Academic Edi o : And ea Vania
Recei ed: 15 Ap il 2025
Re ised: 21 May 2025
Accep ed: 23 May 2025
Published: 28 May 2025
Ci a ion: Kou aki, D.; S e anou, G.;
Geni sa idi, S.-M.; Ramouzi, E.;
Ky kili, A.; Kon ogianni, M.D.;
Kokkou, E.; Giannopoulou, E.;
Kassa i, P.; Cha manda i, E. Explo ing
Me abolic Signa u es: Un a eling he
Associa ion wi h Obesi y in Child en
and Adolescen s. Nu ien s 2025,17,
1833. h ps://doi.o g/10.3390/
nu17111833
Copy igh : © 2025 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/).
Sys ema ic Re iew
Explo ing Me abolic Signa u es: Un a eling he Associa ion wi h
Obesi y in Child en and Adolescen s
Diaman o Kou aki 1, Ga y allia S e anou 2, So ia-Ma ia Geni sa idi 1, Eleni Ramouzi 1, A hanasia Ky kili 3,
Me opi D. Kon ogianni 3, Eleni Kokkou 1, Eleni Giannopoulou 1, Penio Kassa i 1,4
and E angelia Cha manda i 1,4,*
1Cen e o he P e en ion and Managemen o O e weigh and Obesi y in Childhood and Adolescence,
Di ision o Endoc inology, Me abolism and Diabe es, Fi s Depa men o Pedia ics,
Na ional and Kapodis ian Uni e si y o A hens Medical School, ‘Aghia Sophia’, Child en’s Hospi al,
11527 A hens, G eece; [email p o ec ed] (D.K.); [email p o ec ed] (S.-M.G.);
[email p o ec ed] (E.R.); [email p o ec ed] (E.K.); [email p o ec ed] (E.G.);
[email p o ec ed] (P.K.)
2ECONCARE—Heal h Resea ch & Consul ing, 11528 A hens, G eece; [email p o ec ed]
3Depa men o Nu i ion and Die e ics, School o Heal h Sciences and Educa ion,
Ha okopio Uni e si y o A hens, 17671 A hens, G eece; [email p o ec ed] (A.K.); [email p o ec ed] (M.D.K.)
4Di ision o Endoc inology and Me abolism, Cen e o Clinical, Expe imen al Su ge y and
T ansla ional Resea ch, Biomedical Resea ch Founda ion o he Academy o A hens, 11527 A hens, G eece
*Co espondence: [email p o ec ed]; Tel.: +30-213-2013-384
Abs ac : Backg ound: Childhood obesi y is a g owing global heal h conce n. Me abolomics,
he comp ehensi e s udy o me aboli es wi hin biological sys ems, o e s a powe ul ap-
p oach o be e de ine he pheno ype and unde s and he complex biochemical al e a ions
associa ed wi h obesi y. The aim o his sys ema ic e iew was o summa ize cu en
knowledge in he ield o me abolomics in childhood obesi y and o iden i y me abolic
signa u es o bioma ke s associa ed wi h o e weigh /obesi y (O /Ob) and Me abolically
Unheal hy Obesi y (MUO) in child en and adolescen s. Me hods: We pe o med a sys em-
a ic sea ch o Medline and Scopus da abases acco ding o PRISMA guidelines. We included
only longi udinal p ospec i e s udies o andomized con olled ials wi h
≥
12 mon hs
o ollow-up, as well as me a-analyses o he abo e ha assessed he ela ion be ween
me abolic signa u es ela ed o obesi y and Body Mass Index (BMI) o o he measu es o
adiposi y in child en and adolescen s aged 2–19 yea s wi h o e weigh o obesi y. Ini ially,
595 eco ds we e iden i ied om PubMed and 1565 om Scopus. A e emo ing duplica es
and sc eening o ele ance, 157 epo s we e assessed o eligibili y. F om he addi ional
sea ch, 75 new eco ds we e e ie ed, o which none we e eligible o ou s udy. Finally,
7 epo s we e included in he p esen sys ema ic e iew (4 epo ing on O /Ob and 4 on
MUO). Resul s: The p esen ed s udies sugges ha he me abolism o amino acids and
lipids is p ima ily a ec ed by childhood obesi y. Me aboli es like glycop o ein ace yls,
he Apolipop o ein B/Apolipop o ein A-1 a io, and lac a e ha e eme ged as po en ial
bioma ke s o insulin esis ance and me abolic synd ome, highligh ing hei po en ial
alue in clinical applica ions. Conclusions: The e is a need o u u e longi udinal s udies
o assess me abolic changes o e ime, in e en ional s udies o e alua e he e icacy o
he apeu ic s a egies, and la ge-scale popula ion s udies o explo e me abolic di e si y
ac oss di e en demog aphics. Ou indings e eal speci ic bioma ke s in he amino acid
and lipid pa hway ha may se e as ea ly indica o s o childhood obesi y and i s associa ed
ca diome abolic complica ions.
Keywo ds: me abolomics; me abolic signa u es; me abolic bioma ke s; childhood obesi y
Nu ien s 2025,17, 1833 h ps://doi.o g/10.3390/nu17111833
Nu ien s 2025,17, 1833 2 o 18
1. In oduc ion
Obesi y has eme ged as a signi ican global heal h issue, wi h i s p e alence ha ing
nea ly ipled om 1975 o 2016 [1]. Acco ding o he Wo ld Heal h O ganiza ion (WHO),
app oxima ely 60% o adul s in Eu ope will be o e weigh o obesi y in 2022 [
2
]. This
ala ming end no only poses immedia e heal h isks bu also p edisposes a ec ed subjec s
o long- e m heal h complica ions, such as hype ension, le en icula hype ophy,
insulin esis ance and diabe es melli us ype 2 (DM2), me abolic dys unc ion-associa ed
s ea o ic li e disease (MASLD), as well as men al heal h issues and cance [
3
]. Fu he mo e,
du ing he las decade, obesi y wi h o wi hou me abolic abe a ions, commonly e med
Me abolically Unheal hy Obesi y (MUO) o Me abolically Heal hy Obesi y (MHO), espec-
i ely, has been ex ensi ely in es iga ed [
4
]. Me abolically Unheal hy Obesi y (MUO) e e s
o subjec s wi h obesi y who exhibi me abolic abno mali ies, such as insulin esis ance,
ele a ed blood p essu e, dyslipidemia (ele a ed iglyce ides and low HDL choles e ol
concen a ions), and ch onic in lamma ion. Unlike me abolically heal hy obesi y (MHO),
whe e subjec s ha e excess body a bu no mal me abolic p o iles, MUO is s ongly associ-
a ed wi h an inc eased isk o DM2, ca dio ascula disease, and non-alcoholic a y li e
disease (NAFLD).
The in ica e in e play o gene ic, epigene ic, en i onmen al, and li es yle ac o s
con ibu es o he mul i ace ed na u e o his epidemic [
3
]. In he ques o a be e unde -
s anding o he unde lying mechanisms and po en ial in e en ions, me abolomics has
eme ged as a powe ul ool, o e ing insigh s in o he me abolic al e a ions associa ed wi h
childhood obesi y [5,6].
Me abolomics is a ield o s udy wi hin he b oade discipline o sys ems biol-
ogy, which ocuses on he comp ehensi e analysis o small molecules o me aboli es
(<1500 KDa) in a biological sample [
7
,
8
]. Me aboli es a e he end p oduc s o cellula
p ocesses, and hei concen a ions can p o ide insigh s in o he biochemical pa hways and
physiological s a us o an o ganism a a speci ic poin in ime. I is pa icula ly use ul in
unde s anding he dynamic esponses o biological sys ems o a ious al e a ions, includ-
ing gene ic, epigene ic, o p o ein-le el modi ica ions, exposu e o en i onmen al ac o s
(physical exe cise, die , and mic obiome) and diseases, and helps b idge he gap be ween
geno ype and pheno ype.
The p ima y goal o me abolomics is o p o ile and quan i y he comple e se o
me aboli es p esen in a biological sample, such as blood, u ine, o issues. This p o iling
in ol es he use o ad anced analy ical echniques, such as mass spec ome y (MS) and
nuclea magne ic esonance (NMR) spec oscopy, coupled wi h a ious ch oma og aphic
sepa a ions o iden i y and quan i y he di e se a ay o me aboli es [
9
]. This way, he
sys ema ic s udy o small molecules wi hin biological sys ems may help us gain insigh in o
he me abolic changes associa ed wi h obesi y, such as adipocy e- ela ed in lamma ion and
insulin esis ance [
10
]. The in-dep h s udy o he unique me abolic inge p in s associa ed
wi h obesi y may help us iden i y po en ial bioma ke s and al e ed me abolic pa hways,
and disco e no el he apeu ic a ge s. Nume ous s udies ha e unde sco ed he u ili y
o me abolomics in elucida ing he complex in e play be ween gene ic p edisposi ion,
die e ic habi s, gu mic obiome, and en i onmen al ac o s in he pa hogenesis o obesi y
in adul s [
11
]. Howe e , o he bes o ou knowledge, ew s udies ha e been conduc ed
in child en and adolescen s [
12
]. Me abolic signa u es may di e in ea ly li e, gi en ha
child en do no usually ecei e medical ea men o obesi y. The e o e, me abolomic
p o iling in child en and adolescen s will no only acili a e he iden i ica ion o po en ial
bioma ke s o he p e en ion and managemen o childhood obesi y and i s associa ed
complica ions, bu i will also un a el no el he apeu ic a ge s.
Nu ien s 2025,17, 1833 3 o 18
The aim o his sys ema ic e iew was o summa ize he cu en knowledge on
me abolomics, childhood obesi y, and MUO, and o iden i y me abolic signa u es o
bioma ke s associa ed wi h obesi y in child en and adolescen s, he eby o e ing a comp e-
hensi e analysis o s udies ha employ me abolomic app oaches. Th ough c i ical exami-
na ion o he li e a u e, his e iew aims o gain a be e unde s anding o he me abolic
in icacies associa ed wi h childhood obesi y and in o m he di ec ion o u u e esea ch
and he apeu ic s a egies.
2. Ma e ials and Me hods
2.1. S udy Design
This sys ema ic li e a u e e iew (SLR) was conduc ed ollowing he P e e ed Re-
po ing I ems o Sys ema ic Re iews and Me a-Analyses (PRISMA) p o ocol [
13
]. The
objec i es we e o mula ed using he PICO/PECO (Popula ion, In e en ions/Exposu e,
Compa a o s, Ou comes) amewo k (Table 1). The e iew was egis e ed in he
In e na ional P ospec i e Regis e o Ongoing Sys ema ic Re iews (PROSPERO 2023
CRD42023494461; h ps://www.c d.yo k.ac.uk/p ospe o/display_ eco d.php?ID=CRD4
2023494461, accessed on 29 Decembe 2023).
Table 1. PICO/PECO amewo k o s udy selec ion on me abolomic bioma ke s and childhood
obesi y isk.
Va iable De ini ion
Popula ion Child en and adolescen s aged 2–19 yea s
Exposu e/In e en ion
Me abolomics, me abolic signa u es, and me abolic bioma ke s
Compa a o No in e en ion, any in e en ion, o s anda d ca e
The absence o he exposu e o a di e en le el o exposu e
Ou come
O /Ob and MUO isk
Associa ion o me abolic signa u es/bioma ke s wi h
obesi y/adiposi y/me abolic diso de s/endoc ine diso de s
2.2. Eligibili y C i e ia
The e iew included longi udinal p ospec i e s udies and andomized con olled ials
(RCTs), wi h a minimum o 12 mon hs o ollow-up, and me a-analyses o he abo e in o de
o ensu e a be e quali y o me hodological design, which would also allow e iological
assump ions. The s udies examined he me abolic signa u es ela ed o obesi y, Body Mass
Index (BMI), o /and o he measu es o adiposi y and MUO in child en and adolescen s
aged 2–19 yea s wi h o e weigh o obesi y. The language was es ic ed o English and he
geog aphic loca ion included only Wes e n coun ies (Eu ope, USA, Canada, and Oceania)
ha sha e simila socioeconomic, physical, and die a y en i onmen s. The inclusion and
exclusion c i e ia a e shown in Table 2.
Table 2. Inclusion and exclusion c i e ia.
Pa ame e Inclusion C i e ia
o All Domains
Exclusion C i e ia
o All Domains
Pa icipan s Human subjec s
Animals
Human subjec s wi h monogenic diso de s
(e.g., MC4R de iciency, lep in de iciency, e c.),
synd omic o ms o obesi y (e.g., P ade –Willi,
Als om synd ome, e c.), o subjec s ecei ing
medica ion known o a ec weigh (an idep essan s,
an iepilep ics, an ipsycho ics, mood s abilize s,
an imanic agen s, and co icos e oids)
Nu ien s 2025,17, 1833 4 o 18
Table 2. Con .
Pa ame e Inclusion C i e ia
o All Domains
Exclusion C i e ia
o All Domains
Age 2 o 19 yea s old <2 yea s old and >19 yea s old
A icle ype Pee - e iewed jou nal
a icles
Le e s, edi o ials, s udy o e iew p o ocols,
p e-p in s
S udy a ea Eu ope, USA, Canada,
Oceania Asia, A ica, Sou h Ame ica
S udy design
Longi udinal p ospec i e
s udies, andomized
con olled ials wi h
≥12 mon hs o ollow-up,
and me a-analyses o
he abo e
C oss-sec ional s udies, con olled expe imen s,
in i o s udies, in i o animal s udies, in silico
s udies, and scoping e iews
Time o publica ion
1 Janua y 2013–3 July 2024
o o iginal publica ions and
1 Janua y 2018–3 July 2024
o me a-analyses
O iginal publica ions p io o 31 Decembe 2012 and
me a-analyses p io o 31 Decembe 2017
Language English Non-English
2.3. Li e a u e Sea ch
A comp ehensi e li e a u e sea ch was conduc ed using PubMed and Scopus
da abases o s udies published om 1 May 2023 o 16 Sep embe 2023. An addi ional da a
sea ch was pe o med on 3 July 2024 o upda e he esul s, e ie ing s udies published a e
16 Sep embe 2023. The sea ch s a egy included a complex s ing o keywo ds ela ed o
me abolic bioma ke s, obesi y, adiposi y, and associa ed me abolic and endoc ine diso de s
in child en and adolescen s. The de ailed sea ch s ings used o MEDLINE (PubMed) and
Scopus a e p esen ed in he Supplemen a y Ma e ials, File S1.
2.4. S udy Selec ion
Two independen esea che s (GS and DK) sc eened he eco ds iden i ied om he
da abases. In ins ances o disag eemen , a hi d esea che (EC) conduc ed a inal e iew.
2.5. Da a Ex ac ion, Ou comes, and Da a Syn hesis
Rele an da a om eligible s udies we e ex ac ed, including publica ion de ails, s udy
design, sample size, pa icipan cha ac e is ics, me abolic signa u es, bioma ke s assessed,
and ou comes ela ed o obesi y and me abolic diso de s. The p ima y ou comes assessed
we e obesi y and MUO in pedia ic popula ions.
2.6. Validi y Assessmen
All included s udies we e assessed o isk o bias using he Risk O Bias In Non-
andomized S udies—o Exposu es (ROBINS-E) ool [
14
]. The isk o bias o each s udy
was e alua ed ac oss se en domains: con ounding (D1), measu emen o exposu e (D2),
selec ion o pa icipan s (D3), pos -exposu e in e en ions (D4), missing da a (D5), mea-
su emen o ou comes (D6), and selec ion o epo ed esul s (D7). Th ee o he included
s udies we e pos hoc analyses o pa icipan s who unde wen a li es yle in e en ion
(“Obeldicks”) wi hin a non- andomized con olled ial [
15
,
16
] o a double-blind, andom-
ized in e en ion ial [
17
]. Since he exposu e o in e es (me aboli es) was no ac i ely
assigned, ROBINS-E was deemed he mos app op ia e ool o assessing he isk o bias in
hese s udies.
Nu ien s 2025,17, 1833 5 o 18
2.7. Da a Managemen and Syn hesis
Da a we e managed using Mendeley and Excel. Da a ex ac ion o ms we e pilo ed
and e ined o ensu e consis ency and accu acy. Disc epancies be ween e iewe s we e
esol ed h ough discussion and consensus. The ex ac ed da a we e syn hesized o p o ide
a comp ehensi e analysis o he me abolic signa u es associa ed wi h childhood obesi y
and MUO. The syn hesis in ol ed quali a i e analyses o summa ize he indings and
iden i y po en ial bioma ke s and he apeu ic a ge s. The cha ac e is ics o he included
s udies, e.g., s udy design, coun y, sample size, age, ollow-up pe iod, me hodology, key
me aboli es iden i ied, and epo ed ou come a e p esen ed in Table 3.
Table 3. Cha ac e is ics o he included s udies.
S udy
Coun y
S udy Design Sample
Size
Age,
Mean ±SD
Follow-Up
Pe iod
Me hodology
Key Me aboli es
Iden i ied
Singh
e al.,
2023
[18]
USA
Longi udinal
coho s udy
(Buckeye Teen
Heal h S udy)
81
(100%
males)
16.08 ±1.20
yea s 1 yea UPLC-QTOF-
MS (u ine)
Glycylp oline,
3’-Sialyllac ose,
Fo miminoglu amic acid,
4-hyd oxyp oline,
Ci ulline, Inosine
Mansell
e al.,
2022
[19]
Aus alia
Longi udinal
coho s udy
(COBRA coho )
98
(52%
males)
10.3 ±3.5
yea s 5 yea s NMR
(se um)
XL-VLDL-L, L-VLDL-L,
S-VLDL-L, ApoB/ApoA1,
VLDL-C, MUFAs,
MUFAs%, alanine,
phenylalanine, y osine,
py u a e, glycop o ein
ace yls, HDL-C, LA%,
Omega-6%, PUFAs,
Ace oace a e,
3-hyd oxybu y a e
Reineh
e al.,
2014
[15]
Ge many
Pos hoc analysis
o pa icipan s
who unde wen
a li es yle
in e en ion
(“Obeldicks”)
wi hin a
non- andomized
con olled ial
160
(61.3%
males)
11 ±2 yea s 1 yea HPLC-MS
(se um)
Glu amine, me hionine,
LPCaC18:1, LPCaC18:2,
LPCaC20:4, PCaeC36:2
Hellmu h
e al.,
2019
[17]
Eu ope
(mul i)
Pos hoc
longi udinal
analysis o
bioma ke
changes o e
2.5 yea s in
pa icipan s om
he CHOP s udy,
a double-blind,
andomized
in e en ion ial
396
(50%
males)
5.5 ±0.07
yea s 2.5 yea s UPLC-QTOF-
MS (se um)
F ee ca ni ine, SM 32:2,
SM 34:2, Ca n 3:0
Ojanen
e al.,
2021
[20]
Finland Longi udinal
coho s udy
396
(0%
males)
11.2 ±0.4
yea s 7.5 yea s NMR
(se um)
ApoB/ApoA a io,
GlycAs
Nu ien s 2025,17, 1833 6 o 18
Table 3. Con .
S udy
Coun y
S udy Design Sample
Size
Age,
Mean ±SD
Follow-Up
Pe iod
Me hodology
Key Me aboli es
Iden i ied
Hellmu h
e al.,
2016
[16]
Ge many
Pos hoc analysis
o pa icipan s
who unde wen
a li es yle
in e en ion
(“Obeldicks”)
wi hin a
non- andomized
con olled ial
80
(45%
males)
11.5 ±2.4
yea s 1 yea HPLC-MS
(se um)
Acylca ni ines, amino
acids
Hosking
e al.,
2019
[21]
UK,
Swi ze -
land
Longi udinal
coho s udy
(Ea lyBi d
coho )
190
[S udy 1:
40 (50%
males);
S udy 2:
150 (70%
males)]
4.8–5.1 yea s
S udy 1:
9 yea s;
S udy 2:
11 yea s
1H NMR
(se um)
Amino acids, lipids,
lac a e
2.8. E hical Conside a ions
Since his s udy is a sys ema ic e iew, e hical app o al was no equi ed. Howe e ,
e hical s anda ds we e main ained h oughou he e iew p ocess, ensu ing he in eg i y
and accu acy o he indings.
3. Resul s
3.1. Cha ac e is ics o Included S udies
Ini ially, 595 eco ds we e iden i ied om PubMed and 1565 om Scopus. A e
emo ing duplica es and sc eening o ele ance, 175 epo s we e assessed o eligibili y.
Ul ima ely, 7 (4 longi udinal and 3 pos hoc analyses o in e en ional s udies) epo s we e
included in he e iew. F om he addi ional sea ch, 124 new eco ds we e e ie ed, om
which none we e eligible o ou s udy. The low diag am is p esen ed in Figu e 1.
Se en epo s, which we e de i ed om six s udies, me he inclusion c i e ia and
we e included in his sys ema ic e iew. These s udies we e conduc ed in a ious coun-
ies, including he USA [
18
], Ge many [
15
–
17
], Belgium [
17
], I aly [
17
], Poland [
17
],
Spain [
17
], Aus alia [
19
], UK [
21
], Swi ze land [
21
] and Finland [
20
]. The included s udies
we e p ima ily longi udinal coho s udies [
18
–
21
] and pos hoc analyses o in e en ion
s udies [
15
–
17
], wi h ollow-up pe iods anging om 1 yea [
15
,
16
,
18
] o 11 yea s [
21
].
The in e en ion pa included li es yle ecommenda ions ega ding physical ac i i y,
nu i ion, and beha io al he apy o he child en and hei amilies. The sample size
o hese s udies a ied signi ican ly, om 40 o 396 pa icipan s, and he age a baseline
anged om 2 o 19 yea s. Se um and u ine samples we e used o he assessmen o
me abolomic bioma ke s.
The included s udies examined he associa ion be ween me abolic p o iles and obesi y-
ela ed ou comes using a ious app oaches (Table 4). Singh e al. (2023) explo ed he
me abolic ea u es associa ed wi h inc eased BMI a one-yea ollow-up [
18
]. Mansell
e al. (2022) explo ed he associa ion be ween changes in BMI and me abolomic p o-
iles o e a 5.5-yea ollow-up pe iod [
19
]. Reineh e al. (2014) assessed he me abo-
li e changes in child en wi h obesi y who unde wen a li es yle in e en ion and com-
pa ed hose wi h subs an ial weigh loss o hose wi hou subs an ial weigh loss [
15
].
Hellmu h e al. (2019) used me aboli e concen a ions a 5.5 yea s o p edic BMI z-sco es a
age 8 in he CHOP s udy [
17
]. Ojanen e al. (2021) de eloped a s anda dized isk sco e o
Nu ien s 2025,17, 1833 7 o 18
me abolic synd ome (Me S), ha ing inco po a ed me abolic and ca dio ascula pa ame e s
ha con e ca diome abolic isk [
20
]. Hellmu h e al. (2016) in es iga ed he associa ion
be ween me aboli e changes and HOMA-IR o e a one-yea li es yle in e en ion (physical
ac i i y, nu i ion educa ion, and beha io he apy) [
16
]. Hosking e al. (2019) examined
he ela ion be ween indi idual me aboli es and insulin esis ance (HOMA-IR) in heal hy
child en, aking in o accoun he e ec s o age, BMI, g ow h, pube y, adiposi y, and physi-
cal ac i i y [
21
]. This s udy included a pilo phase o iden i y me abolically dis inc p o iles
ela ed o insulin esis ance and a ollow-up phase ex ending he analysis o he age o
16 yea s o alida e he indings.
Reco ds ini ially e ie ed:
PubMed (n = 595)
Scopus (n = 1,565)
Addi ional eco ds e ie ed on
2
nd
sea ch (n = 124)
Reco ds emo ed be o e sc eening:
Duplica e eco ds emo ed (n = 686; o
hose 49 we e om he 2
nd
sea ch)
Reco ds sc eened:
(n = 1598) Reco ds excluded: (n = 1422)
Repo s sough o e ie al:
(n = 176)
Repo s no e ie ed: (n = 1)
Repo s assessed o eligibili y:
(n = 175)
Repo s excluded: 168
O he s udy designs (n = 47)
O he objec i es (n = 53)
O he age g oups (n = 19)
Asia, A ica, Sou h Ame ica (n = 19)
Le e s, e iews, e c. (n = 17)
<12 mon hs o ollow-up (n = 12)
Animals (n=1)
S udies included in e iew:
n = 6
Ou come: O /Ob (n = 4)
Ou come: MUO (n = 4)
Repo s o included s udies*:
n = 7
Iden i ica ion o s udies
Iden i ica ion
Sc eening
Included
Eligibili y
Figu e 1. PRISMA low diag am. No es: O /Ob = o e weigh /obesi y; MUO = Me abolically
Unheal hy Obesi y. * Two epo s we e e e ed o a single s udy.
Nu ien s 2025,17, 1833 8 o 18
Table 4. Ou comes o in e es , s a is ical analysis, and esul s o included s udies.
Au ho , Yea (Re e ence) Ou comes S a is ical Analysis Resul s
Singh e al., 2023 [18]
Signi ican me abolic ea u es
associa ed wi h posi i e
change in BMI a 1-yea
ollow-up.
Es ima e (95% CI) based on a
s a i ied linea eg ession
model (age, ace, BMI z-sco e,
and o al ene gy in ake).
Glycylp oline: −0.018 (−0.029, 0.007) p= 0.002,
3’-Sialyllac ose: 0.009 (0.002, 0.016) p= 0.006,
o miminoglu amic acid: 0.016 (0.004, 0.028)
p= 0.008, glycylp oline: −0.014 (−0.025, 0.003)
p= 0.01, 4-hyd oxyp oline: 0.016 (0.003, 0.03)
p= 0.016, Ci ulline: 0.01 (0.002, 0.018) p= 0.013,
4-Vinylsy ingol: −0.01 (−0.02, 0.001) p= 0.022,
Ci ulline: 0.012 (0.001, 0.023) p= 0.025,
Inosine: 0.005 (0.0004, 0.01) p= 0.03,
Mansell e al., 2022 [19]
Associa ion o change in BMI
om baseline o he end o
ollow-up (5.5 yea s) wi h he
change in me abolomic
p o iles.
Coe icien s (95% CI)
[Benjamini–Hochbe g
adjus ed p- alue] o he
change in log concen a ions
o me aboli es in SD uni s
dec ease in BMI o e ime pe
uni (kg/m 2) om linea
eg ession models adjus ed
o age a each ime poin and
sex.
lipop o ein subclasses: XL-VLDL-L: −0.038
(−0.066 o −0.01), p= 0.04; L-VLDL-L: −0.038
(−0.066 o −0.01), p= 0.04; S-VLDL-L: −0.039
(−0.071 o −0.008), p= 0.05; Apolipop o eins:
ApoB/ApoA1:
−
0.046 (
−
0.073 o
−
0.019), p= 0.01;
choles e ols: VLDL-C: −0.035 (−0.062 o −0.008),
p= 0.05; HDL-C: 0.045 (0.011 o 0.08), p= 0.04;
HDL2-C: 0.049 (0.016 o 0.082), p= 0.02; a y acids:
unsa u a ion: 0.059 (0.022 o 0.097), p= 0.02;
MUFAs: −0.041 (−0.068 o −0.014), p= 0.02;
LA%: 0.065 (0.03 o 0.101), p= 0.01; Omega-6%:
0.069 (0.034 o 0.103), p= 0.003; PUFAs%: 0.065
(0.03 o 0.1), p= 0.01; MUFAs%: −0.061 (−0.094 o
−0.028), p= 0.01; amino acids: alanine: −0.072
(
−
0.105 o
−
0.04), p= 0.002; phenylalanine:
−
0.069
(−0.102 o −0.037), p= 0.002; y osine: −0.068
(−0.099 o −0.037), p= 0.002; glyce ides and
phospholipids: o al iglyce ides: −0.043 (−0.069
o −0.016), p= 0.02; VLDL-TGs: -0.042 (−0.07 o
−0.015), p= 0.02; TG/PG: −0.052 (−0.081 o
−0.023), p= 0.01; glycolysis- ela ed me aboli es:
py u a e: −0.077 (−0.114 o −0.039), p= 0.002;
ke one bodies: Ace oace a e: 0.065 (0.021 o 0.109),
p= 0.02; 3-hyd oxybu y a e: 0.066 (0.018 o 0.113),
p= 0.04; in lamma ion: glycop o ein ace yls:
−0.063 (−0.092 o −0.035), p= 0.002. Addi ional
adjus men o pube al s a us con i med
s a is ically signi ican associa ions o a y acids:
LA%, PUFAs%, and MUFAs%; amino acids:
alanine, phenylalanine, and y osine;
glycolysis- ela ed me aboli es: py u a e; and
in lamma ion: glycop o ein ace yls.
Reineh e al., 2014 [15]
Change in me aboli es
be ween g oups (child en
wi h obesi y wi h subs an ial
weigh loss and child en wi h
obesi y wi hou weigh
loss; all unde wen a li es yle
in e en ion).
The 14 me aboli es
[glu amine, me hionine,
p oline, nine phospholipids
(PCaeC34:1, C34:2, C34:3,
C36:2, C36:3, C38:2,
LPCaC18:1, C18:2, and C20:4),
and wo acylca ni ines (C12:1
and C16:1)] we e compa ed
be ween baseline and 1-yea
ollow-up.
The 14 me aboli es did no change signi ican ly in
child en wi hou weigh loss. In child en wi h
subs an ial weigh loss, glu amine [mean (SD) a
baseline: 567 (120), ollow-up: 588 (102), p= 0.013],
me hionine [mean (SD) a baseline: 27 (6),
ollow-up: 29 (6), p= 0.026], LPCaC18:1 [mean (SD)
a baseline: 10 (2.8), ollow-up: 10.9 (3), p= 0.003],
LPCaC18:2 [mean (SD) a baseline: 12.3 (5.2),
ollow-up: 13.5 (5.2), p= 0.035], LPCaC20:4 [mean
(SD) a baseline: 19.6 (8.2), ollow-up: 21.7 (7.7),
p= 0.011] and PCaeC36:2 [mean (SD) a baseline:
4.5 (1.7), ollow-up: 4.8 (1.4), p= 0.026] inc eased
signi ican ly, while he o he eigh me aboli es did
no change signi ican ly.
Nu ien s 2025,17, 1833 9 o 18
Table 4. Con .
Au ho , Yea (Re e ence) Ou comes S a is ical Analysis Resul s
Hellmu h e al., 2019 [17]
Resea che s used he
me aboli e concen a ions a
5.5 yea s o p edic he BMI
z-sco e a 8 yea s o age in he
CHOP s udy.
Linea eg ession models
adjus ed o child age
and gende .
Plasma le els o ee ca ni ine (p= 6.17 ×10−6),
SM 32:2 (p= 2.16
×
10
−4
), SM 34:2 (p= 3.09
×
10
−4
)
and Ca n 3:0 (p= 4.09 ×10−2) we e signi ican ly
posi i ely associa ed wi h he BMI z-sco e a 8
yea s o age. Howe e , a e adjus ing o he BMI
z-sco e a 5.5 yea s, no me aboli e eached he
signi icance le el. Rega ding HOMA, glu amine a
age 5.5 yea s was signi ican ly nega i ely
associa ed (p= 0.013/0.003) wi h HOMA indices a
8 yea s in bo h he unadjus ed and adjus ed linea
models. NEFAs 26:1 (p= 0.012/0.015), 26:2
(p= 0.002/0.01), and 26:3 (p= 0.009/0.015) a age
5.5 yea s we e signi ican ly posi i ely associa ed
wi h HOMA indices a 8 yea s in bo h he
unadjus ed and adjus ed linea models. Only
se ine le els emained signi ican ly associa ed
wi h HOMA in he adjus ed model (p= 0.032).
Ojanen e al., 2021 [20]
To assess ca diome abolic isk,
a s anda dized con inuously
dis ibu ed a iable o
clus e ed me abolic isk (Me S
sco e) was cons uc ed.
The isk sco e was calcula ed
by s anda dizing and hen
summing he ollowing
con inuously dis ibu ed
me abolic ai s: mean a e ial
p essu e ([(2
×
dias olic blood
p essu e) + sys olic blood
p essu e]/3); abdominal a
mass; as ing plasma glucose;
se um HDL choles e ol x −1;
and as ing se um iglyce ide
z-sco e. The z-sco es o each
a iable and Me S sco es we e
calcula ed sepa a ely o each
ime poin . A highe sco e
indica ed a highe
ca diome abolic isk.
Reg ession analysis wi h
Me S sco e as he dependen
a iable and me abolic
bioma ke s iden i ied by
LASSO as independen
a iables, a e Bon e oni
co ec ion o mul iple es s.
Baseline ApoB/ApoA a io and GlycAs posi i ely
p edic ed while L-HDL-PLs nega i ely p edic ed
7.5-yea Me s ( = 0.471 and
p< 0.0001; = 0.400 and p= 0.0005; and =
−
0.465
and p< 0.0001, espec i ely,
p: adjus ed o mul iple compa isons by
Bon e oni). And 2-yea ApoB/ApoA a io and
GlycAs posi i ely p edic ed and L-HDL-PLs
nega i ely p edic ed 7.5-yea Me s ( = 0.449 and
p< 0.0001; = 0.440 and p< 0.0001; and =
−
0.445
and p< 0.0001, espec i ely, p: adjus ed o
mul iple compa isons by Bon e oni) only.
ApoB/ApoA a io, GlycAs, and L-HDL-PLs
emained signi ican p edic o s o Me S sco e
(p< 0.0001 o all). These associa ions we e also
obus o mul i-co a ia e adjus men , including
insulin, lep in, adiponec in, sex s e oids, IGF-1,
physical ac i i y, and ene gy yield nu ien in akes.
Hellmu h e al., 2016 [16]
Associa ion o changes in
me aboli e concen a ions
wi h change in HOMA o e
he one-yea in e en ion.
Change was de ined as he
ela i e change o e he
one-yea in e en ion, wi h
es ima es epo ed alongside
95% con idence in e als
(CIs). To assess he associa ion
be ween me aboli es and
ma ke s o insulin esis ance,
a wo-s ep obus eg ession
app oach was used. Fi s ,
me aboli e le els we e
adjus ed o BMI using age-
and sex-adjus ed obus
eg ession (M-es ima o wi h
Hube bi-squa e weigh ing).
The esiduals om his model
we e hen eg essed on he
ela i e change in HOMA
o e he in e en ion pe iod,
using obus eg ession o
minimize he in luence o
ou lie s.
All: Ca n C0 1.10 [0.29; 1.90] p= 0.008, Ca n
C6:1-DC −0.33 [−0.59; −0.06] p= 0.015, Ca n
C6-oxo −0.24 [−0.43; −0.05] p= 0.014, P o 0.81
[0.19; 1.40] p= 0.011; a io o Ca n C5/Ca n C6-oxo
0.24 [0.07; 0.41] p= 0.007, a io o Ca n
C6-oxo/xLeu −0.19 [−0.34; −0.03] p= 0.016, Ty
0.79 [0.17; 1.40] p= 0.015; weigh loss: AAA sum
1.04 [0.29; 1.80] p= 0.009, Ca n C0 1.71 [0.88; 2.50]
p< 0.001, Ca n C3 0.49 [0.03; 0.96] p= 0.036; Ca n
C6:1-DC −0.29 [−0.47; −0.10] p= 0.003; Ca n
C6-oxo −0.21 [−0.35; −0.08] p= 0.003, P o 0.72
[0.11; 1.30] p= 0.023, a io o Ca n C4/Ca n C5-oxo
0.48 [0.18; 0.77] p= 0.0030, a io o Ca n C5/Ca n
C6-oxo 0.22 [0.08; 0.35] p= 0.002, a io o Ca n
C6:1-DC/Ca n C5:1
−
0.22 [
−
0.41;
−
0.03] p= 0.024,
a io o Ca n C6-oxo/xLeu −0.15 [−0.25; −0.04]
p= 0.007, T p 1.13 [0.14; 2.10] p= 0.027, Ty 1.09
[0.51; 1.70] p= 0.001, Val 0.73 [0.07; 1.40] p= 0.033;
no weigh loss: a io o Ca n C5/Ca n C6-oxo 0.29
[0.02; 0.57] p= 0.041.
Nu ien s 2025,17, 1833 16 o 18
s ingen me hodological app oaches in u u e s udies o enhance he eliabili y o he
conclusions d awn. As such, con inued explo a ion o me abolomic p o iles in childhood
obesi y is wa an ed, pa icula ly in pedia ics, o de elop a ge ed in e en ions and
p e en he long- e m consequences o his condi ion.
Supplemen a y Ma e ials: The ollowing suppo ing in o ma ion can be downloaded a h ps:
//www.mdpi.com/a icle/10.3390/nu17111833/s1. File S1. Sea ch s ings used o MEDLINE
(PubMed) and Scopus.
Au ho Con ibu ions: Concep ualiza ion, E.C.; me hodology, D.K., G.S., A.K., M.D.K., P.K. and E.C.;
so wa e, G.S., alida ion, P.K. and E.C.; o mal analysis, D.K., G.S., P.K. and E.C.; in es iga ion, D.K.,
G.S. and P.K.; esou ces, P.K. and E.C.; da a cu a ion, D.K., G.S. and P.K.; w i ing—o iginal d a
p epa a ion, D.K., G.S. and P.K.; w i ing— e iew and edi ing, D.K., G.S., S.-M.G., E.R., A.K., M.D.K.,
E.K., E.G., P.K. and E.C.; isualiza ion, E.C.; supe ision, P.K. and E.C.; p ojec adminis a ion, P.K.
and E.C.; unding acquisi ion, E.C. All au ho s ha e ead and ag eed o he published e sion o
he manusc ip .
Funding: The wo k leading o hese esul s has ecei ed unding om he HORIZON Eu opean
Resea ch and Inno a ion Ac ion p ojec unde G an Ag eemen No. 101080718. The p ojec is
en i led “Mul i-Pilla F amewo k o child en An i-Obesi y Beha io building on an EU biobank,
Mic o Momen s and Mobile Recommenda ion Sys ems”, Ac onym: BIO-STREAMS, h ps://www.
bio-s eams.eu/.
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen : No applicable.
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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