Adipose Tissue as a Major Launch Spot for Circulating Extracellular Vesicle-Carried MicroRNAs Coordinating Tissue and Systemic Metabolism

Ci a ion: Diez-Roda, P.;
Pe ez-Na a o, E.; Ga cia-Ma in, R.
Adipose Tissue as a Majo Launch
Spo o Ci cula ing Ex acellula
Vesicle-Ca ied Mic oRNAs
Coo dina ing Tissue and Sys emic
Me abolism. In . J. Mol. Sci. 2024,25,
13488. h ps://doi.o g/10.3390/
ijms252413488
Academic Edi o : Jung-Hyun Lee
Recei ed: 25 No embe 2024
Re ised: 7 Decembe 2024
Accep ed: 11 Decembe 2024
Published: 17 Decembe 2024
Copy igh : © 2024 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
Re iew
Adipose Tissue as a Majo Launch Spo o Ci cula ing
Ex acellula Vesicle-Ca ied Mic oRNAs Coo dina ing Tissue
and Sys emic Me abolism
Paula Diez-Roda †, Elena Pe ez-Na a o †and Ruben Ga cia-Ma in *
Depa men o Immunology and Oncology, Cen o Nacional de Bio ecnología (CNB)-CSIC, 28049 Mad id, Spain;
[email p o ec ed] (P.D.-R.); elena.pe [email p o ec ed] (E.P.-N.)
*Co espondence: [email p o ec ed]
†These au ho s con ibu ed equally o his wo k.
Abs ac : Ci cula ing mic oRNAs (miRNAs), especially anspo ed by ex acellula esicles (EVs),
ha e ecen ly eme ged as majo new pa icipan s in in e o gan communica ion, playing an impo -
an ole in he me abolic coo dina ion o ou issues. Among hese, adipose issue displays an
ex ao dina y abili y o sec e e a as lis o EV-ca ied miRNAs in o he ci cula ion, ep esen ing
new ho mone-like ac o s. Despi e he limi a ions o cu en me hodologies o he unequi ocal
iden i ica ion o he o igin and des ina ion o EV-ca ied miRNAs
in i o
, ecen in es iga ions
clea ly suppo he impo an egula o y ole o adipose-de i ed ci cula ing miRNAs in shaping he
me abolism and unc ion o o he issues including he li e , muscle, endoc ine panc eas, ca dio as-
cula sys em, gas oin es inal ac , and b ain. He e, we e iew he mos ecen indings ega ding
miRNAs anspo ed by adipose-de i ed EVs (AdEVs) a ge ing o he majo me abolic o gans and
he implica ions o his dialog o physiology and pa hology. We also e iew he e he cu en and
po en ial u u e diagnos ic and he apeu ic applica ions o AdEV-ca ied miRNAs.
Keywo ds: adipose issue; mic oRNAs; ex acellula esicles; exosomes; me abolism; in e cellula
communica ion
1. In oduc ion
Adipose issue was adi ionally obse ed as a long- e m ene gy s o age o gan, bu i
is now ecognized as a issue playing a majo ole in he in eg a ion o sys emic me abolism.
This is media ed, a leas in pa , by i s abili y o sec e e nume ous p o ein ac o s, named
adipokines [
1
]. These p o eins ha e di e se egula o y unc ions bo h locally and in o he
issues on insulin sensi i i y, in lamma ion, ene gy balance, and many o he p ocesses [
1
,
2
].
Howe e , ecen esea ch has g ea ly expanded he epe oi e o non-p o ein molecules ha
pa icipa e in in e cellula communica ion, ep esen ing no el adipokine-like messenge s.
These include se e al lipids ( e med lipokines [
3
]) and RNAs, especially miRNAs. miRNAs
a e sho non-coding single-s anded RNAs p oduced by i ually all cells in ou body ha
play a pe asi e ole in pos ansc ip ional egula ion, es ima ed o con ol he exp ession
o up o 60% o ou genes [
4
]. T ansc ibed as double-s anded p i-miRNAs, hey a e la e
p ocessed by D osha and Dice o gene a e a miRNA duplex, om which one o he wo
s ands cons i u e he ma u e miRNAs ha in e ac wi h A gonau e (AGO) [
4
]. AGO cons i-
u es an in eg al pa o he miRNA-Induced Silencing Complex (RISC) ha ul ima ely leads
o he ep ession o mRNA a ge s mainly by wo complemen a y molecula mechanisms:
mRNA des abiliza ion/decay and ansla ional ep ession. B ie ly, once AGO is loaded
wi h a single-s anded miRNA, i scans he ansc ip ome, sea ching o complemen a y
mRNA a ge s. In mos cases, miRNA only pai s h ough i s i s 2–8 nucleo ides om
he 5
′
end (called he seed egion) wi h he mRNA a ge , o en wi hin he 3
′
-un ansla ed
egion (3
′
UTR) [
4
,
5
]. This leads o he ec ui men o he adap o p o ein TNRC6, he
In . J. Mol. Sci. 2024,25, 13488. h ps://doi.o g/10.3390/ijms252413488 h ps://www.mdpi.com/jou nal/ijms
In . J. Mol. Sci. 2024,25, 13488 2 o 23
polyA-binding p o ein PABPC, and se e al deadenylases (e.g., CNOT, PAN2-PAN3, e c.),
which sho en he polyA- ail o he a ge mRNA [
6
,
7
]. In addi ion, ec ui men o DDX6
and 4E-T pe mi s he cap-binding p o ein 4EHP o displace eIF4E om he 5
′
cap, leading
o mRNA decapping. Bo h p ocesses (3
′
polyA deadenyla ion and 5
′
decapping) esul in
mRNA des abiliza ion and decay h ough he ac ion o exonucleases [
6
,
7
]. In addi ion, he
dissocia ion o eIF4E om he cap s uc u e impedes ibosomal assembly and scanning o
he a ge mRNA, hus leading o ansla ional ep ession [
6
,
7
]. Mo eo e , in a e cases
in mammals whe e miRNA and a ge mRNA ex ensi ely pai beyond he seed egion,
AGO (mainly AGO2) di ec ly slices he mRNA a ge , esul ing in s onge ep ession [
4
].
The la e is he p edominan mode o ac ion o small in e e ing RNAs (siRNAs). siRNAs
a e sho RNAs simila in size o miRNAs ha , by di ec ly inco po a ing in o he RISC
complex, also lead o he inhibi ion o a ge genes. Howe e , siRNAs o en a ge a unique
gene by ull complemen a i y whe eas miRNAs ypically exe global inhibi o y e ec s on
a gi en biological p ocess by a ge ing mul iple genes wi hin he same o ela ed pa hway.
Due o he abundance o RNases in blood and o he ex acellula bio luids [
8
], he
possibili y o RNAs (including miRNAs) pa icipa ing in long-dis ance in e cellula com-
munica ion was ne e deemed as possible un il he disco e y o ex acellula miRNA
ca ie s. The i s iden i ica ions o miRNAs as no el pa icipan s in in e cellula communi-
ca ion we e made in he la e 2000s, when hey we e ound o be ca ied by ex acellula
esicles (EVs) and deli e ed o ecipien cells, leading o changes in cellula unc ion [
9
,
10
].
Since hen, o he ex acellula miRNA ca ie s besides EVs ha e been iden i ied such as
ci cula ing RNA-binding p o eins (RBPs), lipop o eins, and nanopa icles [
11
–
14
]. While
he e has been ex ensi e esea ch on EV-ca ied miRNAs in in e o gan communica ion, he
con ibu ion o hese o he miRNA ehicles has been ba ely s udied. Fo his eason, he
indings highligh ed he e e e o miRNAs anspo ed in EVs.
2. Classi ica ion o EVs
E e y euka yo ic cell is able o elease EVs o he ex acellula en i onmen . They
cons i u e he e ogenous popula ions o memb ane pa icles loaded wi h speci ic epe -
oi es o mac omolecules including p o eins, di e en RNA sub ypes (miRNAs, RNAs,
snoRNAs, snRNAs, and many o he s), lipids, me aboli es, and e en o ganelles such as
mi ochond ia [
15
–
17
]. F om he di e en subclasses o RNA, miRNAs a e among he mos
abundan ca goes, al hough he exac con ibu ion is echnically challenging o de e mine
due o biases a ising om he di e en p o iling me hods and om s iking di e gences
in he sec e o y pa e n among cellula models [
18
–
21
]. The a o emen ioned b oad and
po en egula o y unc ion o miRNAs has a ac ed much a en ion in ecen yea s, o
he poin whe e hey a e now commonly iewed as majo e ec o s o he in e cellula
communica ion unc ion media ed by EVs.
EVs can be subca ego ized in h ee main g oups based on hei size and o igin. Exo-
somes a e 50–200 nm in diame e and ha e he mos complex biogenesis, which s a s wi h
he o ma ion o endosomal in agina ions, he eby c ea ing mul i esicula bodies (MVB)
(Figu e 1). They la e use o he plasma memb ane o he elease o exosomes o he ex a-
cellula space. This highly in ica ed and egula ed p ocess implies he coo dina ed ac ion
o mul iple p o eins o he endosomal so ing complex equi ed o anspo (ESCRT), Rab
GTPases, cy oskele on, and lipids such as ce amide [
22
]. In con as , mic o esicles (also
named ec osomes) a e 100–1000 nm in diame e and de i e om di ec budding o he
plasma memb ane, in a p ocess ha sha es some s eps wi h he o ma ion o exosomes [
22
]
(Figu e 1). Apop o ic bodies a e la ge esicles (up o 5000 nm in diame e ) ha a e eleased
when cells unde go apop osis [
23
,
24
]. This classi ica ion is subjec o con inuous deba e as
eme ging mode n echnologies, such as asymme ic low ield- low ac iona ion (AF4),
ha e ecen ly allowed o dis inguish di e en subclasses o EVs wi hin hese majo g oups
such as la ge and smalle exosomes [
13
,
24
,
25
]. In addi ion, non-memb anous ex acellula
nanopa icles, such as exome es and supe me es (~35 and 28 nm in a e age, espec i ely),
ha e also been iden i ied in bio luids and cell supe na an s, al hough hei o igin and
In . J. Mol. Sci. 2024,25, 13488 3 o 23
abili y o ca y miRNAs is s ill unde deba e [
13
,
14
,
26
,
27
] (Figu e 1). The epe oi e o
non-memb anous ex acellula miRNA ca ie s also includes RNA-binding p o eins (RBPs)
and lipop o eins [
11
,
12
]. Al hough u he in es iga ion is de ini ely needed o be e de ine
hese new elemen s, a ailable da a indica e ha each o hese no el subca ego ies o EVs,
nanopa icles, RBPs, and lipop o eins a e en iched in pa icula subse s o ca goes and
pe o m dis inc biological unc ions [
11
–
14
,
28
]. Once eleased, EVs (and po en ially also
nanopa icles) can in e ac wi h he p oduce (au oc ine communica ion) o nea by cells
(pa ac ine), o a el h ough he ci cula ion and in e ac wi h dis an cells (endoc ine).
Despi e some cases o unspeci ic in e ac ion/up ake by usion wi h he plasma memb ane
o he ecipien cell ha e been epo ed, mos da a suppo ha his is a la gely cell- ype
dependen p ocess, which only occu s i he EV and a ge cell sha e he igh combina ion
o ligand and ecep o in hei su aces [
23
,
29
] (Figu e 1). This selec i e in e ac ion can
igge EV in e naliza ion in o endosomal compa men s h ough a ious mechanisms.
These include endocy osis (ei he dependen on cla h in, ca eolin, o lipid a -associa ed
lo illins), mic opinocy osis, and phagocy osis [
23
,
29
]. Once in endosomes, he EV ca go
can be ecycled, e-sec e ed, o escape o he cy osol whe e he miRNAs can be inco -
po a ed in o he miRNA signaling pa hway o he ecipien cell, leading o pheno ypic
changes [23,29,30] (Figu e 1).
In . J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 3 o 25
non-memb anous ex acellula nanopa icles, such as exome es and supe me es (~35 and
28 nm in a e age, espec i ely), ha e also been iden ified in biofluids and cell supe na-
an s, al hough hei o igin and abili y o ca y miRNAs is s ill unde deba e [13,14,26,27]
(Figu e 1). The epe oi e o non-memb anous ex acellula miRNA ca ie s also includes
RNA-binding p o eins (RBPs) and lipop o eins [11,12]. Al hough u he in es iga ion is
defini ely needed o be e define hese new elemen s, a ailable da a indica e ha each o
hese no el subca ego ies o EVs, nanopa icles, RBPs, and lipop o eins a e en iched in
pa icula subse s o ca goes and pe o m dis inc biological unc ions [11–14,28]. Once
eleased, EVs (and po en ially also nanopa icles) can in e ac wi h he p oduce (au o-
c ine communica ion) o nea by cells (pa ac ine), o a el h ough he ci cula ion and
in e ac wi h dis an cells (endoc ine). Despi e some cases o unspecific in e ac ion/up ake
by usion wi h he plasma memb ane o he ecipien cell ha e been epo ed, mos da a
suppo ha his is a la gely cell- ype dependen p ocess, which only occu s i he EV and
a ge cell sha e he igh combina ion o ligand and ecep o in hei su aces [23,29] (Fig-
u e 1). This selec i e in e ac ion can igge EV in e naliza ion in o endosomal compa -
men s h ough a ious mechanisms. These include endocy osis (ei he dependen on
cla h in, ca eolin, o lipid a -associa ed flo illins), mic opinocy osis, and phagocy osis
[23,29]. Once in endosomes, he EV ca go can be ecycled, e-sec e ed, o escape o he
cy osol whe e he miRNAs can be inco po a ed in o he miRNA signaling pa hway o he
ecipien cell, leading o pheno ypic changes [23,29,30] (Figu e 1).
Figu e 1. EV-ca ied miRNAs as new playe s in in e cellula communica ion. In dono cells, miR-
NAs a e loaded in o mul i esicula bodies (MVB) o he elease o exosomes, o in o plasma mem-
b ane-de i ed mic o esicles. Fo exosomes, some sho sequences named EXOmo i s p omo e hei
so ing in o o ming exosomes by in e ac ing wi h RNA-binding p o eins (RBP). Exosomes, mi-
c o esicles, and apop o ic bodies (no depic ed in he figu e) a e commonly e e ed as ex acellula
esicles (EVs). miRNAs a e also sec e ed h ough unclea mechanisms in o he ca ie s such as
RBPs, lipop o eins, and nanopa icles (exome es and supe me es). By a eling h ough he ci cu-
la ion, EVs can each dis an cells, whe e hey a e in e nalized by endocy osis and subsequen in-
co po a ion in o he ecipien ’s endosomal sys em, o o a much lesse ex en , h ough di ec mem-
b ane usion. In bo h cases, miRNAs a e able o each he cy osol o he ecipien cell and a e inco -
po a ed in o he miRNA signaling pa hway by binding o he RISC complex, ul ima ely leading o
he egula ion o he exp ession o mRNA a ge s in he ecipien cell.
Figu e 1. EV-ca ied miRNAs as new playe s in in e cellula communica ion. In dono cells, miRNAs
a e loaded in o mul i esicula bodies (MVB) o he elease o exosomes, o in o plasma memb ane-
de i ed mic o esicles. Fo exosomes, some sho sequences named EXOmo i s p omo e hei so ing
in o o ming exosomes by in e ac ing wi h RNA-binding p o eins (RBP). Exosomes, mic o esicles,
and apop o ic bodies (no depic ed in he igu e) a e commonly e e ed as ex acellula esicles (EVs).
miRNAs a e also sec e ed h ough unclea mechanisms in o he ca ie s such as RBPs, lipop o eins,
and nanopa icles (exome es and supe me es). By a eling h ough he ci cula ion, EVs can each
dis an cells, whe e hey a e in e nalized by endocy osis and subsequen inco po a ion in o he
ecipien ’s endosomal sys em, o o a much lesse ex en , h ough di ec memb ane usion. In bo h
cases, miRNAs a e able o each he cy osol o he ecipien cell and a e inco po a ed in o he miRNA
signaling pa hway by binding o he RISC complex, ul ima ely leading o he egula ion o he
exp ession o mRNA a ge s in he ecipien cell.
In . J. Mol. Sci. 2024,25, 13488 4 o 23
None o he cu en me hods o EV isola ion including ul acen i uga ion, size-
exclusion ch oma og aphy (SEC), o densi y-g adien cen i uga ion a e able o e icien ly
sepa a e exosomes om he smalles mic o esicles due o hei o e lapping size [
24
,
25
,
31
].
Fu he mo e, he e a e no speci ic ma ke s o each class o EV, as e en classical ex-
osomal ma ke s such as e aspanins CD9, CD63, and CD81 a e also p esen in mi-
c o esicles [
23
,
31
,
32
], hus p e en ing hei selec i e isola ion by using an ibody-based
immunoa ini y cap u e. As a consequence o hese echnical limi a ions, he e a e no
e icien me hodological app oaches ha p o ide a eliable isola ion and cha ac e iza ion o
he indi idual ca ego ies o EVs. Fo his eason, and al hough some publica ions e e o
exosomes o mic o esicles as he p edominan ex acellula pa icle p esen in hei isola es,
we will e e o he gene al e m EVs h oughou his e iew.
3. Adipose Tissue: Ex ao dina y Sec e o y Capaci y
Al hough ex acellula miRNAs a e po en ially in ol ed in he dialog among all
o gans in ou body, hey seem o be pa icula ly impo an o adipose issue-based com-
munica ion. This idea is suppo ed by ou ini ial obse a ion ha he dele ion o Dice
in adipocy es (ADice KO mice) is associa ed wi h a signi ican down egula ion o nea ly
wo- hi ds o he ci cula ing EV-ca ied miRNAs [
33
]. Simila esul s we e ob ained in
human immunode iciency i us-1 (VIH-1)-in ec ed pa ien s who de eloped lipodys ophy,
a common como bidi y associa ed wi h his pa hogen [
34
,
35
]. Adipose issue unde going
lipodys ophy upon HIV-1 in ec ion shows educed Dice exp ession, especially in he
do soce ical egion, h ough unclea mechanisms [
36
,
37
]. Al hough o a lesse ex en han
in ADice KO animals, lipodys ophy HIV-1 pa ien s also display a gene al down egula ion
in he exp ession o many ci cula ing EV-ca ied miRNAs [
34
]. These da a sugges ha a
la ge p opo ion o ci cula ing EV-ca ied miRNAs a e de i ed om adipose issue. O he
s udies om mul iple labo a o ies ha e con i med he ex ao dina y capaci y o adipocy es
o sec e e EVs, which inc eases e en u he in obesi y [
18
,
38
–
41
]. Al hough he e is no
expe imen al e idence
in i o
ye , a plausible explana ion is ha hese ex a ci cula ing
EVs in obese pa ien s and mice may p edominan ly de i e om expanded adipose issue,
al hough i is impo an o no e ha o he issues also espond o obesi y by changing hei
EV sec e ion a e and ca go con en [
42
,
43
]. Despi e he la ge body o e idence suppo -
ing he ex ao dina y capaci y o adipocy es o sec e e EVs, he molecula mechanisms
unde lying his phenomenon emain unknown. Simila ly, he exac molecula pa hways
esponsible o he di e en miRNA asso men s o adipose issue-de i ed EVs (AdEVs) in
pa hological condi ions such as obesi y ha e ba ely been in es iga ed. One such p ocess
could be obesi y-induced low-g ade ch onic in lamma ion, al hough many o he pa hways
ha a e dys egula ed in obesi y could also play a ole [44,45].
How miRNAs (and o he ca goes) end up in EVs ep esen s a ascina ing new a ea
o esea ch. The seminal s udies ha i s obse ed bioac i e miRNAs in EVs al eady
no ed ha ce ain subse s o miRNAs we e en iched o deple ed in hese esicles compa ed
o hei pa en al cells [
9
,
10
], sugges ing he exis ence o miRNA selec ion mechanisms.
This obse a ion has been u he con i med by a long lis o subsequen epo s [
46
–
54
].
Accumula i e esea ch has p o ided impo an insigh s in o he molecula mechanisms
ha de e mine which miRNAs a e so ed in EVs and hus may se e a messenge unc ion.
Some e anucleo ide sequences (commonly e e ed o as EXOmo i s) en iched in he
miRNAs ha end o be so ed in o esicles we e ini ially desc ibed in some pa icula
cell ypes [
49
,
51
,
53
], al hough o he mo i -independen mechanisms ha e been also de-
sc ibed [
48
,
54
]. Ou ecen mul icellula compa a i e analysis o EV and cellula miRNAs
e ealed ha each cell ype including adipocy es uses a pa icula subse o EXOmo i s o
so miRNAs in EVs [
18
]. While some EXOmo i s a e widely p esen in he EV-en iched
miRNAs eleased by mul iple cell ypes, o he s a e la gely cell- ype speci ic. In e es ingly,
he miRNAs ha a e selec i ely deple ed om EVs—and he e o e en iched in he cel-
lula body—also con ain small sequence mo i s ha we named CELLmo i s. Simila o
EXOmo i s, CELLmo i s can be ei he b oadly dis ibu ed ac oss di e en cell ypes o
In . J. Mol. Sci. 2024,25, 13488 5 o 23
cell- ype speci ic. To u he complica e he p ocess o miRNA selec ion o exclusion om
EVs, we iden i ied cases o mo i s ha beha e as an EXOmo i in one cell ype and as a
CELLmo i in ano he [
18
]. S ong expe imen al suppo o EXOmo i s and CELLmo i s
o egula e miRNA dis ibu ion comes om he ac ha adding o emo ing hese mo i s
om a gi en miRNA subs an ially changes i s EV e sus cellula des ina ion [
18
,
49
,
51
,
53
].
The mechanisms guiding he selec ion o EXOmo i -con aining miRNAs o he exclusion o
hose wi h CELLmo i s om EVs a e a om being unde s ood. A ailable da a sugges
ha hese p ocesses la gely ely on RBPs ha ac selec i ely in di e en EXOmo i s and
cell ypes (Figu e 1). Fo ins ance, in b own adipocy es, ALYREF and FUS pa icipa e in
he EV loading o CGGGAG-con aining miRNAs, he s onges EXOmo i ound in his
cell ype [
18
]. O he EXOmo i - eade RBPs include SYNCRIP, hnRNPA2/B1, and Lupus
La [
49
,
51
–
53
]. Howe e , in o ma ion on he iden i y o each mo i - eade RBP is lacking
o he as majo i y o iden i ied EXO and CELLmo i s. Simila ly, i s ill emains unclea
how he RBP binds o he miRNA and d i es i in o he o ming EV. The ac ha hese
miRNA-binding RBPs a e gene ally no ound wi hin he EV ca go [
50
] poin ha hey
may alloca e he miRNA in he o ming EV while hey emain in he cell. In e es ingly,
ecen da a ha e shown ha he p ocesses o miRNA so ing as well as he EV elease
a e a e egula ed by me abolic ac o s such as insulin o glucagon [
55
,
56
]. This aises he
exci ing possibili y ha he dys egula ion o miRNA so ing mechanisms may accoun
o he al e ed EV-miRNA signa u e and subsequen me abolic abno mali ies obse ed in
se e al me abolic diseases such as obesi y and diabe es.
4. Adipose Tissue EV Axes
4.1. Technical Limi a ions o EV S udy
Fo adipose issue, accumula ing e idence suppo s i s ole as a hub o he elease
o ci cula ing miRNAs impac ing he unc ion o a la ge numbe o issues and cell ypes.
He e, we highligh he mos ecen indings on AdEV miRNAs ha ha e been shown o
shape he me abolism and unc ion o o he issues.
As discussed below, in es iga ion o e he pas decade has iden i ied nume ous miR-
NAs eleased by adipocy es and o he adipose- esiden cells ha ha e an impac on he
unc ion o ano he cell ype in a dis an o gan. Howe e , he s udy o in e cellula commu-
nica ion is a echnically challenging a ea o esea ch: he unequi ocal demons a ion o he
adipose o igin o a gi en miRNA is de ini ely no i ial, as is he alida ion o i s deli e y
o a pa icula a ge cell ype due o se e al limi a ions associa ed wi h cu en me hod-
ologies (Table 1). The e o e, he use o complemen a y me hodologies a e ecommended
o ully demons a e an in e o gan communica ion ole o a gi en ci cula ing miRNA.
One o he p ocedu es o en used o iden i y a po en ial a ge issue is he exogenous
adminis a ion o EVs, usually a e labelling wi h luminescen , luo escen , adioac i e,
o supe pa amagne ic ace s [
57
,
58
] (Table 1). Howe e , cau ion mus be aken be o e
d awing conclusions om his ype o expe imen . Exogenously-adminis e ed EVs (usually
a sup aphysiologic concen a ions) display a ma ked opism o he li e , spleen, lungs,
and kidneys, all o which a e en iched in phagocy es ha seem o pe o m supe io EV
up ake [
57
]. A i icial ca ie s such as lipid nanopa icles (LNPs) a e also p e e en ially
aken up om he ci cula ion by li e o spleen cells, which has a o ed he de elopmen
o d ug deli e y s a egies using LNPs o a ge hese issues [
59
,
60
]. In exogenous EV ad-
minis a ion expe imen s, he cellula sou ce o he EVs seems o ha e a minimal in luence
in de ining he a ge issues [
57
,
61
]. In con as , when he EVs a e eleased endogenously,
hei issue dis ibu ion di e s signi ican ly om ha o exogenous EVs, wi h o he issues
such as adipose, lung, bone ma ow, and gas oin es inal ac leading he EV up ake
while li e and spleen we e among he issues wi h he lowes EV accumula ion [
57
,
62
].
This sugges s ha he li e and he o he o gans whe e EVs end o accumula e (lungs,
kidneys, and spleen) [
57
] migh ac as sink issues o sup aphysiological doses o exoge-
nous EVs and ein o ces he need o obus expe imen al alida ion o iden i y in e o gan
communica ion axes in i o (Table 1).

In . J. Mol. Sci. 2024,25, 13488 6 o 23
Table 1. Cu en me hodologies o s udy miRNA-based in e o gan communica ion. Table desc ibing
he lis o common me hodologies including hei a ionali y and limi a ions used o asc ibe adipocy e
o igin o ci cula ing miRNAs as well as o he alida ion o miRNA deli e y o a ge issues.
P ocedu es o alida e adipose o igin o a ci cula ing miRNA
Me hod Ra ionali y Limi a ions
In i o cell lines miRNAs eleased o cul u e medium om
adipocy e models 3T3-L1, F442A,
PAZ6, e c.
Cell lines migh no ully ecapi ula e miRNA
sec e ion pa e n om
endogenous adipocy es
In i o adipocy es de i ed
om ADSCs
miRNAs eleased o cul u e medium by
adipocy es di e en ia ed in i o
om ADSCs
miRNA sec e ion pa e n migh be in luenced by
di e en ia ion cock ail ing edien s and hei
concen a ions, e iciency o di e en ia ion
and iming
Obesi y
I a ci cula ing miRNA inc eases in pa allel o he
inc ease in a mass, i migh de i e
om adipocy es
Changes in ci cula ing miRNAs migh de i e
om any o he many cell ypes a ec ed
by obesi y
Adipose ma ke s in EV Cap u e adipocy e-speci ic EVs using su ace
p o eins o downs eam miRNA p o iling
Lack o adipose-speci ic EV ma ke , al hough
some a e en iched (FABP4, pe ilipin,
TGFBI, Adiponec in)
Adipose issue explan s o p ima y adipocy es Incuba e a explan s/adipocy es ex i o and
s udy eleased miRNAs o he medium
Collagenase diges ion migh dis up cell
memb anes and induce he elease o cellula
miRNA con en
Incuba ion in ha sh condi ions (o en se um
s a ed o 24 h) di e om endogenous
condi ions, po en ially inducing cell dea h and
al e ing miRNA elease pa e n
Explan s: eleased miRNAs could de i e om
any o he cell ypes.
Isola ed adipocy es: lack o ex acellula ma ix
and cell in e ac ions. Floa ing condi ions can al e
eleased miRNA signa u e
Vi al ec o wi h adipose-speci ic p omo e
An adipocy e p omo e (Adiponec in o Fabp4)
d i es he exp ession o he miRNA/an agomiR
o which he elease is being analyzed
Some adipocy e p omo e s migh no be ully
speci ic, e.g., Fabp4 also exp essed in
mac ophages and endo helial cells
Lipec omy/BATec omy o
a ansplan a ion
Remo al/ ansplan o a om ano he animal
leading o educed/augmen ed eleased le els o
a gi en miRNA
These se e e p ocedu es migh a ec eleased
miRNA signa u es om a and o he issues.
O he cell ypes di e en om adipocy es migh
be he p edominan miRNA sou ce
Adypocy e-speci ic miRNA KO, o
Adipocy e-Dice KO (ADice KO) mice
Dele ion o a miRNA gene o Dice om
adipocy es leading o absence/ educ ion elease
o ha miRNA
Good suppo o adipocy e o igin, bu i is cos ly
and ime consuming. In animals KO o a miRNA,
ca e mus be aken o a oid dele ing
o e lapping genes
ADice KO mouse displays a global pheno ype,
po en ially a ec ing miRNA exp ession and
sec e ion om o he issues
P ocedu es o alida e miRNA deli e y o a gi en issue/cell ype
Me hod Ra ionali y Limi a ions
In i o cell lines miRNA inco po a ion upon ea men o cell
models in cul u e
Cell lines migh no ully ecapi ula e miRNA
up ake beha iou o endogenous cells
Adminis a ion o labelled EV (e.g., by lipophilic
dyes) in o mice De ec ion o he ace signal in a a ge issue
The a ic o exogenous EVs po en ially di e
om endogenous EVs. Lipophilic dyes can o m
agg ega es simila in size o EVs.
Vi al ec o wi h adipose-speci ic p omo e
d i ing he exp ession o a EV-localized label
De ec ion o he label signal in ano he issue
di e en om adipose
Good suppo o adipose- o- a ge issue EV
a ic, hough does no p oo ans e o
a speci ic miRNA
Vi al ec o wi h adipose-speci ic p omo e
d i ing miRNA mimic/an agomiR exp ession
De ec ion o enhanced/ educed ma u e miRNA
p esence in a issue di e en om adipose
wi hou changes in p ecu so miRNA
Good suppo o adipose- o- a ge issue
miRNA ans e
Gene ic o e exp ession o a miRNA o i s
inhibi o in adipose issue
De ec ion o enhanced/ educed ma u e miRNA
p esence in a issue di e en om adipose
wi hou changes in p ecu so miRNA
Good suppo o adipose- o- a ge issue
miRNA ans e
4.2. Adipose Tissue o Li e
In e cellula communica ion be ween he li e and adipose issue has been ex ensi ely
in es iga ed in ecen yea s. Solid accumula i e da a suppo ha a la ge numbe o EV-
ca ied miRNAs each he li e cells, whe e hey media e an impo an egula o y unc ion
o e hepa ic and sys emic me abolism (Figu e 2). One o he i s s udies o demons a e
adipose- o-li e communica ion ia ex acellula miRNAs was ou wo k wi h mice de icien
In . J. Mol. Sci. 2024,25, 13488 7 o 23
o Dice in adipocy es (ADice KO) [
33
]. These mice de eloped a massi e down egula ion
o ci cula ing EV miRNAs accompanied by ele a ed hepa ic ib oblas g ow h ac o -21
(Fg 21) mRNA and p o ein le els. Fu he expe imen s con i med ha miR-99b eleased
in b own and whi e adipocy e EVs can a ge FGF21 in hepa ocy es, he eby egula ing
he hepa ic and ci cula ing le els o his key ho mone in ol ed in ca bohyd a e and lipid
me abolism [
33
,
63
]. La e s udies ha e epo ed o he whi e adipocy e-de i ed miRNAs
ha con ol sys emic glucose me abolism by a ge ing he li e . This is he case o miR-
548ag, whose exp ession is inc eased in se um and adipose issue in obesi y. In hepa ocy es,
his miRNA di ec ly a ge s he DNA-me hyl ans e ase DNMT3B, which subsequen ly
leads o he up egula ion o DPP4, a p o ein in ol ed in glucose me abolism by deg ading
inc e ins such as glucagon-like pep ide-1 (GLP-1) [
64
,
65
]. Acco dingly, he ci cula ing le els
o miR-548ag ca ied by EVs we e associa ed wi h wo sened glucose ole ance and insulin
sensi i i y [
64
]. Simila indings ha e been desc ibed o miR-222, which is also ele a ed in
obesi y [
66
,
67
]. Gonadal WAT was epo ed o be he majo sou ce o EV-ca ied miR-222,
as emo al o his a depo blun ed he high- a die (HFD)-induced miR-222 inc ease in he
ci cula ion [
67
]. Mechanis ically, miR-222 impai s insulin signaling in hepa ocy es h ough
a ge ing IRS1 [
67
]. Simila ly, miR-4431 is ano he obesi y-associa ed miRNA ha has been
linked o wo sened glucose ole ance and insulin sensi i i y [
68
]. Al hough he exp ession
o his miRNA inc eases se e al- old in he WAT and se um o obese indi iduals, i eaches
e en highe le els in he li e , indica ing ha miR-4431 migh also be p oduced di ec ly
by hepa ocy es [
68
]. In con as o p e ious miRNAs ha we e up egula ed in obesi y,
miR-141-3p was ound o be down egula ed in adipose-de i ed EVs isola ed om gene ic-
and die -induced obesi y models. By a ge ing phospha ase and ensin homolog (PTEN),
his miRNA was shown o inhibi insulin sensi i i y and glucose up ake in hepa ocy es
in i o (AML12 cells) [69].
In . J. Mol. Sci. 2024, 25, x FOR PEER REVIEW 8 o 25
This is he case o miR-548ag, whose exp ession is inc eased in se um and adipose issue
in obesi y. In hepa ocy es, his miRNA di ec ly a ge s he DNA-me hyl ans e ase
DNMT3B, which subsequen ly leads o he up egula ion o DPP4, a p o ein in ol ed in
glucose me abolism by deg ading inc e ins such as glucagon-like pep ide-1 (GLP-1)
[64,65]. Acco dingly, he ci cula ing le els o miR-548ag ca ied by EVs we e associa ed
wi h wo sened glucose ole ance and insulin sensi i i y [64]. Simila findings ha e been
desc ibed o miR-222, which is also ele a ed in obesi y [66,67]. Gonadal WAT was e-
po ed o be he majo sou ce o EV-ca ied miR-222, as emo al o his a depo blun ed
he high- a die (HFD)-induced miR-222 inc ease in he ci cula ion [67]. Mechanis ically,
miR-222 impai s insulin signaling in hepa ocy es h ough a ge ing IRS1 [67]. Simila ly,
miR-4431 is ano he obesi y-associa ed miRNA ha has been linked o wo sened glucose
ole ance and insulin sensi i i y [68]. Al hough he exp ession o his miRNA inc eases
se e al- old in he WAT and se um o obese indi iduals, i eaches e en highe le els in
he li e , indica ing ha miR-4431 migh also be p oduced di ec ly by hepa ocy es [68]. In
con as o p e ious miRNAs ha we e up egula ed in obesi y, miR-141-3p was ound o
be down egula ed in adipose-de i ed EVs isola ed om gene ic- and die -induced obesi y
models. By a ge ing phospha ase and ensin homolog (PTEN), his miRNA was shown
o inhibi insulin sensi i i y and glucose up ake in hepa ocy es in i o (AML12 cells) [69].
Figu e 2. Adipose-de i ed miRNAs deli e ed o o he me abolic o gans. Scheme ep esen ing he
miRNAs eleased by WAT/BAT and deli e ed o he skele al muscle, li e , panc ea ic isle s, b ain,
ca dio ascula sys em, and gu . The numbe s in b acke s indica e he e e ence in he main ex .
Aside om whi e adipocy es, b own adipocy es a e also impo an sende s o AdEV-
loaded miRNAs a ge ing he li e . Indeed, despi e hei lowe mass, b own adipocy es
appea o be s onge EV sende cells compa ed o whi e adipocy es. This was e idenced
by he supe io es o a ion o ci cula ing miRNA le els in ADice KO mice a e he ans-
plan a ion o wild- ype b own adipose issue (BAT) compa ed o a lowe , bu s ill ema k-
able, es o a ion when ansplan ed whi e adipose issue (WAT) [33]. The unc ional con-
sequences o he BAT- o-li e axis ha e been u he illus a ed in cold-exposed mice. In
hese condi ions, b own adipocy es elease mo e EVs, which con ain, among o he s, miR-
378a-3p and miR-132-3p. These wo miRNAs each hepa ocy es, whe e hey p omo e glu-
coneogenesis by a ge ing p110α (by miR-378a-3p) and ep ess lipogenesis by SREBF1 a -
ge ing (by miR-132-3p) [70,71].
Figu e 2. Adipose-de i ed miRNAs deli e ed o o he me abolic o gans. Scheme ep esen ing he
miRNAs eleased by WAT/BAT and deli e ed o he skele al muscle, li e , panc ea ic isle s, b ain,
ca dio ascula sys em, and gu . The numbe s in b acke s indica e he e e ence in he main ex .
Aside om whi e adipocy es, b own adipocy es a e also impo an sende s o AdEV-
loaded miRNAs a ge ing he li e . Indeed, despi e hei lowe mass, b own adipocy es
appea o be s onge EV sende cells compa ed o whi e adipocy es. This was e idenced by
he supe io es o a ion o ci cula ing miRNA le els in ADice KO mice a e he ansplan-
a ion o wild- ype b own adipose issue (BAT) compa ed o a lowe , bu s ill ema kable,
In . J. Mol. Sci. 2024,25, 13488 8 o 23
es o a ion when ansplan ed whi e adipose issue (WAT) [
33
]. The unc ional conse-
quences o he BAT- o-li e axis ha e been u he illus a ed in cold-exposed mice. In hese
condi ions, b own adipocy es elease mo e EVs, which con ain, among o he s, miR-378a-3p
and miR-132-3p. These wo miRNAs each hepa ocy es, whe e hey p omo e gluconeogen-
esis by a ge ing p110
α
(by miR-378a-3p) and ep ess lipogenesis by SREBF1 a ge ing (by
miR-132-3p) [70,71].
In addi ion o ma u e adipocy es, o he adipose- esiden cells elease miRNAs ha
ha e impo an implica ions o hepa ic, and hence, sys emic me abolism. A good example
is adipose issue mac ophages, whose EV-ca ied miRNA p o ile signi ican ly di e s in
obese e sus lean condi ions. Some o hese miRNAs, such as miR-155 and miR-690, co e-
la e posi i ely o nega i ely, espec i ely, wi h insulin esis ance in hepa ocy es, adipocy es,
and muscle cells [
72
,
73
]. O he adipose- esiden cells ha ha e been ex ensi ely s udied
in his con ex a e adipose-de i ed s em cells (ADSCs) due o hei majo egene a i e
p ope ies in di e en issues and condi ions [
74
], as u he ou lined in he nex sec ions.
Thei eleased EVs can each he li e , among o he issues, whe e hey exe egene a i e
unc ions. Fo ins ance, ADSC- eleased miR-223-3p supp esses hepa ic lipid accumula ion
and ib osis by E2F1 a ge ing, while miR-144-3p and miR-486a-3p ac i a e hepa ocy e
p oli e a i e pa hways by supp essing TXNIP exp ession [75,76].
Recip ocal communica ion om he li e o adipose issue media ed by EVs has been
much less s udied han he e e se di ec ion. In his ega d, some epo s ha e shown ha
hepa ic EVs p omo e glucose up ake in adipocy es h ough a a ie y o mechanisms, one o
which is he miR-130a-3p-media ed a ge ing o PHLPP2, a modula o o he AKT-GLUT4
axis [
77
,
78
]. Adipocy e a ge ing o hepa ic EVs also plays a ole in disease such as obesi y
and a y li e . Speci ically, obesi y implies changes in he miRNA con en o EVs eleased
om p ima y hepa ocy es. A subse o hese miRNAs, wi h he s onges e ec media ed
by le -7e-5p, has been shown o p omo e lipid accumula ion in adipocy es [
43
]. Some o
hese miRNAs we e ound o be ele a ed in ci cula ing EVs om pa ien s wi h concomi an
obesi y and a y li e bu no in hose wi h a a y li e alone, sugges ing a po en ial
in ol emen o hese hepa ic miRNAs in a mass gain [43].
4.3. Adipose Tissue o Skele al Muscle
O e all, he egula o y po en ial o AdEV-ca ied miRNAs in skele al muscle me abolism
and unc ion has been less s udied han in he li e , bu s ill, a good numbe o miRNAs ha e
been shown o be in ol ed in his communica ion axis (Figu e 2). One o he i s miRNAs
epo ed o be in ol ed in adipocy e- o-muscle communica ion was miR-130b [
79
]. This
miRNA was ound o inhibi he skele al muscle exp ession o PGC-1
α
, a mas e egula o
o lipid oxida ion and mi ochond ial biogenesis [
79
]. La e on, miR-27a, whose le els
inc ease in adipose issue, se um, and skele al muscle unde obese condi ions, was shown
o p omo e muscle insulin esis ance h ough he inhibi ion o PPAR
γ
, a leas in an
in i o
myo ube model [
80
]. Simila ly, obesi y-associa ed ci cula ing miR-222 [
66
], in addi ion o
hepa ocy es, can also each muscle cells o down egula e IRS1 and insulin signaling, he eby
con ibu ing o insulin esis ance and glucose in ole ance in obesi y [
67
]. Indeed, obesi y
also al e s he sec e ion and ca go con en o EVs sec e ed by muscle cells. In e es ingly,
in con as o he enhanced sec e ion o EVs by adipose issue in obesi y [
40
,
41
], muscle
explan s om obese animals sec e e a lowe numbe o EVs compa ed o lean explan s [
42
].
The miRNAs con ained in hese EVs may also be key ac o s con ibu ing o boos obesi y-
induced a gain, as hey ha e been shown o p omo e lipid accumula ion in adipocy es [
42
].
Beyond he obesi y con ex , he e a e o he si ua ions ha illus a e he close ecip ocal
c oss alk be ween muscle and adipose issue media ed by EV-miRNAs. Fo ins ance,
p omo ing muscle ac i i y h ough exe cise o syne gis abla ion esul s in he enhanced
deli e y o EV-loaded miR-1 o adipocy es, he eby enhancing ca echolamine-induced
lipolysis [81,82].
EV-ca ied miRNAs ha e also eme ged as key elemen s o he c oss alk be ween
muscle and adipose p ogeni o s. Fo ins ance, adipocy e p ogeni o s esiding in skele al
In . J. Mol. Sci. 2024,25, 13488 9 o 23
muscle ( ib oadipogenic p ogeni o s, FAPs) pa icipa e in muscle egene a ion upon inju y.
FAPs sec e e EV-ca ied miRNAs (such as miR-127-3p) in a pa ac ine manne o elease
muscle s em cells (MuSCs) om quiescence by a ge ing he myogenic gene S1PR3, hus
allowing muscle mass eco e y [
83
,
84
]. Con e sely, MuSCs can also ha e an in luence on
adipose p ogeni o s. Fo ins ance, MuSCs can educe he p oli e a ion and di e en ia ion
o ADSCs by sec e ing EV-loaded miR-146-5p, a miRNA p e iously shown o a ge insulin
ecep o [85,86].
4.4. Adipose Tissue o Panc ea ic Isle s
Despi e he pi o al ole o panc ea ic isle s in he egula ion o sys emic me abolism,
he s udy o he po en ial con ibu ion o adipocy e- eleased miRNAs o he physiology
and pa hology o be a cells and o he isle cells has ba ely been in es iga ed in compa ison
o o he o gans. Howe e , some ecen epo s ha e iden i ied subse s o ci cula ing
miRNAs wi h po en ial adipocy e o igin ha egula e be a cell p oli e a ion and ac i i y
(Figu e 2). Fo ins ance, miR-132-3p, whose exp ession is ele a ed in isce al adipocy es and
panc ea ic isle s unde obese condi ions, is linked o enhanced be a cell egene a ion [
87
–
90
].
Simila ly, miR-15b and miR-146b supp essed insulin sec e ion in an
in i o
model o be a
cells [
91
]. Howe e , whe he adipocy es ep esen he main sou ce o he ci cula ing pool
o hese h ee a o emen ioned miRNAs was no e i ied [
91
]. In con as , he adipocy e
o igin was con i med o ano he clus e o EV-ca ied miRNAs (miR-29a-3p, miR-200a-3p,
miR-218-5p and miR-322-5p) ha inhibi ea ly insulin sec e ion by p ima y isle s and
a be a cell line (MIN6) exposed o high glucose condi ions [
92
]. These miRNAs we e
iden i ied by looking a he EVs eleased by epidydimal obese adipocy es in o cell cul u e
medium [
92
]. Using an al e na i e app oach, Zhang and colleagues in e ed miR-27a-5p
as an adipocy e EV-ca ied miRNA egula ing insulin sec e ion in be a cells [
93
]. In his
case, miR-27a-5p le els inc ease in mouse and human isle s unde obesi y condi ions while
i s p ecu so dec eases, sugges ing an ex a-isle o igin. The ise in he exp ession o bo h
ma u e and p ecu so miR-27a wi h obesi y speci ically in epididymal a sugges ed an
adipocy e o igin o his miRNA. Fu he
in i o
expe imen s using adipocy e-speci ic
o e exp ession o neu aliza ion app oaches con i med he EV-media ed anspo o his
miRNA om adipocy es o isle s, whe e i a ge ed a calcium anspo e (CACNA1C)
and he eby blun ed insulin sec e ion [
93
]. The ini ial igge o he ele a ed sec e ion o
hese p e ious miRNAs in EVs om adipocy es subjec ed o obesi y condi ions was no
asce ained. In his ega d, AdEVs eleased by adipocy es ha we e p e iously exposed o
in lamma o y cy okines ha e been shown o p omo e be a cell apop osis and impai insulin
sec e ion in ecipien be a cells
in i o
[
44
]. These dele e ious e ec s may be media ed, a
leas in pa , by he dis inc AdEV-miRNA signa u e induced by he p e ea men wi h
p oin lamma o y ac o s [
44
]. Taken oge he , hese da a sugges ha miRNAs eleased
om in lamed adipocy es may be in ol ed in he me abolic de e io a ion o be a cells in
obesi y and diabe es. Aside om adipocy es, comp ehensi e
in i o
expe imen s ha e
also con i med he elease o p oin lamma o y miR-155-5p in adipose issue mac ophage-
de i ed EVs, which a e able o supp ess insulin sec e ion and cellula p oli e a ion in be a
cells
in i o
[
94
]. The po en ial egula o y ac ions o miRNAs eleased om adipose issue
cells on o he panc ea ic isle cells di e en om be a cells emain o be in es iga ed.
4.5. Adipose Tissue o Ca dio ascula Sys em
Fa accumula ion, especially in isce al depo s, is s ongly associa ed wi h ad e se
ca dio ascula e en s [
95
]. The con ibu ing ole o adipose issue in ca dio ascula disease
(CVD) is illus a ed by he p o ec i e e ec o isce al a emo al in se e al mouse models
o ca diac dys unc ion [
96
,
97
]. Due o i s ana omical p oximi y o he myoca dium, epica -
dial adipose issue (EAT), a sub ype o isce al a depo , has ecei ed much a en ion as
a po en ial sou ce o AdEV-ca ied miRNAs egula ing ca diac unc ion. Indeed, se e al
miRNAs eleased in EAT-de i ed AdEVs ha e been shown o egula e me abolism, he
p oduc ion o eac i e oxygen species, and con ac ile unc ion when adminis e ed o en-
In . J. Mol. Sci. 2024,25, 13488 16 o 23
Funding: This wo k was suppo ed by a g an PID2022-141519OA-I00, unded by Spanish Min-
is y o Science, Inno a ion, and Uni e si ies/Spanish Agency o In es iga ion/Eu opean Union
(MICIU/AEI, e . 10.13039/501100011033), and by a g an RYC2021-033875-I unded by he Spanish
Na ional Resea ch Council (CSIC) o R.G.-M. A Fo macion Pe sonal In es igado (PFI) ellowship
(PREP2022-000779) suppo ed P.D.-R. We used Bio ende o he d awing o he igu es displayed in
his a icle.
Con lic s o In e es : The au ho s decla e no con lic s o in e es .
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