mice under high fat diet (HFD) modulate insulin metabolism in target cells through their proteinaceous cargo. [24] In addition, AdEVs also modulate macrophage polarization using miRNAs. [25,26] Recent studies support the idea that AdEVs lipids may also play a role in energy homeostasis and the development of obesity.…”

“…[ 22–24 ] For example, EVs released by adipocytes of mice under high fat diet (HFD) modulate insulin metabolism in target cells through their proteinaceous cargo. [ 24 ] In addition, AdEVs also modulate macrophage polarization using miRNAs. [ 25,26 ]…”

Precise Identification and Profiling of Surface Proteins of Ultra Rare Tumor Specific Extracellular Vesicle with Dynamic Quantitative Plasmonic Imaging

“…Actively shed by cells, EVs carry molecular components (proteins, nucleic acids, and other metabolites) of parental cells . Present in most body fluids, EVs participate in cell–cell communications, , immune response, and cancer metastasis. , Tumor-derived EVs (tEVs) can serve as a class of biomarkers for cancer diagnosis. Profiling the type and expression level of surface proteins of cancer-related EVs enables identifying cancer origins − and classifying cancer types. − Accurate detection of tEVs is still challenging.…”