Leptin and Nutrition in Gestational Diabetes

nu ien s Re iew Lep in and Nu i ion in Ges a ional Diabe es An onio Pé ez-Pé ez 1,*, Te esa Vila iño-Ga cía1, Pila Guadix 2, JoséL. Dueñas 2 and Víc o Sánchez-Ma gale 1,* 1Depa men o Medical Biochemis y and Molecula Biology, and Immnology, School o Medicine, Vi gen Maca ena Uni e si y Hospi al, 41009 Se ille, Spain; [email p o ec ed] 2Obs e ics and Gynecology Se ice, Vi gen Maca ena Uni e si y Hospi al, 41009 Se ille, Spain; [email p o ec ed] (P.G.); [email p o ec ed] (J.L.D.) *Co espondence: [email p o ec ed] (A.P.-P.); [email p o ec ed] (V.S.-M.); Tel: +34-955008111 (A.P.-P. & V.S.-M.) Recei ed: 18 May 2020; Accep ed: 30 June 2020; Published: 2 July 2020   Abs ac : Lep in is highly exp essed in he placen a, mainly by ophoblas ic cells, whe e i has an impo an au oc ine ophic e ec . Mo eo e , inc eased lep in le els a e ound in he mos equen pa hology o p egnancy: ges a ional diabe es, whe e lep in may media e he inc eased size o he placen a and he e us, which becomes mac osomic. In ac , lep in media es he inc eased p o ein syn hesis, as obse ed in ophoblas s om ges a ional diabe ic subjec s. In addi ion, lep in seems o acili a e nu ien s anspo o he e us in ges a ional diabe es by inc easing he exp ession o he glyce ol anspo e aquapo in-9. The high plasma lep in le els ound in ges a ional diabe es may be po en ia ed by lep in esis ance a a cen al le el, and obesi y-associa ed in lamma ion plays a ole in his lep in esis ance. The e o e, he impo ance o an i-in lamma o y nu ien s o modi y he pa hology o p egnancy is clea . In ac , nu i ional in e en ion is he i s -line app oach o he ea men o ges a ional diabe es melli us. Howe e , mo e nu i ional in e en ion s udies wi h nu aceu icals, such as polyphenols o polyunsa u a ed a y acids, o nu i ional supplemen a ion wi h mic onu ien s o p obio ics in p egnan women, a e needed in o de o achie e a high le el o e idence. In his con ex , he Medi e anean die has been ecen ly ound o educe he isk o ges a ional diabe es in a mul icen e andomized ial. This e iew will ocus on he impac o ma e nal obesi y on placen al in lamma ion and nu ien s anspo , conside ing he mechanisms by which lep in may in luence ma e nal and e al heal h in his se ing, as well as i s ole in p egnancy pa hologies. Keywo ds: nu i ion; polyphenolic compounds; bioac i e compounds; lep in esis ance; obesi y; in lamma ion; ges a ional diabe es melli us; Medi e anean die 1. In oduc ion Ges a ional diabe es (GDM) is a hype glycemic s a e ha is ecognized o he i s ime du ing p egnancy [ 1 ], and i s pa hophysiology is no ully cla i ied ye . GDM is one o he mos common complica ions in p egnancy, a ec ing 3–8% o all p egnancies [ 2 ]. This p e alence has inc eased in ecen decades ( ≥ 20% o p egnancies in some pa s o he wo ld), bo h in de eloped and de eloping coun ies, due o inc eased a e age age o p egnan women and inc eased obesi y [ 3 ], one o he g ea es public heal h challenges o he 21s cen u y. Al hough he GDM pheno ype is highly he e ogeneous [ 4 ], hal o i s p e alence can be explained by o e weigh and obesi y [ 5 ]. Indeed, obese women ha e an inc eased isk o GDM compa ed o women o no mal weigh [ 4 ]. Mo eo e , in women wi h GDM, p e-p egnancy obesi y, excessi e ges a ional weigh gain and poo glycemic con ol a e also linked wi h o he s p egnancy complica ions, such as ges a ional hype ension and p eeclampsia [ 6 ]. I has e en been epo ed ha excessi e ges a ional weigh gain was he a iable wi h he g ea es e ec on he Nu ien s 2020,12, 1970; doi:10.3390/nu12071970 www.mdpi.com/jou nal/nu ien s Nu ien s 2020,12, 1970 2 o 18 p obabili y o a newbo n wi h mac osomia (a condi ions associa ed wi h an inc eased isk o pe ina al mo ali y and neona al mo bidi y). GDM also inc eases, in u n, he isk, in bo h mo he and o sp ing, o de eloping ype 2 diabe es, me abolic synd ome and obesi y [ 7 , 8 ]. The e o e, obesi y du ing p egnancy is an impo an isk ac o o ad e se heal h ou comes bo h in he mo he and o sp ing, and imposes subs an ial economic bu dens. The e o e, p e en ion o obesi y would be di ec ly ela ed o a lowe isk o GDM. Impai ed glucose homeos asis in GDM is also ela ed o highe p oduc ion o eac i e oxygen species (ROS), consequen ly deple ing he an i-oxida i e s a us. This is why, o es ain he sp ead o epidemic excess weigh , women mus ecei e a comp ehensi e in e en ion be o e, du ing, and a e p egnancy. Li es yle changes, including nu i ion ini ia ed du ing ea ly p egnancy, ha e been unsuccess ul o e all in p e en ing GDM in a - isk obese women [ 9 ]. Now, he e is a consensus ega ding he need o e ec i e in e en ions a ge ing obesi y and li es yle ha educe he me abolic bu den ea lie in li e, well be o e mo he hood, and i unde lines ha such in e en ions may bene i bo h he mo he and he u u e o sp ing. Al hough ene gy es ic ion leading o weigh loss is a success ul die a y in e en ion o imp o ing obesi y-associa ed me abolic diso de s, o he die a y in e en ions, such as hose leading o a educ ion in adipose issue in lamma ion ega dless o weigh loss, ha e no been explo ed in de ail. In his sense, lep in, p oduced by adipocy es, is a key egula o o appe i e and is p esen in ele a ed concen a ions in obesi y [ 10 ]. The e o e, new esea ch in o nu i ional mechanisms ha es o e lep in me abolism and signals o ene gy homeos asis may inspi e new ea men op ions o obesi y- ela ed diso de s such as GDM. In his e iew, we wan ed o add ess he cu en insigh s and eme ging concep s on po en ially aluable nu ien s and ood componen s o modula e lep in me abolism. Mo eo e , obesi y is associa ed wi h a ch onic low-g ade in lamma ion in he adipose issue [ 11 ], and se e al die a y ood componen s, such as phenols, pep ides, and i amins, a e able o dec ease he g ade o in lamma ion and imp o e lep in sensi i i y by up- o down- egula ion o lep in- ela ed genes. O he s ood componen s, such as sa u a ed a y acids should be a oided, since hey may wo sen ch onic in lamma ion, subsequen ly inc easing he isk o pa hological complica ions. Finally, gi en he c ucial ole ha he placen a plays in media ing p egnancy ou comes, i is impo an o conside he impac o mic onu ien supplemen a ion on he mechanisms associa ed wi h placen al unc ion, as well as ma e nal and e al homeos asis. 2. Lep in The ho mone lep in, disco e ed in 1994 [12], c i ically egula es body weigh and me abolism a cen al le el in he b ain [ 13 ], and dis up ion o lep in/lep in ecep o (LEPR) signaling esul s in mo bid obesi y and se e e me abolic disease [ 14 , 15 ]. In indi iduals o no mal weigh , he b ain esponds o inc eased plasma lep in le els by educing ood in ake and inc easing ene gy expendi u e [ 16 , 17 ]. Lep in and lep in ecep o s a e highly exp essed in he p eop ic a ea (POA), in he a cua e nucleus (ARC) o he hypo halamus as well as in o he egions, such as he la e al hypo halamus, en omedial hypo halamus and do somedial hypo halamus (DMH) [ 18 ]. The e, i egula es ene gy homoeos asis and he neu oendoc ine unc ion, among o he unc ions [ 19 ]. In hese egions, lep in signaling is media ed by he JAK2/S a 3 pa hway, in which se e al nega i e egula o s o JAK2, including SOCS3 and PTP1B, ha e been epo ed o p omo e obesi y [ 20 , 21 ], suppo ing he no ion ha JAK2 inhibi o y molecules inc ease isk o lep in esis ance and obesi y. The e o e, hype lep inemia and hypo halamic in lamma ion in die -induced obesi y may ac i a e a common nega i e egula o o lep in signaling, SOCS3 o PTP1B, and con ibu e o cen al lep in esis ance. In ac , up- egula ion o SOCS3 in p oopiomelanoco in (POMC) neu ons leads o impai men o STAT3 signaling, wi h consequen ial lep in esis ance and obesi y, as well as glucose in ole ance [ 22 ]. I has also been epo ed ha mice wi h whole body o neu on-speci ic dele ion o PTP1B a e hype sensi i e o lep in, and a e esis an o die -induced obesi y [ 23 ]. Impo an ly, obesi y is associa ed wi h impai ed adipose sympa he ic ne e ansmissions [ 24 , 25 ], bu he unde lying mechanism is poo ly unde s ood. In his con ex , he lep in esis ance a a cen al le el may p e en nega i e eedback on he an i-in lamma o y ac ion o he sympa he ic ne ous sys em (SNS) [ 15 , 26 ]. Tha is why lep in is now conside ed one o he adipokines Nu ien s 2020,12, 1970 3 o 18 esponsible o he in lamma o y s a e ound in obesi y ha could p edispose o GDM. Su p isingly, Sh2b1 (an SH2 and PH domain-con aining adap o p o ein) [ 27 , 28 ] has eme ged as an endogenous sensi ize o lep in ac ion on he sympa he ic ne ous sys em (SNS) and ene gy expendi u e, pe haps by enhancing JAK2 ac i a ion [ 29 ]. In his way, he LepR Sh2b1 neu on media es lep in s imula ion o he SNS and suppo s he p ese a ion o adipose SNS agains degene a ion [30]. Apa om he JAK-2/S a -3 pa hway, ac i a ion o he MC4R signaling pa hway by p oopiomelanoco in (POMC)-de i ed melanocy e s imula ing ho mone (MSH) pep ides also ep esen s a c i ical con e gence poin in he con ol o body weigh . The lep in–melanoco in pa hway (MC4R pa hway) in eg a es pa allel inpu s om he o exigenic pep ides gh elin, neu opep ide Y (NPY) and agou i- ela ed pep ide (AgRP), and ac i a ion o he MC4R pa hway dominan ly coun e ac s hese o exigens. Limi ed e icacy o li es yle in e en ion in indi iduals wi h mu a ions in gene-encoding componen s o his pa hway demons a es i s impo ance in he con ol o body weigh homeos asis [31,32]. The e o e, lep in can ac as me abolic swi ch connec ing he nu i ional s a us o he body o high ene gy-consuming p ocesses. This is especially impo an in p egnancy, whe e lep in no only modula es sa ie y and ene gy homoeos asis in he mo he [ 13 , 33 ], bu i is also p oduced by he placen a, which esponds o he en i onmen a emp ing o main ain e al iabili y. This placen al p oduc ion o lep in is one o he majo sou ces o highe le els o ma e nal ci cula ing lep in o he han ma e nal gain o a mass [ 34 ]. Thus, he e ec s o placen al lep in on he mo he may con ibu e o endoc ine-media ed al e a ions in ene gy balance, such as he mobiliza ion o ma e nal a , which could u he agg a a e he insulin esis ance associa ed wi h p egnancy and he onse o GDM [ 35 , 36 ]. In ac , obese p egnan women ha e signi ican ly ele a ed plasma lep in concen a ions compa ed wi h nonobese p egnan women h oughou p egnancy [ 1 ]. Mo eo e , ma e nal obesi y is also associa ed wi h changes in he placen al unc ion and s uc u e, which likely impac e al g ow h and de elopmen . Fo example, obesi y has been associa ed wi h se e al changes ela ed mainly wi h placen al size, hype ascula iza ion, highe b anching capilla ies o he illi (cho angiosis) [ 37 , 38 ] and inc eased glycogen deposi s, among o he s. Inc eased mac ophage in il a ion is also e iden in he placen a o obese women, sugges ing an exagge a ion o he in lamma o y s a e which occu s in no mal p egnancy [ 39 ]. Howe e , i is unclea which his ological changes a e due o he pa hophysiology and which a e compensa o y adap a ions o his disease. Rega dless, al e a ions in placen al nu ien and ho mone anspo e capaci y ha e been demons a ed in human and animal models o obesi y, and a e hypo hesized as a mechanism leading o an accele a ed e al g ow h ajec o y and mac osomia [ 1 ]. In his sense, we ha e demons a ed ha he inc eased exp ession o aquapo in-9 (AQP9) (o o he s aquaglyce opo ins) obse ed in placen as om obese women wi h GDM could be media ed by hype lep inemia, sugges ing an inc ease in he anspo o glyce ol o he e us and hus con ibu ing o he inc eased ene gy in ake equi emen s in he mac osomic e us in GDM [ 40 ]. Lep in has also been iden i ied as a c i ical ophic ac o ha in luences he de elopmen o he hypo halamic p ojec ions [ 40 ]. Al e a ions in he pa e n o lep in sec e ion (p ema u e peak, excess, o de iciency) du ing neona al li e could ha e signi ican ad e se e ec s on hypo halamic de elopmen and me abolic pheno ype [ 41 ] (Figu e 1). Finally, one o he pe iphe al unc ions o lep in is a egula o y ole in he in e play be ween ene gy me abolism and he immune sys em, which is, in pa , esponsible o he in lamma o y s a e associa ed o obesi y [ 42 ]. Se e al in lamma o y media o s p oduced by in lamma o y cells also egula e lep in exp ession and p omo e he de elopmen o ch onic in lamma ion [ 43 ]. In his ega d, lep in e ec s include he in lamma ion and he modula ion o inna e and adap i e immuni y [ 44 , 45 ]. The e o e, p oin lamma o y lep in ac ions migh also ha e signi ican implica ions in he pa hogenesis o GDM [29,46]. Taken all oge he , since hypo halamic in lamma ion esul s in cen al lep in esis ance and hepa ic insulin esis ance [ 47 ], blocking he pe iphe al and cen al in lamma ion induced by a high a die could ha e he po en ial o ea obesi y and GDM. The e o e, no el he apies inco po a ing e ec i e Nu ien s 2020,12, 1970 4 o 18 na u al agen s (mac o and mic onu ien s), pa icula ly agen s wi h he dual p ope ies o p e en ing in lamma ion and con olling body weigh by imp o ing lep in sensi i i y, migh be an al e na i e in e en ion a ge ing obesi y and GDM. Nu ien s 2020, 12, x FOR PEER REVIEW 4 o 19 p e en ing in lamma ion and con olling body weigh by imp o ing lep in sensi i i y, migh be an al e na i e in e en ion a ge ing obesi y and GDM. Figu e 1. E ec s o bioac i e ood compounds on he lep in esis ance associa ed wi h obesi y and ges a ional diabe es. Lep in le els a e inc eased in ges a ional diabe es wi h obesi y (1). The high plasma lep in le els may be po en ia ed by lep in esis ance a cen al le el, in which SOCS3 and PTPB a e induced by lep in and in ol ing in a nega i e eed-back loop. The esul ing e ec is a dec ease in he lep in- induced ac i a ion o he JAK2/STAT-3 signaling, leading o a educ ion in he cen al e ec s o lep in (2). Lep in also impac s he placen a i sel in an au oc ine/pa ac ine ashion. The in eg a ion o nume ous signaling by in acellula egula o y pa hways such as MAPK, PI3K and JAK-STAT has been demons a ed o inc ease he size o he placen a and o a ec placen al nu ien anspo and e al g ow h (mac osomia) (3). Bioac i e ood compounds such as polyphenols migh educe ci cula ing lep in le els, pa ly dec easing lep in exp ession in he placen a om women wi h GDM. The esul ing e ec is a dec ease in he lep in esis ance a a cen al le el and op imal placen al nu ien s anspo . 3. Nu ien s and Bioac i e Food Componen s Use ul o Coun e ac ing Hype lep inemia and Lep in Resis ance in GDM Since he landma k Hype glycemia and Ad e se P egnancy Ou comes (HAPO) s udy in 2010, an in e na ional consensus on diagnos ic c i e ia has no been eached nea ly a decade la e [47]. Howe e , he e is now a consensus ega ding he need o e ec i e in e en ions a ge ing obesi y. In his ega d, since i s -line medical (pha maceu ical) he apy has ecen ly been called in o ques ion [48] and he socioemo ional componen o nu i ion he apy o GDM has a dominan in luence on adhe ence [49], o he die a y s a egies should be u he in es iga ed in de ail. Fo example, since die plays an impo an ole in in lamma ion, and bo h obesi y and GDM a e conside ed a s a e o ch onic in lamma ion, a heal hy and ac i e li e s yle, which includes a die ich in ui s, ege ables, non-suga ed oods, non-ul a-p ocessed oods associa ed wi h a highe p e en ion o in lamma o y diseases should be inco po a ed in o he die [50]. Howe e , a high consump ion o ed, p ocessed Figu e 1. E ec s o bioac i e ood compounds on he lep in esis ance associa ed wi h obesi y and ges a ional diabe es. Lep in le els a e inc eased in ges a ional diabe es wi h obesi y (1). The high plasma lep in le els may be po en ia ed by lep in esis ance a cen al le el, in which SOCS3 and PTPB a e induced by lep in and in ol ing in a nega i e eed-back loop. The esul ing e ec is a dec ease in he lep in-induced ac i a ion o he JAK2/STAT-3 signaling, leading o a educ ion in he cen al e ec s o lep in (2). Lep in also impac s he placen a i sel in an au oc ine/pa ac ine ashion. The in eg a ion o nume ous signaling by in acellula egula o y pa hways such as MAPK, PI3K and JAK-STAT has been demons a ed o inc ease he size o he placen a and o a ec placen al nu ien anspo and e al g ow h (mac osomia) (3). Bioac i e ood compounds such as polyphenols migh educe ci cula ing lep in le els, pa ly dec easing lep in exp ession in he placen a om women wi h GDM. The esul ing e ec is a dec ease in he lep in esis ance a a cen al le el and op imal placen al nu ien s anspo . 3. Nu ien s and Bioac i e Food Componen s Use ul o Coun e ac ing Hype lep inemia and Lep in Resis ance in GDM Since he landma k Hype glycemia and Ad e se P egnancy Ou comes (HAPO) s udy in 2010, an in e na ional consensus on diagnos ic c i e ia has no been eached nea ly a decade la e [ 47 ]. Howe e , he e is now a consensus ega ding he need o e ec i e in e en ions a ge ing obesi y. In his ega d, since i s -line medical (pha maceu ical) he apy has ecen ly been called in o ques ion [ 48 ] and he socioemo ional componen o nu i ion he apy o GDM has a dominan in luence on adhe ence [ 49 ], o he die a y s a egies should be u he in es iga ed in de ail. Fo example, since die plays an impo an ole in in lamma ion, and bo h obesi y and GDM a e conside ed a s a e o ch onic in lamma ion, a heal hy and ac i e li e s yle, which includes a die ich in ui s, ege ables, non-suga ed oods, non-ul a-p ocessed oods associa ed wi h a highe p e en ion o in lamma o y diseases should be inco po a ed in o he die [ 50 ]. Howe e , a high consump ion o ed, p ocessed mea , sa u a ed o ans- a , ul a-p ocessed ood based on e ined ing edien s o alcohol associa ed wi h p o-in lamma o y p ocesses should be a oided [35,36]. Nu ien s 2020,12, 1970 5 o 18 Since obese women and women wi h GDM show high ci cula ing lep in le els and a e hence conside ed lep in- esis an [ 51 , 52 ], we ha e iden i ied nu i ional s a egies o coun e ac lep in esis ance in bo h obesi y and GDM. In his con ex , se e al mic o- and mac o-nu ien s and bioac i e ood componen s migh ha e he abili y o inc ease lep in sensi i i y and o e e se lep in esis ance in obesi y and GDM. 3.1. Polyphenolic Compounds Polyphenolic compounds such as la onoids ep esen an impo an bioac i e componen in plan s ( ui s, ege ables, legumes, ea, e c.) wi h some speci ic pa s o hese oods iche in la onoids han o he s ( o example he peel o ce ain ui s) [ 53 ]. The accumula ion o la onoids o en occu s in plan s subjec ed o abio ic s esses. This ac has made hei de e mina ion an a ac i e ield in ood science and, in ecen yea s, an inc eased numbe o s udies ha e analyzed hei po en ial bene i s in human heal h. As men ioned abo e, bo h he impac o nu i ional s a us on he immune sys em, specially T cells [ 54 , 55 ] and he ole o lep in as a media o o in lamma ion [ 42 ], as well as a link be ween ene gy s o es and he immune esponse, ha e been p oposed [ 56 , 57 ]. In his sense, he (poly)phenols migh modula e bo h he lep in e ec and ci cula ing lep in le els using di e en expe imen al app oaches. Fo example, i has been epo ed ha la onoids ha e an i-in lamma o y p ope ies and hus ha e an impo an ole in he con ol o se e al immune cells and immune mechanisms ha a e impo an in he in lamma o y p ocesses. Mo e speci ically, ce ain la onoids (my ice in, que ce in, p ocyanidins) can inhibi mul iple cen al kinases ha a e in ol ed in mul iple signaling pa hways ela ed o in lamma ion [ 58 ], such as phosphoinosi ol kinase, p o ein kinase C (PKC), phospha idylinosi ol kinase and y osine kinase o cyclin-dependen kinase-4 [ 59 ]. Besides, la onoids can modula e hese p o ein kinases ia inhibi ion o ansc ip ion ac o s (e.g., NF- κ B and AP-1) [ 60 ]. In iguingly, bo h insulin and lep in sha e se e al signaling pa hways, such as mi ogen-ac i a ed p o ein kinase (MAPK) and he phospha idylinosi ol 3-kinase (PI3K) pa hway, which may also ac i a e se e al p o ein kinases in ol ed in signal ansduc ion du ing he in lamma ion p ocess, ia NF- κ B. In his con ex , ou g oup ha e demons a ed ha he inc ease in placen al lep in exp ession is media ed by NF κ B signaling [ 61 ]. The e o e, in GDM, associa ed wi h insulin esis ance, hype insulinemia and hype lep inemia [ 62 , 63 ], la onoids migh down egula e he syne gis ic in e ac ion be ween insulin and lep in signaling in he in lamma o y p ocesses. In addi ion, la onoids migh also dec ease lep in exp ession in he placen a o women wi h GDM. I has also been epo ed ha high cAMP le els inhibi lep in exp ession by human cho ionic gonado opin (hCG), and hese inc eased le els o cAMP ha e been associa ed wi h an i-in lamma o y unc ions [ 64 ]. In his sense, la onoids ha e also demons a ed he po en ial o block cAMP deg ada ion and p olong cAMP signaling [ 65 ]. Finally, la onoids may ha e an impac on cell ac i a ion, signaling ansduc ion and cy okine p oduc ion in se e al immune cells. Fo ins ance, la onoids ha e been shown o inhibi ma u a ion o dend i ic cells (DCs) by supp essing he exp ession o CD83 and CD80, which would ansla e in o an inhibi o y e ec in he sec e ion o p o-in lamma o y cy okines [ 66 , 67 ]. These e ec s a e con a y o lep in, which p omo es he swi ch owa ds Th1 cell immune esponses by inc easing in e e on- γ (IFN- γ ) exp ession and acili a es Th17 esponses. All hese indings posi ion la onoids as modula o s o immune esponse and, e y speci ically, as inhibi o s o ansc ip ion ac o s, in ol ed in he exp ession o di e en p o-in lamma o y genes such as he lep in gene [60]. On he o he hand, i is well known ha he imbalance be ween he oxida i e and an i-oxida i e sys ems plays a c ucial ole in he pa hogenesis o se e al human diseases such as obesi y and diabe es, among o he s [ 68 – 70 ]. In his con ex , la onoids a e also po en an ioxidan s ha a e able o sca enge ee adicals and dec ease hei o ma ion. Fo example, g ape juice by-p oduc s a e a sou ce o phenolic compounds wi h demons a ed an ioxidan ac i i ies [ 71 ]. In hese, he main phenolic compounds include la ones (lu eolin) [ 71 , 72 ], la onols (my ice in, ise in, que ce in and kaemp e ol de i a i es) [ 70 , 73 ], an hocyanins (cyanidin-3-glucoside) [ 74 ], la an-3-ols (ca echin and Nu ien s 2020,12, 1970 6 o 18 epica echin monome s and p oan hocyanidins) [ 75 , 76 ], s ilbenes ( es e a ol), and phenolic acids [ 74 ]. The mos s udied o hese is es e a ol, which has been demons a ed o diminish ci cula ing lep in le els and o educe in ake [ 77 ] by inc easing phospho-STAT3 con en in he hypo halamus, wi h no changes in SOCS3. This sugges ha es e a ol migh imp o e he lep in sensi i i y in obesi y [78,79]. P oan hocyanidins (PACs), known as condensed annins, a e ound in a wide a ie y o ui s (e.g., be ies), in addi ion o g apes, and o he sou ces such as lowe s, seeds o some plan s, nu s o ba ks [ 80 , 81 ]. Plan and ood-de i ed PACs a e also a ac ing a en ion due o hei abili y o p e en ch onic diseases [ 82 ]. Fo example, PACs om g ape seeds and blackbe y–bluebe y e men ed be e ages ha e shown high an i-in lamma o y and an ioxidan ac i i y in i o [ 83 ] and ha e shown a b oad he apeu ic heal h e ec agains diabe es melli us and obesi y. In his ega d, obesi y and ela ed complica ions such as GDM a e linked wi h highe suscep ibili y o oxida i e s ess and he adminis a ion o g ape seed ex ac s has shown an imp o emen in he oxida i e s a us in obese people by inhibi ing lipid pe oxida ion and a oiding ROS p oduc ion [ 84 ]. Mo eo e , PACs can educe in lamma ion by dec easing he oxida i e s ess o o he indi ec mechanisms [ 85 ]. In his sense, PACs om g ape seed ex ac modula e IL-6, TNF- α and adiponec in gene exp ession in adipose issue, hus, educing he die -induced low-g ade in lamma ion [ 86 ]. PAC- ich ex ac s ha e also p o ed o be in ol ed in obesi y modula ion (e en a low doses) h ough he supp ession o ood in ake and he inc ease in ene gy expendi u e [ 87 ], possibly by media ing lep in le els. Howe e , he mechanism unde lying his e ec o g ape seed PACs has no been ully elucida ed. Finally, g ape seed ex ac imp o ed he insulin esis ance index as well as he plasma glucose and insulin le els in die -induced obese animal models [88], al hough he e a e disc epancies in his ega d. O he bioac i e ood compounds ha e also been p o en o be able o educe ci cula ing lep in le els in obesi y. My ice in, a bio la onoid abundan in o he s ui s (e.g., be ies), as well as ea and ege ables, has been shown o educe hype lep inemia and o a o insulin ac ion ia PI3-kinase pa hway ac i a ion, and ansloca ion o glucose anspo e sub ype 4 (GLUT4) o he cell memb ane [ 89 ]. Accumula ing e idence also sugges s ha p opolis ex ac s ( ich in la onoids and cinnamic acid de i a i es) ha e he apeu ic e ec s on obesi y by con olling adipogenesis, adipokine sec e ion, ood in ake, and ene gy expendi u e. Pa icula ly, conside ing he ano ec ic ac i i y o lep in, p opolis has po en ial o a enua e eeding and subsequen ly p e en obesi y [ 90 ]. Mo eo e , a ious epo s in animal and cellula models ha e demons a ed ha p opolis and i s de i ed compounds imp o e insulin sec e ion and insulin sensi i i y by modula ing oxida i e s ess, he accumula ion o ad anced glyca ion end p oduc s (AGEs), and adipose issue in lamma ion, all o which con ibu e o insulin esis ance o de ec s in insulin sec e ion [ 91 , 92 ]. Fo example, se e al la onoids in p opolis, such as que ce in, ch ysin, lu eolin, amen o la one, lu eolin 7-O-glucoside and daidzein, ha e been ound o ha e he apeu ic e ec s in diabe ic animal models by di e en mechanisms [ 93 , 94 ]. I has also been epo ed ha p opolis mi iga es me abolic dys unc ion h ough no maliza ion o in es inal mic o lo a [ 95 ]. The e o e, p opolis in ake migh ha e bene icial e ec s o me abolic diso de s such as GDM, a ibu able o la onoids and na u al phenols. Howe e , p opolis migh ha e ad e se e ec s on pa ien s and, he e o e, moni o ing o biological e ec s should be ca ied ou . The polyphenols o oli es and oli e lea es also ha e nume ous bene icial e ec s on human heal h, such as an ioxidan capaci y, hypoglycemic [ 96 ] and an i-in lamma o y [ 97 ], as well as a coadju an ole in he ea men o obesi y [ 98 ]. In his sense, oleu opein, esponsible o he bi e as e o oli e lea es and d upes, and i s de i ed o m, he mos abundan phenolic compounds p esen in oli es and oli e oils, a e well known o hei hypoglycemic p ope y; possibly by he po en ial o a ec ing glucose-induced insulin elease and/o inc easing pe iphe al glucose up ake [ 99 ]. This hypoglycemic e ec is also a ibu ed, a leas in pa , o he an ioxidan ac i i y o oleu opein [ 100 ]. Mo eo e , i has been epo ed ha oleu opein down- egula es lep in mRNA le els in epididymal adipose issue and educes se um lep in le els [ 101 ]. Tha is why he p ophylac ic use o oleu opein has been p oposed in he educ ion in complica ions esul ing om oxida i e s ess in obesi y and diabe es [ 99 ]. O he majo phenolic componen s p esen —no only in oli e ex ac s bu in ui s (e.g., g apes), such as lu eolin Nu ien s 2020,12, 1970 7 o 18 and lu eolin-4 0 -O- β -D-glucopy anoside—ha e been shown o inhibi he o ma ion o AGEs and, hus, migh delay he de elopmen o diabe ic complica ions [ 96 ]. Howe e , hese e ec s ha e been es ed in animals and i is necessa y o pe o m s udies in humans in o de o con i m he bene i s a ibu ed o polyphenols om oli es in GDM. 3.2. Polyunsa u a ed Fa y Acids (PUFAs) The de eloping e us equi es subs an ial amoun s o a y acids o suppo apid cellula g ow h and ac i i y, and especially, me abolic de i a i es o he essen ial a y acids such as linolenic acid ( Ω -3) and linoleic acid ( Ω -6) and polyunsa u a ed a y acids (PUFAs) a e c ucial [ 102 ]. The mos biologically impo an PUFAs a e docosahexaenoic acid (DHA) and eicosapen aenoic acid (EPA) [ 102 ]. In his con ex , DHA appea s o be c ucial o he e us and in an o ea ly neu al de elopmen (b ain and isual sys em) [ 103 ]. Howe e , mode n die a y ends ha e led o an imbalance in he consump ion o PUFAs, wi h de iciency in Ω -3 and inc easing Ω -6 PUFA in ake which a exceeds nu i ional equi emen s, p omo ing he pa hogenesis o many p e alen human diseases including GDM [104]. The placen a may play a key ole in he egula ion o a y acid a ailabili y ia he elease o placen al-de i ed lep in, a po en s imula o o lipolysis [ 105 ]. In ac , ma e nal ci cula ing o al a y acid concen a ions inc ease du ing p egnancy, enhancing placen al access o a y acids. Howe e , as men ioned abo e, GDM is associa ed wi h oxida i e s ess and placen al in lamma ion [ 106 ], and impai ed placen al a y acid anspo has been epo ed [107]. Gi en ha PUFAs exhibi bo h an i-oxida i e and an i-in lamma o y ac i i ies, ma e nal die a y DHA and EPA supplemen a ion has been p oposed as a po en ial he apeu ic in e en ion o his placen a- ela ed diso de . Fo example, ma e nal die a y supplemen a ion wi h Ω -3 PUFAs du ing p egnancy exe s bene icial e ec s such as educed in lamma ion by ei he dis up ing p oin lamma o y eicosanoid gene a ion o p omo ing he gene a ion o an i-in lamma o y o ms [ 108 ]. Mo eo e , i has been also epo ed ha die a y supplemen a ion wi h Ω -3 PUFAs modula es he ac i i y o key ansc ip ion ac o s (pe oxisome p oli e a o -ac i a ed ecep o s (PPARs) and/o nuclea ac o κ B (NF- κ B)) and he G-p o ein-coupled ecep o (GPR120) in ol ed in in lamma o y signaling [109–111] . Consequen ly, die a y supplemen a ion wi h Ω -3 PUFAs migh educe isk o p egnancy complica ions [ 112 ] as well as he adipose issue in lamma ion ia GPR120-media ed supp ession o mac ophage p oin lamma o y cy okine sec e ion, including lep in [ 113 ]. Indeed, DHA and EPA ha e been shown o educe ci cula ing lep in le els ac i a ing he adenosine 5’-monophospha e-ac i a ed p o ein kinase (AMPK) pa hway [ 114 ]. Ano he bene icial e ec o he Ω -3 PUFAs on GPR120 is he inc ease in he ansloca ion o in acellula esicles con aining GLUT4, which enhances glucose up ake by adipocy es [ 111 ]. Oleic acid, a monounsa u a ed a y acid (MUFA), also educes hype lep inemia ia down- egula ing PPAR γ mRNA le els in abdominal isce al whi e adipose issue in obese mice [ 115 ]. Th ough modula ion o adipokine sec e ion, hese a y acids also a o insulin sensi i i y [116]. Finally, excessi e oxida i e s ess in u e o-placen al issues plays a pi o al ole in he de elopmen o GDM [ 106 ]. In his con ex , Ω -3 PUFAs could po en ially limi oxida i e damage by educing ROS gene a ion [117]. Howe e , i would be impo an o asce ain he po en ial isks o excessi e die a y PUFA in ake gi en he suscep ibili y o PUFAs o lipid pe oxida ion, which may exace ba e cellula damage caused by an oxida i e insul [118]. All oge he , hese indings highligh he po en ial bene i o die a y supplemen a ion wi h PUFAs o limi oxida i e damage and in lamma ion associa ed wi h obesi y and GDM, al hough u he esea ch in humans is equi ed o cla i y whe he hese a y acids can p e en GDM and he po en ial isks associa ed i hey a e used as supplemen s. 3.3. Te penes The e is e idences ha ca es ol and/o i s me aboli es (kahweol), na u al di e penes ex ac ed om co ee beans, can p e en some ch onic diseases such as me abolic disease [ 119 – 121 ]. In his Nu ien s 2020,12, 1970 8 o 18 con ex , i has been demons a ed ha ca es ol p omo es insulin sec e ion and also inc eased glucose up ake in muscle cells, simila ly o ha o an idiabe ic osigli azone. Mo eo e , kahweol can ac i a e he AMPK pa hway, a cen al modula o o he me abolism o glucose and lipid ha s imula es glucose up ake and inhibi s he lipid accumula ion. A la ge numbe o s udies ha e also shown ha ca es ol and kahweol ha e an i-in lamma ion and an ioxidan ac i i y, as well as an inhibi o y e ec on cell p oli e a ion. Mo e speci ically, ca es ol blocks he AP-1 pa hway o educe PGE2 p oduc ion and blocks he PI3K/Ak pa hway, p omo ing apop osis in umo cells [ 122 ]. All hese e ec s could be bene icial in he placen al o e g ow h obse ed in GDM. Howe e , despi e he ac ha ca eine has been shown o ac i a e STAT-3 ia decline o ER s ess in he hypo halamus [ 123 ], i has been epo ed ha kahweol down- egula ed he STAT3 signaling pa hway by inhibi ing i s cons i u i e phospho yla ion and ac i a ion [ 124 ], which may agg a a e he lep in esis ance in obesi y. The e o e, u he esea ch and clinical ials a e needed o con i m whe he he co ee di e penes migh be used o p e en o ea GDM in humans. E idence has been epo ed ega ding he e ec o ea p e en ing obesi y and abno mal glucose and lipid me abolism [ 125 ]. In his sense, in addi ion o phenolic componen s, a majo bioac i e componen o ea ex ac is easaponin, a i e pene wi h signi ican an i-in lamma o y p ope ies. Mo e speci ically, easaponin inhibi s p oin lamma o y cy okines by supp essing NF κ B signaling ups eam o IKK/I κ B α [ 125 ]. The an i-in lamma o y e ec s o easaponin ha e been associa ed wi h an imp o ed glycemic s a us in animal models. Mo eo e , easaponin dec eases he exp ession o hypo halamic p oin lamma o y cy okines as well as he in lamma o y signaling in he mediobasal hypo halamus [ 125 ]. This may con ibu e o imp o ed lep in sensi i i y and hypo halamic lep in signaling ia p-STAT3. In ac , easaponin signi ican ly dec eases he le el o SOCS3, a nega i e egula o o cen al lep in signaling in he hypo halamus o high- a die -induced obese mice. The e o e, easaponin has impo an e ec s in imp o ing glucose ole ance, cen al lep in sensi i i y, and hypo halamic lep in signaling [ 125 ], and i migh be a po en ial candida e as he apeu ic in e en ion o obesi y and GDM. 3.4. P obio ics Ea ly epo s o expe imen al and human s udies ega ding he ole o gu mic obio a p omo ing gu ba ie unc ions and con olling in lamma o y esponses ha e a ac ed scien i ic in e es . The gu mic obio a is highly sensi i e o he die and may be in ol ed in a accumula ion, a o ing hyd olysis and abso p ion o indiges ible polysaccha ides and, hus, excessi e s o age o nu ien s [ 126 , 127 ]. In ac , a dis inc i e gu mic obio a composi ion in obesi y has been epo ed in humans [ 127 ]. Fo example, a lowe ibe in ake has been epo ed o be associa ed wi h educed gu mic obio a di e si y and ichness, g ea e abundance o genus associa ed wi h ype 2 diabe es melli us [ 128 , 129 ], and genus wi h known p o-in lamma o y capaci y [ 34 ]. Physiological weigh gain du ing p egnancy [ 130 , 131 ] also in luences he gu mic obio a composi ion in pa allel wi h weigh gain, a o ing a highe numbe o Bi idobac e ium spp and a lowe p opo ion o S aphylococcus spp [ 132 ]. These shi in mic obial composi ion a e mo e p onounced in obese p egnancy and women wi h o e weigh gain du ing p egnancy [ 130 – 133 ]. The e o e, a easonable s a egy o igh GDM migh be based on speci ic p obio ics, which migh coun e ac excessi e abso p ion and s o age o nu ien s by modi ica ion o he gu mic obio a composi ion. P obio ics in GDM migh balance he e ec o abe an indigenous mic obio a and no malize he inc eased in es inal pe meabili y, as well as he sec e ion o p oin lamma o y media o s, including lep in. The e o e, as men ioned in a clinical ial [ 134 ], speci ic p obio ics o p obio ic oods migh be used as die a y adjunc s o educe he isk o diseases associa ed wi h abe an gu mic obio a composi ion, inc eased in es inal pe meabili y o al e ed immunological o me abolic balance such as GDM. In ac , he impac o p obio ics on GDM migh be mo e p onounced in a high- isk popula ion (e.g., obesi y). Mo eo e , p obio ics supplemen a ion would no only a ec he ma e nal me abolic s a e, bu would also modula e e al physiology and migh ha e a long- e m p og amming e ec on child heal h [ 135 – 137 ]. Howe e , cu en knowledge Nu ien s 2020,12, 1970 9 o 18 abou gu mic obio a and die esponse in p egnancy complica ed by GDM is limi ed and u u e s udies ha in eg a e gene ics and clinical a iables should be aken in o accoun . 3.5. O he s Bioac i e Compounds Lycopene is a lipophilic ca o enoid which is esponsible o he ed colo in a ious ege ables and ui s, and is commonly ound in oma oes [ 138 , 139 ]. This ca o enoid is known o i s an ioxidan and an i-in lamma o y e ec s [ 140 ], and has been epo ed o imp o e diseases wi h ch onic in lamma o y backg ounds such as obesi y. As men ioned abo e, hype lep inemia is associa ed wi h p o-in lamma o y esponses and wi h he ch onic subin lamma o y s a e obse ed in obesi y [ 141 ]. In his con ex , i has been sugges ed ha lycopene supplemen a ion may a enua e he in lamma o y esponse in obesi y, a leas in pa , by minimizing hype lep inemia [ 142 , 143 ]. O he bioac i e compounds o many c uci e ous ege ables (e.g., wa e c ess and b occoli) a e iso hiocyana es (ITCs), cha ac e ized by he p esence o hiol- eac i e chemicals ha can modi y c i ical cys eine esidues on a a ie y o cellula p o eins [ 144 – 146 ]. As men ioned abo e, accumula ing e idence sugges s ha PTP1B could be in ol ed in he pa hways leading o lep in esis ance as a majo nega i e egula o o lep in and insulin signaling. In his sense, ITCs ha e been ound o inac i a e PTP1B [ 147 , 148 ], which has a eac i e cys eine esidue a he ca aly ic cen e [ 147 ]. Pa icula ly, phene hyl iso hiocyana e (PEITC), a ela i ely non oxic cons i uen , in addi ion o inhibi ing cellula PTP1B ac i i y, has been demons a ed o enhance phospho yla ion o LEPRb, JAK2, and STAT3 in he hypo halamus, esul ing in he s imula ion o lep in signaling and signi ican ly educed ood in ake [149]. 3.6. Mic onu ien s Mic onu ien s include nume ous mine als and i amins de i ed om he die ha a e essen ial o cellula me abolism and op imal issue unc ion. I has been epo ed ha an adequa e supply o mic onu ien s du ing p egnancy may signi ican ly educe he isk o de eloping diso de s o p egnancy, including GDM [ 150 ]. Th oughou he cou se o p egnancy, he e may be inc eased isk o mic onu ien de iciency in esponse o he equi emen s o he g owing e us [ 151 ]. The e o e, al hough a heal hy die would be he ideal way o co e he mic onu ien equi emen s, i is possible ha he physiological challenge o p egnancy migh equi e addi ional nu i ional suppo o mic onu ien s [ 152 ]. The majo i y o supplemen s on he ma ke con ain a wide a ie y o i amins (B g oup i amins, i amins C, D, E and ola e) and mine als (i on, coppe , zinc, iodine, selenium [ 153 ]. Howe e , despi e he bene i s o mic onu ien s in suppo ing ma e nal, placen al, and e al homeos asis du ing p egnancy [ 152 , 154 ], insigni ican e idence and a ied esul s ha e been no ed upon andomized ials o supplemen a ion [ 155 ]. Such a iabili y may be linked o a ia ions in speci ic mic onu ien supplemen p epa a ions and popula ion con ex s [ 155 ]. The e o e, he possibili y ha mic onu ien s supplemen a ion could p e en complica ions o p egnancy wa an s u he in es iga ion wi h la ge ials in his ield [151]. 4. Medi e anean Die Despi e he publica ion o nume ous andomized ials on die and li es yle in e en ions in p egnancy [ 156 ], as men ioned abo e, no clea die a y ecommenda ions ha e eme ged o imp o e p egnancy ou comes o women wi h me abolic isk ac o s, pa icula ly GDM. This can be a ibu ed o he lack o obus e idence on e ec i eness o he die [ 157 ]. The adi ional die , “Medi e anean die ”, has long been associa ed wi h p e en i e ac i i y agains ch onic in lamma ion-associa ed diseases, which a e suppo ed by obse a ional and epidemiological da a. The Medi e anean-s yle die includes componen s such as a high in ake o nu s, ex a i gin oli e oil, ui , ege ables, non- e ined g ains, legumes and mic onu ien s, as well as mode a e o high consump ion o ish and low consump ion o p ocessed mea , suga y d inks, as ood, and ood ich in animal a [ 158 ]. These key componen s o his die migh help o con ol he ac i i y o obesi y and GDM as well as o he in lamma o y pa hologies. 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