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Reiss et al. Vessel Plus 2020;4:19 I http://dx.doi.org/10.20517/2574-1209.2020.04 Page 5 of 10
[77]
microparticles, which are larger in size but have similar composition and structure . It is difficult to
differentiate between these, but we have tried to confine this discussion as much as possible to exosomes.
The appearance of adipose-derived exosomes in the circulation has been documented in humans and
[79]
mice [78,79] . Adipocyte-derived exosomes may be considered a form of adipokine . In mice, adipose tissue is
[79]
an important source of circulating exosomal miRNAs in the obese state . The miRNA cargo of adipocyte-
derived exosomes may influence pathways involved in obesity and atherosclerosis [80-82] . Many miRNAs
have been shown to be differentially expressed in obese adipocyte exosomes, compared to lean adipocyte
[84]
[83]
exosomes in both mouse and human . Adipocyte-derived exosomes affect insulin resistance . Mice with
adipose tissue-specific knockout of Dicer, a large multi-domain ribonuclease enzyme responsible for the
biogenesis of miRNA, produce exosomes with low miRNA content and exhibit a form of lipodystrophy
marked by loss of WAT and whitening of BAT, as well as insulin resistance and dyslipidemia [79,85] . When
WAT from wild type mice is transplanted into Dicer knockouts, circulating miRNAs are restored and
glucose tolerance improves. Phenotypic change of cultured Dicer knockout brown preadipocytes to a
white adipocyte-like state was modulated by specific miRNAs miR362, miR365 and miR346. Exosomes
from adipose tissue macrophages of obese mice confer poor glucose tolerance and insulin resistance when
[86]
transferred to lean mice . A comparison of miRNA content of adipose tissue macrophage exosomes of
obese versus lean mice showed that miR155 was much more abundant in exosomes from obese mice and
this miRNA was shown to inhibit insulin signaling via downregulation of peroxisome proliferator-activated
receptor γ, a key regulator of adipocyte differentiation, glucose and lipid metabolism. Mice with knockout
of miR155 fed a high fat diet for 12 weeks exhibited less obesity-induced glucose intolerance and insulin
resistance, compared to wild type mice on a high fat diet. When wild type bone marrow was transplanted
into miR155 knockouts, glucose tolerance and insulin sensitivity were impaired with feeding of high fat
diet.

In mice, fibroblast growth factor (FGF)-21, a member of the FGF family with hormone-like actions that
regulates glycolipid metabolism, can be downregulated in liver by miRNA29b carried in exosomes [87,88] .
This effect of adipose tissue exosomes on FGF21 may be pro-atherogenic since FGF21 is considered
[89]
atheroprotective and improves the cardiometabolic profile in obesity and diabetes . Exosomes released
from adipose tissue of obese mice and injected into wild type mice induce activation of monocyte
differentiation to macrophages in the latter, causing inflammatory cytokine production through the toll-
[90]
like receptor (TLR) 4 pathway . Macrophages in atherosclerotic lesions express TLRs, including TLR4, a
type of pattern recognition receptor that is known to mediate inflammatory activation and TLR4-deficient
[91]
mice are protected from forming atherosclerotic lesions . Both pro-inflammatory/pro-atherosclerotic
(M1) and anti-inflammatory (M2) macrophage phenotypes were induced by adipose tissue exosomes. The
obese mouse adipose exosomes also caused insulin resistance in wild type mice. Mouse exosomes derived
from visceral adipose tissue cause foam cell formation in a mouse macrophage cell line, likely due to
inhibition of cholesterol efflux due to decreased expression of ATP binding cassette transporter (ABC) A1
and ABCG1, reverse cholesterol transport proteins that are needed to prevent lipid overload [92,93] . Adipocyte
[94]
exosomes affect macrophage function in humans as well .
Exosomes from adipose tissue may also influence vascular endothelial cells, but this is not as well-studied
as in macrophages. Vascular endothelial cells take up adipose tissue exosomes and it is postulated that
obese adipose tissue may secrete exosomes with pro-inflammatory cargo that could then activate the
endothelium [95-97] . Confirmation of the interaction of adipocyte exosomes and vascular endothelium awaits
further study.

Pericytes are pluripotent contractile cells embedded in the basal membrane surrounding endothelial
cells that directly interact with endothelium, and are increasingly recognized for their involvement in
atherosclerosis [98,99] . At this time, there is no data on adipocyte exosome effect on pericytes or pericyte-