Vol.:(0123456789)
Neu oMolecula Medicine (2025) 27:19
h ps://doi.o g/10.1007/s12017-025-08842-4
REVIEW
Lep in andLep in Signaling inMul iple Scle osis: ANa a i e Re iew
JuanAn onioFlo es‑Co de o1· AmaliaA anaz‑Mu illo1· Te esaVila iño‑Ga cía2· An onioPé ez‑Pé ez1·
Guille moIzquie do3· RocíoFlo es‑Campos1,4· Lou desHon ecillas‑P ie o1,5,6· DanielJ.Ga cía‑Domínguez1,6·
Víc o Sánchez‑Ma gale 1,5,6,7
Recei ed: 28 June 2024 / Accep ed: 19 Feb ua y 2025
© The Au ho (s) 2025
Abs ac
Obesi y, a pandemic heal h p oblem, is now conside ed as a ch onic in lamma o y s a e, ela ed o many au oimmune dis-
eases, such as mul iple scle osis. Thus, adipokines, in lamma o y media o s sec e ed by adipose issue, play an impo an
ole modula ing he immune esponse. In his con ex , obesi y, especially du ing adolescen age, seems o be a key ac o o
he de elopmen o mul iple scle osis. Lep in, he main p o-in lamma o y adipokine sec e ed by he adipose issue, has been
ound inc eased in pa ien s wi h mul iple scle osis and is able o egula e he immune sys em p omo ing a p o-in lamma o y
esponse. Lep in signaling in bo h inna e and adap a i e immune cells migh ha e immunomodula o y e ec s in he con ex
o mul iple scle osis. In his way, lep in has been ound o p oduce a Th1 and Th17 esponse, inc easing M1 mac ophages and
dec easing egula o y T cells and Th2 esponse. Mo eo e , ci cula ing in lamma o y adipokines, such as lep in, ha e been
ound in people wi h mul iple scle osis. In he p esen wo k, we a e e iewing li e a u e o upda e he body o knowledge
ega ding he ole o obesi y and lep in in mul iple scle osis.
Keywo ds Lep in· Obesi y· Mul iple Scle osis· In lamma ion
In oduc ion
Mul iple Scle osis (MS) s ands as he mos p e alen au o-
immune demyelina ing disease a ec ing he cen al ne ous
sys em (CNS), ma ked by in lamma ion, selec i e myelin
des uc ion, and gliosis, ul ima ely leading o neu onal loss.
Ini ially published in 2008 h ough a collabo a i e e o
be ween he MS In e na ional Fede a ion (MSIF) and he
Wo ld Heal h O ganiza ion (WHO), he i s edi ion aimed
o de e mine he global p e alence o MS. Subsequen ly, in
a e ised second edi ion, he MS In e na ional Fede a ion
epo ed a ise in diagnosed people wi h MS om 2.3 mil-
lion in 2013 o 2.8 million in 2020 and 2.9 million in 2023.
This inc ease can be a ibu ed o enhanced MS diagnosis,
imp o ed ea men and suppo , and enhanced capabili ies
in allying indi iduals wi h MS in No he n Hemisphe e
coun ies, including he USA, Canada, and Eu ope (The
Mul iple Scle osis In e na ional Fede a ion, A las o MS,
3 d Edi ion, Sep embe 2020; www. a las o ms. o g). Mo eo-
e , shi s in li es yle habi s, such as wes e n die s and sed-
en a ism, may con ibu e o he obse ed inc ease (Da gahi
e al., 2017). MS exhibi s a highe incidence in women han
men, anging om 2:1 o 3:1 depending on he sou ce. Mo e
Juan An onio Flo es-Co de o and Amalia A anaz-Mu illo should be
conside ed as i s au ho s.
* Víc o Sánchez-Ma gale
ma g[email p o ec ed]
1 Depa men o Medical Biochemis y andMolecula
Biology, andImmunology, Medical School, Uni e si y
o Se ille, Se ille, Spain
2 Depa men o Medical Biochemis y andMolecula
Biology, andImmunology, Medical School, Vi gen del Rocio
Uni e si y Hospi al, Se ille, Spain
3 Neu ology Se ice, Vi gen Maca ena Uni e si y Hospi al,
Uni e si y o Se ille, Se ille, Spain
4 Depa men o Clinical Oncology, Hospi al Uni e si a io
Vi gen Maca ena, Uni e si y o Se ille, Se ille, Spain
5 Clinical Biochemis y Se ice, Hospi al Uni e si a io Vi gen
Maca ena, Uni e si y o Se ille, Se ille, Spain
6 Ins i u e o Biomedicine o Se ille, IBiS/Vi gen del
Rocío-Vi gen Maca ena Uni e si y Hospi al/CSIC/Uni e si y
o Se ille, Se ille, Spain
7 Depa men o Medical Biochemis y andMolecula
Biology, andImmunology, Medical School, Vi gen Maca ena
Uni e si y Hospi al, Uni e si y o Se ille, A . Sánchez
Pizjuan 4, 41009Se ille, Spain
Neu oMolecula Medicine (2025) 27:19 19 Page 2 o 13
conc e ely, o RRMS i is 3:1, whe eas o PPMS i is 1:1
(Jakimo ski e al., 2024). While MS can mani es a any age,
i is mo e equen ly obse ed be ween 20 and 40yea s old,
making adolescence a c i ical pe iod o po en ial disease
de elopmen (Da gahi e al., 2017), Consequen ly, a en ion
is wa an ed owa d po en ial isk ac o s, such as obesi y,
ha may inc ease disease incidence du ing adolescence,
e en hough only 3–5% o all indi iduals diagnosed wi h
MS expe ience disease onse be o e 16yea s o age.
The p esen a ion o MS a ies widely among pa ien s,
anging om sudden onse o insidious o slow p og ession
wi h di e se symp oms. Fou main a ian s ha e been delin-
ea ed based on disease e olu ion: elapsing/ emi ing (mos
o he cases), seconda y p og essi e, p ima y p og essi e,
and p og essi e elapsing (Da gahi e al., 2017). The elaps-
ing/ emi ing a ian appea s o ha e a mo e p onounced
immune componen con ibu ing o MS pa hology (Bae-
che -Allan e al., 2018). The ad en o magne ic esonance
imaging (MRI) has e olu ionized bo h he diagnosis and
ea men o MS. The use o gadolinium as in a enous con-
as acili a es he ea ly de ec ion o in lamma o y lesions,
pa icula ly in he elapsing a ian , which o en occu s in
he ini ial phase o MS de elopmen . Howe e , he diag-
nos ic e icacy o gadolinium is less obus in p og essi e
o ms o he disease (Baeche -Allan e al., 2018). Addi ional
diagnos ic ools such as e oked po en ials and ce eb ospi-
nal luid (CSF) examina ion can be aluable. Mononuclea
pleocy osis, ele a ed IgG concen a ion, and he p esence o
oligoclonal bands suppo he diagnosis o MS.
Despi e ongoing esea ch leading o ad ancemen s in
MS managemen , he e is cu en ly no e ec i e ea men
p omo ing emyelina ion o neu al epai . Con empo a y
ea men s aim o supp ess he immune sys em (e.g., gla i-
ame ace a e, IFN-be a, na alizumab, ingolimod, and alem-
uzumab, among o he s). While he p ognosis o he disease
has imp o ed, a signi ican p opo ion o people wi h MS
ul ima ely expe ience p og essi e neu ological disabili y.
Like many o he au oimmune diseases, mul iple scle osis
(MS) is a mul i ac o ial condi ion in luenced by a ious isk
ac o s, encompassing en i onmen al, gene ic, and epige-
ne ic elemen s (see Fig.1). Despi e nume ous p oposed an i-
gens, none ha e been conclusi ely con i med as he de ini-
i e cause o he disease. P esen ly, obesi y is ecognized as
a p o-in lamma o y s a e and is conside ed a po en ial isk
ac o o a ious in lamma ion- ela ed condi ions, including
diabe es, ca dio ascula disease, cance , and au oimmune
diseases, such as mul iple scle osis (Kinlen e al., 2018).
Adipokines, including lep in—a majo adipokine p oduced
by adipose issue—may con ibu e o he complica ions o
obesi y due o hei p o-in lamma o y ac ions (Pé ez-Pé ez
e al., 2017, 2020a; Sánchez-Ma gale e al., 2010). Howe e ,
i is hypo hesized ha a dys egula ion in adap i e immune
esponse, coupled wi h a p o-in lamma o y en i onmen ,
plays a pi o al ole in media ing he disease p ocess.
In his con ex , wi h a ocus on obesi y as a po en ial isk
ac o o mul iple scle osis (MS), he objec i e o his a i-
cle is o comp ehensi ely e iew he li e a u e pe aining o
he oles o obesi y and lep in in he de elopmen o MS.
Fig. 1 Risk ac o s o mul iple
scle osis
Neu oMolecula Medicine (2025) 27:19 Page 3 o 13 19
Pa hophysiology
To di ec his e iew, we will ocus on MS as an au oim-
mune disease in luenced by en i onmen al ac o s ac ing
upon a gene ically suscep ible hos (Baeche -Allan e al.,
2018). The disease is cha ac e ized by in lamma ion, selec-
i e myelin des uc ion, and gliosis, e en ually leading o
neu onal dea h. In he con empo a y unde s anding o MS
pa hophysiology, he adap i e immune sys em is ecognized
o play a signi ican ole.
A dis inc i e pa hological ea u e o MS is he p esence o
pe i enula in lamma o y lesions, gi ing ise o demyelina -
ing plaques ha p ecede axon degene a ion (Ko nek & Lass-
mann, 1999; Ku zelnigg e al., 2005; Lucchine i e al., 2011;
Fisniku e al., 2008; Lemus e al., 2018; T app e al. 1999).
This esponse igge s eac ions agains myelina ion,
in ol ing a ious immune cells, such as CD4 + and CD8 + T
cells, B cells, o na u al kille (NK) cells. Addi ionally,
in lamma o y lesions e eal he p esence o o he cell ypes,
including mic oglial cells and in il a ed mac ophages, o m-
ing a na ow im a ound he in lamma o y si e (P ineas e al.,
2001). Thus, bo h adap i e and inna e immune sys ems a e
implica ed in he complex pa hophysiology o MS.
The subsequen sec ions will del e in o he a ious e en s
occu ing in MS, encompassing immuni y and in lamma o y
esponses, demyelina ion, and axonal degene a ion.
Reduced i amin D le els, diminished sun exposu e, ciga-
e e smoking, obesi y, and exposu e o he Eps ein–Ba
i us (EBV) appea o be en i onmen al isk ac o s o
MS (Baeche -Allan e al., 2018) (Fig.1). Consequen ly, ou
ocus will be on obesi y as a po en ial isk ac o o MS, as
discussed in he ollowing sec ion and below.
Obesi y andMul iple Scle osis
Obesi y can be conside ed as a s a e whe e an excessi e
body mass index exis s. An al e a ion in ene gy balance
be ween in ake and expendi u e is p oduced du ing an obe-
si y s a e. The majo ac o ha causes ene gy expendi u e
is exe cise. Ne e heless, exe cise accoun s o only 20–30%
o ene gy expendi u e in he seden a y li es yle o Wes e n
socie ies, whe eas 70–80% co esponds o basal me abolism.
Acco ding o he WHO, 35% o he global popula ion exhib-
i s an inc eased body mass index (BMI), alling in o he
ca ego ies o o e weigh (> 25kg/m2) o obesi y (> 30kg/
m2) (Ve sini e al., 2014). Mo eo e , a ise in adipose issue
has been co ela ed wi h cogni i e dys unc ion (de Candia &
Ma a ese, 2018; Flo es-Co de o e al., 2022). A subs an ial
body o compiled e idence suppo s he associa ion be ween
me abolic changes, such as obesi y, and neu odegene a ion
in a ious neu ological diso de s, including mul iple scle o-
sis (MS), owing o ch onic neu oin lamma ion. Indeed, he
epidemiological link be ween obesi y and neu odegene a ion
has been alida ed in di e se animal models (de Candia &
Ma a ese, 2018; P ocaccini e al., 2016).
Se e al immune sys em- ela ed diseases ha e been con-
nec ed o obesi y. Agg a a ed o ms o au oimmune dis-
eases ha e been iden i ied in obese indi iduals, exhibi ing
a weake he apeu ic esponse (Bapa e al., 2022; K is-
ad e al., 2015). Ele a ed BMI has been implica ed in an
inc eased isk o de eloping MS (Gian ancesco e al., 2014;
Heds öm e al., 2012; Høglund e al., 2021; Ma odan e al.,
2021), pa icula ly when his ele a ion occu s du ing adoles-
cence (Chi nis e al., 2016; Heds öm e al., 2015; Høglund
e al., 2021; Huppke e al., 2019; Munge e al., 2009). This
inc eased isk o MS su e ing has been linked o obesi y
in he adolescence; mo eo e , obesi y wo sen he i s -line
ea men e icacy, since a highe pe cen age o adolescen
obese people wi h MS mus ollow o a second-line ea -
men because he disease-modi ying d ugs (in e e on be a-
1a o 1b and gla i ame ace a e) we e less e ec i e in obesi y
(Huppke e al., 2019). Owing o ha eason ac o s such as
obesi y mus be aken in accoun when i s -line ea men
is adminis e ed, because obesi y can condi ion he he apy
ou comes. Addi ionally, he heigh ened isk o MS de el-
opmen appea s o be mo e p onounced in emales han
in males (Gian ancesco e al., 2014; Lange -Gould e al.,
2013; Munge e al., 2013) sugges ing a gende -speci ic
e ec .
A p oposed ini ializing mechanism o a ious neu ode-
gene a i e diseases, such as Alzheime ’s Disease o MS,
is a low-g ade in lamma o y s a e associa ed wi h obesi y
(Co eale & Ma odan, 2022; Flo es-Co de o e al., 2022;
Ma odan e al., 2021; Sama a e al., 2023) (Fig.2). No ably,
an an i-in lamma o y en i onmen appea s o p e ail in he
adipose issue o lean indi iduals, whe eas a p o-in lamma-
o y en i onmen cha ac e izes he adipose issue o obese
indi iduals. In lean adipose issue, he e is an an i-in lam-
ma o y p o ile ma ked by he p esence o egula o y T cells
(T eg cells), na u al kille (NK) cells, in a ian NK (iNKT)
cells, M2 mac ophages, inna e lymphoid cells ype 2 (ILC2),
and eosinophils. Con e sely, obese adipose issue exhibi s a
p o-in lamma o y p o ile wi h an inc eased p esence o M1
mac ophages, neu ophils, CD8 + T cells, T helpe 1 (Th1)
cells, and a dec eased p esence o iNKT cells, ILC2 cells,
and T eg cells, as well as Th2 immunosupp essi e media-
o s (e.g., In e leukin-4 (IL-4), IL-10, T ans o ming G ow h
Fac o (TGF-β)). This imbalance esul s in a local and sys-
emic dys egula ion o he immune sys em, leading o an
in lamma o y ch onic low-g ade s a e ha is belie ed o be
ans e ed o he cen al ne ous sys em (CNS), po en ially
exace ba ing MS (Da anzo e al., 2023). Acco dingly, s ud-
ies ealized in animal models show ha a sys emic ch onic
low-g ade in lamma ion o igina ing in adipose issue may
impac he blood–b ain ba ie (BBB), causing a educ ion
Neu oMolecula Medicine (2025) 27:19 19 Page 4 o 13
in anscy osis and igh junc ion p o eins in animal mod-
els (P ei e e al., 2011; Ransoho e al., 2015; Va a ha aj
& Galea, 2017). This, coupled wi h in lamma ion-induced
up egula ion o ascula cell adhesion molecule 1 (VCAM-
1), in e cellula adhesion molecule 1 (ICAM-1), P-selec in,
and E-selec in, could induce leukocy e ex a asa ion (Ca -
alho-Ta a es e al., 2000; Chai & Song, 2014). Addi ion-
ally, bo h Tumo Nec osis Fac o (TNF)-α and IL-1β induce
he exp ession o he chemokines chemokine (C-X-C mo i )
ligand (CXCL)1 and CCL2, u he enhancing leukocy e
ec ui men (Skelly e al., 2013). These p ocesses indica e
possible ansla ion o immune phenomena om adipose
issue o he b ain, which migh induce pa hological e en s,
such as MS.
The onse o MS du ing pedia ic ages is associa ed wi h
g ea e disabili y and disease se e i y compa ed o adul -
onse MS in epidemiological s udies (Pé in e al., 2018).
While he ea ly occu ence o MS o i s p ecu so , clini-
cally isola ed synd ome, was hough o be a e, i s incidence
is inc easing (Lange -Gould e al., 2013). In ac , 3–5% o
adul s wi h MS ha e been ound o exhibi clinical symp-
oms be o e he age o 18 (Gian ancesco e al., 2014). As
highligh ed ea lie , MS is a mul i ac o ial disease in ol ing
bo h gene ic and en i onmen al ac o s (Pé in e al., 2018).
Consequen ly, he ques ion a ises: could obesi y du ing pedi-
a ic age be a isk ac o o MS? Se e al s udies sugges a
posi i e esponse o his ques ion (Pé in e al., 2018; Sikes
e al., 2018). Howe e , mode a e obesi y in p eadolescen
age (5–10yea s) does no appea o be associa ed wi h he
isk o de eloping MS. On he o he hand, a popula ion
based s udied has concluded ha obesi y in adolescence and
young adul hood inc eases 50% he isk o MS (Høglund
e al., 2021). Rega ding he associa ion be ween body mass
index (BMI) and MS p og ession, published s udies p esen
inconclusi e and con adic o y indings. No s a is ically
signi ican associa ion seems o exis be ween BMI and he
p esence o oligoclonal bands in ce eb ospinal luid, dis-
ease du a ion, and expanded disabili y s a us sco e (EDSS)
(Çoban e al., 2015). Howe e , i has been obse ed ha
o e weigh o obese indi iduals espond less a o ably o
in e e on-be a ea men . Addi ionally, some s udies sugges
ha obese and smoking pa ien s ace a highe isk o disease
p og ession compa ed o obese non-smoke s, wi h smoking
ac ing as a po en ial con ounding ac o (Bo e e al., 2016).].
Recen ly, epidemiological da a seem o associa e obesi y
wi h highe disease se e i y and poo e ou come (Lu ul-
lin e al., 2023) and oge he wi h o he isk ac o s such as
smoking may con ibu e o ea ly disease ac i i y (B iggs
e al., 2018).
Gende di e ences ha e been no ed in he associa ion
be ween high BMI and inc eased disabili y o e he yea s.
In obese women, a highe BMI is associa ed wi h a wo se
EDSS, while in men, con a y o expec a ions, o e weigh
o obesi y is linked o a lowe EDSS (Bo e e al., 2016).
Howe e , some s udies ha e only ound a s a is ically posi-
i e associa ion be ween high BMI and disease p og ession
in men (Paz-Balles e os e al., 2017). A po en ial explana ion
o hese esul s is he di e ing body composi ion, wi h a i-
a ions in adipose issue and musculoskele al issue depend-
ing on gende (Bo e e al., 2016).
The e o e, adop ing heal hy li es yle habi s such as no
smoking and a oiding alcohol could po en ially imp o e he
Fig. 2 The e seems o be a
balanced immune s a e in lean
subjec wi h an in ac blood–
b ain ba ie (BBB) and a
heal hy cen al ne ous sys em,
whe eas he e seems o be a
ch onic low-g ade in lamma ion
s a e in obese indi iduals wi h a
comp omised BBB because o
he disbalanced in lamma o y
s a e p esen in hese subjec s.
This si ua ion may acili a e
he in il a ion o immune cells
in o he b ain pa enchyma o
obese indi iduals. Obesi y-
induced in lamma ion may be
a con ibu ing ac o o MS, in
which glial cells a e a acked,
leading o myelin loss and
neu odegene a ion. Lep in is
a p o-in lamma o y adipokine
sec e ed in highe quan i ies by
obese people’s adipose issue
Neu oMolecula Medicine (2025) 27:19 Page 5 o 13 19
p ognosis o pa ien s wi h MS (Paz-Balles e os e al., 2017).
An in e es ing s udy sugges s ha people wi h MS do no
end o gain weigh as he yea s pass, unlike he heal hy pop-
ula ion. This phenomenon can be explained by wo heo ies.
Fi s ly, a e yea s ollowing he onse o he i s symp oms,
mos pa ien s a e al eady o e weigh o obese. The second
explana ion s ems om he p og essi e sa copenia occu ing
in hese indi iduals due o in lamma ion and degene a i e
p ocesses in he disease (Bo e e al., 2016).
P o‑ andAn i‑In lamma o y E ec s
o Adipokines
Bo h ood in ake and ene gy expendi u e a e egula ed by
he CNS, which in eg a es pe iphe al signals such as ho -
mones, me abolic media o s, and signals om he pe iphe al
ne ous sys em. These signals ac h ough he sympa he ic
and he pa asympa he ic ne ous sys ems o con ol basal
me abolism.
The i s iden i ied cause o monogenic obesi y was a de i-
ciency in lep in, a ho mone ha egula es ood in ake and
basal me abolism a he cen al le el (Zhang e al., 1994).
Adminis a ion o lep in has been shown o p e en obesi y
in indi iduals wi h his de iciency (Halaas e al., 1995; Pel-
leymoun e e al., 1995).
Nowadays, adipose issue is conside ed no only a
“lipid s o e,” bu also an endoc ine o gan (Ke shaw &
Flie , 2004). This endoc ine issue sec e es di e en kinds
o pep idic media o s known as adipokines. These ha e a
sec e ion p o ile depending on he adipocy e hype ophy,
ul illing nume ous physiological unc ions, besides in he
adipose issue, in o he a ge o gans, including he b ain,
li e , muscle, ascula u e, hea , panc eas and he immune
sys em (Blühe & Man zo os, 2015). The e a e adipokines
wi h an i- and p o-in lamma o y p ope ies (Dahlman e al.,
2012; Leh e al., 2012a, 2012b; Pé ez-Pé ez e al., 2017).
As an i-in lamma o y adipokines a e adiponec in o apelin,
whe eas in he p o-in lamma o y ones can be ound esis-
in, cheme in, is a in, o he adipokine lep in, which is he
objec i e o his e iew. Lep in, sec e ed in highe quan i-
ies in obese indi iduals, is he p incipal egula o o body
weigh and migh be a ac o in inc easing MS isk in hese
subjec s (Dahlman e al., 2012; Keyhanian e al., 2019)
(Fig.2).
Lep in, encoded by he LEP gene, can be so ou as a
p o-in lamma o y adipokine ha has di e en immunologi-
cal e ec s (Pé ez-Pé ez e al., 2017; Sánchez-Ma gale e al.,
2010). Lep in ac s on speci ic hypo halamic nuclei induc-
ing physiological ne signal o sa ie y and gene a ing ene gy
expendi u e, h ough inducing sec e ion o an ano exigenic
signal (p o-opiomelanoco in) and supp essing an o exi-
genic one (neu opep ide Y) (Kwon e al., 2016). I can signal
h ough six di e en splice a ian s o a ecep o (LepRa,
LepRb, LepRc, LepRd, LepRe, and LepR ), membe o
he Class I cy okine amily (Ta aglia e al., 1995). Only
he long o m (LepRb) can signal in acellula ly (Ma ín-
Rome o & Sánchez-Ma gale , 2001; Sanchez-Ma gale &
Ma in-Rome o, 2001; Wada e al., 2014). The lep in ecep-
o LepRb, when bound o lep in, is able o ac i a e di e -
en signaling pa hways h ough he au ophospho yla ion o
“Janus Kinase 2” (JAK2). Once ac i a ed, i is capable, in
u n, o phospho yla ing di e en y osine esidues o he
lep in ecep o (Ty 985, Ty 1077, and Ty 1138) ha medi-
a e in acellula signaling h ough di e en pa hways. These
in acellula pa hways a e JAK2/signal ansduce ac i a o s
o ansc ip ion 3 (STAT3), phospha idylinosi ol 3-kinase
(PI3K)/p o ein kinase B (Ak ), ex acellula signaling- egu-
la ed kinases (ERK), and signal ansduce ac i a o s o an-
sc ip ion 5 (STAT5) (Ma ín-Rome o & Sánchez-Ma gale ,
2001; Sanchez-Ma gale & Ma in-Rome o, 2001; Wada
e al., 2014). Fu he mo e, lep in in luences bo h inna e and
adap i e immuni ies (Pé ez-Pé ez e al., 2017; Sánchez-
Ma gale e al., 2003). Rega ding inna e immuni y, i ac i-
a es he p oli e a ion o monocy es/mac ophages along
wi h he p oduc ion o p o-in lamma o y cy okines, such
as TNF-α, IL-6, and IL-12, among o he s (Sánchez-Ma -
gale e al., 2010). I also a ec s neu ophils and NK cells
(Ahmed e al., 2007; Tian e al., 2002) as well as dend i ic
cells (Ma ioli e al., 2005). Conce ning adap i e immuni y,
lep in s imula es he p oli e a ion o nai e T lymphocy es
and p omo es di e en ia ion in o Th1 lymphocy es ha
p oduce p o-in lamma o y cy okines like INF-γ and IL-2.
Addi ionally, i supp esses p oli e a ion o egula o y T lym-
phocy es esponsible o immuno ole ance (Ma a ese e al.,
2010; Ve sini e al., 2014), which has been sugges ed o be
in ol ed in he pa hogenesis o MS (Ma a ese e al., 2008).
In addi ion o all he e ec s men ioned abo e, lep in could
play a signi ican ole in he BBB since i al e s pe meabili y
when he endo helium is damaged (de Candia & Ma a ese,
2018).
Howe e , he majo i y o obesi y cases esul om he
in e ac ion o mul iple gene ic ac o s. Typically, obese indi-
iduals exhibi inc eased ci cula ing lep in le els (Considine
e al., 1996; Ma ei e al., 1995a, 1995b), due o esis ance o
he e ec s o lep in (Schwa z e al., 1996). Consequen ly,
ea men wi h lep in is o en ine ec i e. Lep in, a 146-
amino acid (16kDa) polypep ide ho mone (Zhang e al.,
1994), sha es simila i ies wi h membe s o he long-chain
helical cy okine amily (including IL-6, IL-11, IL-12, Leu-
kemia inhibi o y ac o (LIF), g anulocy e-colony s imula -
ing ac o (G-CSF), Cilia y neu o ophic ac o (CNTF),
and oncos a in M) and is p ima ily p oduced by adipose
issue (Ma ei e al., 1995a, 1995b) I belongs o he class I
long-chain helical cy okines and signals by in e ac ing wi h
a class I cy okine ecep o (Ob-R), exp essed in a ious
Neu oMolecula Medicine (2025) 27:19 19 Page 6 o 13
issues and cells (Ta aglia e al., 1995) (Pé ez-Pé ez e al.,
2017; Sánchez-Ma gale e al., 2003, 2010). Lep in le els
co ela e wi h adipose mass, esul ing in highe lep in le els
in obese indi iduals compa ed o leane coun e pa s (F ed-
e ich e al., 1995; Ma ei e al., 1995a, 1995b) Addi ionally,
lep in p oduc ion is egula ed by di e en ho mones, such
as insulin (Pé ez-Pé ez e al., 2013; Wabi sch e al., 1996)
o es ogen, po en ially explaining he highe lep in le els
ound in women (Shimizu e al., 1997).
Lep in ac s cen ally as a sa ie y ac o , inducing ano-
exigenic signals and inhibi ing he p oduc ion o o exi-
genic neu opep ides in he nucleus a cua e (Cowley e al.,
2001). Ne e heless, lep in has a ious ac ions connec ing
me abolism wi h he immune sys em (Pé ez-Pé ez e al.,
2017). I a ec s he inna e immune sys em by ac i a ing he
p oli e a ion o monocy es/mac ophages and inducing he
p oduc ion o p o-in lamma o y cy okines, such as TNF-α,
IL-6, and IL-12 (Lo eda e al., 1998) (Fig.3). Lep in also
ac s on neu ophils and NK cells, whe e he lep in ecep-
o is exp essed—speci ically, he sho o m in neu ophils
(Ob-Ra) (B uno e al., 2005; Za kesh-Es ahani e al., 2004),
and bo h he sho and long o ms in NK cells (Zhao e al.,
2003). Fu he mo e, lep in in luences he adap i e immune
sys em by s imula ing he p oli e a ion o T lymphocy es
and p omo ing di e en ia ion owa d he Th1 pheno ype,
esul ing in he p oduc ion o p o-in lamma o y cy okines,
such as INF-γ and IL-2 (Ma ín-Rome o e al., 2000). Simul-
aneously, lep in supp esses he p oli e a ion o T eg cells
(P ocaccini e al., 2010).
Lep in andMul iple Scle osis
Monocy es a e one o he componen s o he inna e immune
sys em capable o c ossing he blood–b ain ba ie (BBB)
when comp omised, as obse ed in au oimmune dis-
eases like mul iple scle osis (MS). No ably, obesi y has
been shown o exace ba e he expe imen al au oimmune
encephalomyeli is (EAE) mouse model o MS, leading o
BBB dis up ion (S ampanoni Bassi e al., 2020), wi h lep-
in po en ially con ibu ing o his e ec . The lep in ecep-
o is exp essed in human pe iphe al blood mononuclea
cells (Ma ín-Rome o & Sánchez-Ma gale , 2001; Ma ín-
Rome o e al., 2000; Sanchez-Ma gale & Ma in-Rome o,
Fig. 3 The lep in ecep o on in il a ing monocy es is ac i a ed by
lep in, which is p esen a ele a ed le els, pa icula ly in obese indi-
iduals. Lep in ecep o exp ession is inc eased in indi iduals wi h
elapsing mul iple scle osis (MS), and his ecep o is capable o
ini ia ing se e al in acellula signaling pa hways, including JAK2/
STAT3, PI3K/Ak , and ERK. Ac i a ion o he lep in ecep o leads
o an inc eased exp ession o p o-in lamma o y cy okines, such as
IL-6 and TNF-α, as well as enhanced phospho yla ion o STAT3 in
elapsing MS pa ien s. Howe e , SOCS3, a downs eam egula o o
he lep in ecep o and JAK2/STAT3 pa hway, is down egula ed in
MS. Unde non-pa hological condi ions, SOCS3 is ypically up egu-
la ed o nega i ely egula e lep in ecep o signaling. The mechanisms
unde lying he educed exp ession o SOCS3 in MS emain unclea .
Finally, hese in il a ing monocy es c oss he blood–b ain ba ie o
en e he cen al ne ous sys em pa enchyma, whe e hey di e en ia e
in o mac ophages
Neu oMolecula Medicine (2025) 27:19 Page 7 o 13 19
2001) including monocy es (San os-Al a ez e al., 1999)
and ele a ed exp ession has been iden i ied on monocy es o
people wi h elapsing– emi ing MS (RRMS) compa ed o
hose in emission o heal hy con ols (F isullo e al., 2007).
Fu he mo e, esea che s obse ed inc eased p-STAT3 and
dec eased supp esso o cy okine signaling 3 (SOCS3)
exp essions in monocy es o elapsing people wi h MS wi h
highe se um lep in le els han con ols. These indings sug-
ges a po en ial ole o lep in signaling in he exace ba-
ion o MS in elapsing pa ien s, making lep in signaling
a plausible a ge in he igh agains MS (Fig.3). Besides,
lep in may con ibu e o he de elopmen o MS ia oxida-
i e s ess as ecen ly e iewed (Tanaka & Vécsei, 2020).
As Lep in can induce p oli e a ion and phagocy ic ac i -
i y in human mac ophages, as well as sec e ion o p o-
in lamma o y cy okines, such as TNF-α, IL-1β, and IL-6
(Dayaka e al., 2016), besides, in animal models, lep in can
induce he exp ession o IL-6, IL1-β, and TNF-α in mic o-
glia (La ance e al., 2010; Pin eaux e al., 2007; Tang e al.,
2007), a CNS-speci ic mac ophage-like cell, esponsible o
su ey he CNS pa enchyma. Mo eo e , lep in, h ough i s
signaling pa hways and in he con ex o MS, seems o ha e
a p o-in lamma o y ole, which agg a a e disease p og es-
sion: in he con ex o EAE o he mouse model o MS,
lep in adminis e ed exogenously may be able o agg a a e
such s a e, whe eas s a a ion, which p oduces a signi i-
can dec ease in lep in le els, may alle ia e i (Lo d e al.,
1998). Simila ly, adminis a ion o lep in o mice wi hou
lep in de iciency bu suscep ible o expe imen al au oim-
mune encephalomyeli is (EAE) wo sens he disease cou se,
while he adminis a ion o an i-lep in ecep o an ibodies
amelio a es i (Ma a ese e al., 2001). Fu he mo e, he EAE
mouse model has demons a ed insi u lep in p oduc ion in
in lamma o y in il a es and neu ons, occu ing exclusi ely
du ing acu e/ac i e phases o EAE. Con e sely, s a a-
ion delayed disease onse and a enua ed symp oma ology
(Sanna e al., 2003). Co esponding esul s in humans ha e
been obse ed. In people wi h elapsing– emi ing mul iple
scle osis (RRMS), inc eased le els o lep in in ce eb ospi-
nal luid and blood se um ha e been demons a ed (Lock
e al., 2002). T ansc ip ional analysis o lep in exp ession a
si es o in lamma ion in MS b ains showed ele a ed le els
o lep in. Mo e ecen ly, an inc eased isk o MS was co -
ela ed wi h obesi y and lep in in young people (Bis öm
e al., 2021; Ma odan e al., 2021; S ampanoni Bassi e al.,
2020). Simila ly, se um lep in le els dec eased in pa ien s
wi h seconda y p og essi e MS (SPMS) who did no expe i-
ence disease p og ession (Angelucci e al., 2005). Mo eo-
e , lep in le els may be a ma ke o ac i i y in ea ed wi h
in e e on-be a (Ba occhi e al., 2003).
Wi hou conside ing obesi y, no ela ionship wi h body
mass index (BMI) was ound. In a c oss-sec ional s udy
compa ing lep in se um le els be ween people wi h MS
and a con ol g oup, a signi ican inc ease in lep in le els
was desc ibed in indi iduals wi h MS, accompanied by a
dec ease in o exin-A and TGF-β (Moha ami e al., 2022).
Howe e , a di e en s udy epo ed di e en esul s, wi h
signi ican ly lowe blood lep in le els in he case g oup com-
pa ed o he con ol g oup (Cinki e al., 2021). No e ec on
lep in le els unde dime hyl uma a e ea men was ound,
bo h in a longi udinal and a c oss-sec ional s udy, be ween
MS-a ec ed and con ol g oups (Baha noo i e al., 2021)
Simila ly, no e ec on lep in le els o MS isk was iden i-
ied, al hough he e was an e ec on MS isk combined wi h
low i amin D le els in a Mendelian andomiza ion s udy
(Ha oud e al., 2021).
O e all, his may sugges a egula o y ole o lep in,
whe e inc eased le els, as obse ed du ing obesi y, ip he
balance owa d an exace ba ion o he immune sys em and
a loss o immune sel - ole ance, po en ially wo sening MS
p og ession. Howe e , u he clinical in es iga ion in his
ield is necessa y o cla i y he ole o obesi y and lep in in
MS, as he unde lying mechanisms emain unclea .
Die a y In e en ions inObese Pa ien s
wi hMul iple Scle osis
I is well known ha indi iduals wi h mul iple scle o-
sis (MS) exhibi poo e die a y habi s han hei heal hy
coun e pa s, po en ially con ibu ing o obse ed cases o
o e weigh and obesi y among some pa ien s. Addi ionally,
s udies ha e indica ed ha indi iduals wi h die s high in
sa u a ed a s a e h ee imes mo e likely o expe ience dis-
ease elapses, whe eas die s ich in ege ables may educe
his isk. Hence, speci ic die a y habi s appea o be associ-
a ed wi h he p og ession o MS (Mische & Mow y, 2018).
The Medi e anean die , enowned o i s posi i e e ec s
on ca dio ascula heal h, has been examined in a la ge-scale
s udy in ol ing housands o people wi h MS. O e 50% o
hese pa ien s we e ound o ha e ca dio ascula diseases,
which co ela ed wi h a poo e p ognosis and inc eased
disabili y in walking, as indica ed by highe sco es on he
Pa ien -De e mined Disease Scale (PDDS). Ele a ed con-
cen a ions o iglyce ides and low-densi y lipop o ein
(LDL) in he blood we e also linked o a g ea e numbe o
lesions on T2-weigh ed magne ic esonance imaging, po en-
ially esul ing om mic o-ischemic in a c s a he han
ypical MS- ela ed lesions. Howe e , i emains unp o en
ha he Medi e anean die , while bene icial o ascula
pa hologies, imp o es he Expanded Disabili y S a us Scale
(EDSS) o he Fa igue Se e i y Scale (FSS) (Mische &
Mow y, 2018). No ably, many people wi h MS ha e expe-
ienced a clinical imp o emen wi h a low- a die (Yada
e al., 2016; Zhang e al., 2000). Al hough i s impac on
he p ognosis o clinical- adiological ac i i y o he disease
Neu oMolecula Medicine (2025) 27:19 19 Page 8 o 13
has no been conclusi ely demons a ed, he low- a die
p o es use ul o weigh loss, educing a igue, and lowe -
ing LDL and blood choles e ol le els. I is plausible ha he
alle ia ion o a igue in his con ex is mo e closely linked
o a lowe body mass index (BMI) han o he die i sel
(Mische & Mow y, 2018). Inc eased sodium in ake has been
obse ed o wo sen he se e i y o he disease in expe imen-
al au oimmune encephalomyeli is (EAE) models (Kleinewi-
e eld e al., 2013). In con as , high-sodium die s do no
seem o posi i ely in luence he cou se o MS in human
s udies (Co ese e al., 2017; Mische & Mow y, 2018).
Nume ous expe imen al s udies on EAE ha e consis en ly
shown ha calo ie- es ic ed die s can mi iga e he isk o
disease onse , se e i y, neu odegene a ion, in lamma ion,
and inc ease su i al a es in mice (Piccio e al., 2008).
Va ious mechanisms ha e been p oposed o explain how
in e mi en as ing, daily as ing, and calo ie es ic ion can
enhance he clinical cou se o he disease (Choi e al., 2016;
Ka ami e al., 2010). These die a y in e en ions egula e
immune unc ion by dec easing he sec e ion o in e e on-
gamma (IFN-γ), umo nec osis ac o -alpha (TNF-α), lep-
in, and in e leukin-6 (IL-6), while ele a ing concen a ions
o IL-10, he eby educing in lamma ion, demyelina ion, and
MS- ela ed axonal lesions.
Bo h daily and in e mi en calo ie es ic ions h oughou
he week ha e been deemed sa e o weigh loss in people
wi h MS. Addi ionally, hese app oaches help p e en ca -
dio ascula e en s and enhance he emo ional well-being o
indi iduals wi h MS. Se e al s udies ha e sugges ed ha ,
pa icula ly in he ea ly s ages o he disease be o e physical
disabili y se s in, he emo ional s a e o pa ien s is one o
he mos c ucial symp oms associa ed wi h la e disabili y.
Thus, e en i imp o emen s in he clinical and adiologi-
cal condi ion a e no achie ed, weigh loss h ough calo ie
es ic ion can alle ia e symp oms, o e ing emo ional elie
o he pa ien (Fi zge ald e al., 2018).
The posi i e e ec s o hese die a y in e en ions may
be pa ly media ed by he imp o emen in lep in esis ance
and, consequen ly, he educ ion in lep in le els, coun e ing
in lamma ion in MS, as p e iously sugges ed in diabe es and
o he complica ions associa ed wi h obesi y (Mon se a -de
la Paz e al., 2021; Pé ez-Pé ez e al., 2020a, 2020b).
Final Rema ks
Nume ous ac o s con ibu e o ch onic in lamma ion in
he con ex o obesi y, wi h adipokines, pa icula ly lep in,
eme ging as he connec ion be ween obesi y and immuni y.
Lep in, among i s a ious unc ions, suppo s he in i o
su i al o mul iple immune cells implica ed in he pa ho-
genesis o MS. Addi ionally, lep in p omo es in lamma o y
esponses by inc easing he p oli e a ion o , among o h-
e s, Th1 lymphocy es, while simul aneously educing he
numbe o T eg cells. Mos s udies ha e been conduc ed in
animal models and s udies in humans a e sca ce. Ne e he-
less, clinical s udies seem o associa e lep in le els wi h he
disease (Table1).
As can be assessed in he Table, he low numbe o clini-
cal s udies is a clea limi a ion. Ne e heless, o he clini-
cal s udies a e in p og ess o in es iga e he ole o lep in
in MS and he esponse o ea men o nu i ional in e -
en ion: Eud aCT Numbe : 2013-004450-21; ClinicalT i-
als.go : NCT02064816, NCT02411838, NCT03539094,
NCT04593082, NCT02647502, NCT05327322, and
NCT01067573.
Bo h he Medi e anean die and calo ic es ic ion ep e-
sen sa e me hods o weigh loss in obese indi iduals wi h
MS, displaying p omising ou comes, po en ially by imp o -
ing lep in esis ance in he hypo halamus and educing ci -
cula ing le els. Howe e , obus e idence suppo ing di ec
bene i s is s ill lacking (Table1).
In summa y, scien i ic e idence sugges s ha obesi y
se es as a isk ac o o MS, wi h his associa ion becom-
ing mo e p onounced when obesi y occu s du ing c i ical
ages be ween 12 and 18yea s. Highe concen a ions o
p o-in lamma o y adipokines, including lep in, ha e been
obse ed in people wi h MS compa ed o heal hy indi idu-
als. The ela ionship be ween clinical- adiological ac i i y
h oughou he disease cou se and lep in concen a ions
emains unclea . Fu he s udies a e wa an ed o alida e
lep in concen a ion as a bioma ke o po en ial he apeu ic
a ge .
Acknowledgemen s We acknowledge he suppo o he Jun a de
Andalucía.
Table 1 Role o lep in in MS and clinical s udies
Lep in le els E ec s on MS MS pheno ype Re e ences
Inc eased blood lep in and/o lep in ecep o
le els
Disease ac i i y RRMS (Cinki e al., 2021; F isullo e al., 2007; Ma -
odan e al., 2021; Moha ami e al., 2022;
S ampanoni Bassi e al., 2020)
Inc eased lep in le els in CSF Disabili y RRMS (S ampanoni Bassi e al., 2020)
Low lep in le els Lack o p og ession SPMS (Angelucci e al., 2005)
Nu i ional in e en ion ha may lowe lep in
le els
Possible less p og ession PMS, RRMS (Fi zge ald e al., 2018; Mische & Mow y, 2018;
Yada e al., 2016; Zhang e al., 2000)
Neu oMolecula Medicine (2025) 27:19 Page 9 o 13 19
Au ho Con ibu ions J.A.F.-C., A.A.M., V.S.-M., T.V.-G., and A.P.-P.
w o e he d a . R.F.-C., L.H.-P., and D.J.G.-D. p epa ed he igu es.
All au ho s e iewed he manusc ip .
Funding Funding o open access publishing: Uni e sidad de Se illa/
CBUA. L.H-P. is suppo ed by he Conseje ía de Salud y Familias,
Jun a de Andalucía (RH-0047-2021). D.J.G-D. is suppo ed by he VII
Plan P opio de In es igación y T ans e encia o Uni e sidad de Se illa
[Con a o de Acceso (II.4)/VII PPIT-US]. VSM is he PI o he g oup
CTS-151 suppo ed by Jun a de Andalucia.
Da a A ailabili y No da ase s we e gene a ed o analyzed du ing he
cu en s udy.
Decla a ions
Compe ing in e es s The au ho s decla e no compe ing in e es s.
E hical App o al No applicable.
Consen o Pa icipa e No applicable.
Consen o Publica ion No applicable.
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