Research Article Maternal Fructose Intake Induces Insulin Resistance and Oxidative Stress in Male, but Not Female, Offspring

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1 Journl of Nutrition nd Metolism Volume 2015, Article ID , 8 pges Reserch Article Mternl Fructose Intke Induces Insulin Resistnce nd Oxidtive Stress in Mle, ut Not Femle, Offspring Lourdes Rodríguez, 1 Pol Otero, 1 Mrí I. Pndero, 1 Silvi Rodrigo, 1 Jun J. Álvrez-Millán, 1,2 nd Crlos Bocos 1 1 Fcultd de Frmci, Universidd CEU Sn Plo, Urnizción Montepríncipe, Bodill del Monte, Mdrid, Spin 2 CQS Lortory, C/Artists 1, Mdrid, Spin Correspondence should e ddressed to Crlos Bocos; crocos@ceu.es Received 15 Octoer 2014; Accepted 14 Jnury 2015 Acdemic Editor: Phillip B. Hylemon Copyright 2015 LourdesRodríguez et l. This is n open ccess rticle distriuted under the Cretive Commons Attriution License, which permits unrestricted use, distriution, nd reproduction in ny medium, provided the originl work is properly cited. Ojective. Fructose intke from dded sugrs correltes with the epidemic rise in metolic syndrome nd crdiovsculr diseses. However, consumption of everges contining fructose is llowed during gesttion. Recently, we found tht n intke of fructose (10% wt/vol) throughout gesttion produces n impired fetl leptin signlling. Therefore, we hve investigted whether mternl fructose intke produces susequent chnges in their progeny. Methods. Blood smples from fed nd 24 h fsted femle nd mle 90- dy-old rts orn fromfructose-fed, glucose-fed, or control mothers were used.results. After fsting, HOMA-IR nd ISI (estimtes of insulin sensitivity) were worse in mle descendents from fructose-fed mothers in comprison to the other two groups, nd these findings were lso ccompnied y higher leptinemi. Interestingly, plsm AOPP nd uricemi (oxidtive stress mrkers) were ugmented in mle rts from fructose-fed mothers compred to the nimls from control or glucose-fed mothers. In contrst, femle rts did not show ny differences in leptinemi etween the three groups. Further, insulin sensitivity ws significntly improved in fsted femle rts from crohydrte-fed mothers.in ddition, plsm AOPP levels tended to e diminished in femle rts from crohydrte-fed mothers.conclusion. Mternl fructose intke induces insulin resistnce, hyperleptinemi, nd plsm oxidtive stress in mle, ut not femle, progeny. 1. Introduction In the lst few decdes, oesity, metolic syndrome, nd dietes hve esclted to epidemic proportions in mny countries worldwide. These metolic diseses re multifctoril resulting from genetic, physiologicl, ehviourl, nd environmentl influences. Genetic influence lone does not suffice to explin the rte t which these diseses hve incresed [1]. In fct, severl studies demonstrte tht metolic events during pre- nd postntl development modulte metolic disese risks in lter life [2]. Among them, feeding conditions likely constitute one of the most influentil prmeters on the helth of the dult [3]. Thus, diet mnipultion in mothers during criticl developmentl periods (such s gesttion nd/or the erly postntl) hs een used to identify their contriution to oesity nd dietes development in offspring [4]. Given the current worldwide shift towrd westernized lifestyle, there is n urgent need to ddress the reltionship etween the qulity nd quntity of nutrient intke during pregnncy nd/or lcttion nd the metolic fte of the offspring [5]. Fructose, present in dded sugrs such s sucrose nd high-fructose corn syrup, hs een linked to oesity nd metolic syndrome [6 8]. Experimentl studies hve shown tht fructose cn induce leptin resistnce nd fetures of metolic syndrome in rts, wheres glucose intke does not [9 11]. Clinicl studies lso support fructose s cuse of metolic syndrome [12 14]. Interestingly, sex-dependent differences in the influence of fructose for inducing metolic diseses hve een reported. Thus, women, ut not men, exhiit n ssocition etween fructose consumption nd n incresed risk of type 2 dietes mellitus. In reltion to this, it hs een shown tht femlertssujectedtofructosehvemoredetrimentl

2 2 Journl of Nutrition nd Metolism response thn their mle counterprts. Fructose-fed mle rts were resistnt to the heptic effects of leptin, wheres fructose-fed femles hd no signs of leptin resistnce ut hd hyperinsulinemi nd ltered glucose tolernce test [15]. In contrst, in high-fructose-fed rodents, oxidtive stress ws oserved in mle, ut not in femle, rts [16]. Since it hs een well-estlished tht fructose intke modifies lipidemi in lortory nimls nd humns [11, 17] nd mternl diet mnipultions cn ffect the progeny, it might e speculted tht fructose dministrtion during gesttion nd/or lcttion could cuse metolic chnges in the offspring. Unfortuntely, studies investigting ltered mternl nutrition hve used quite different experimentl designs to determine the role of fructose [18 24]. In our previous report, we investigted the effects of low fructose intke throughout gesttion in mothers nd their fetuses [25], nd we otined intriguing results. Fructosefed mothers presented diminished leptin response to fsting nd refeeding, their fetuses displying n impired trnsduction of the leptin signl, nd these findings were not oserved in glucose-fed rts. Therefore, the present study ws designed to determine whether n intke of liquid fructose (10% wt/vol) during pregnncy hd long-term consequences on the offspring. Furthermore, specil ttention hs een given to determine whether ny potentil consequence of the tretment differed etween femle nd mle offspring. 2. Mteril nd Methods 2.1. Animls nd Experimentl Design. Femle Sprgue- Dwley rts weighing g were fed d liitum stndrd rt chow diet (B&K Universl, Brcelon, Spin) nd housed under controlled light nd temperture conditions (12 h light-drk cycle; 22 ± 1 C). The experimentl protocol ws pproved y the Animl Reserch Committee of the University CEU Sn Plo, Mdrid, Spin. The experimentl protocol to which pregnnt rts were sujected ws the sme s previously reported [25]. Briefly, pregnnt nimls were rndomly seprted into control group, fructosesupplemented group (fructose), nd glucose-supplemented group (glucose). Fructose nd glucose were supplied s 10% (wt/vol) solution in drinking wter throughout gesttion. Control nimls received no supplementry sugr. Pregnnt rts were llowed to deliver nd, on the dy of irth, ech suckling litter ws reduced to nine pups per mother. After delivery, oth mothers nd their pups were mintined with wter nd food d liitum. It is remrkle tht these nimls (mothers nd pups) received no susequent dditive in the drinking wter. On the 21st dy fter delivery, the lctting mothers were removed to stop the suckling period nd pups were seprted y gender. When the progeny were 90 dys old, they were sujected to 24-hour fsting. After drwing sl lood smple from the til vein, pellets were removed fromthecges.after24hfsting,secondloodsmplefrom the til vein ws otined. Blood smples were collected into EDTA (1 mg/ml) tues nd plced on ice. Smples were then centrifuged, nd plsm ws stored t 80 Cuntilprocessed for glucose, insulin, leptin, nd other determintions. Where twoorthreepupsfromonelitterwereused,theirdtwere verged Determintions. Plsm liquots were used to mesure glucose y n enzymtic colorimetric test (Spinrect, Giron, Spin). NEFA (nonesterified ( free ) ftty cids) (Wko, Neuss, Germny), glycerol (Sigm Chemicl, St. Louis, MO), triglycerides, nd uric cid (Spinrect) were mesured using commercil kits. Ketone odies were mesured using kinetic method (Rndox Lortories, United Kingdom). Insulin ws determined in plsm smples using specific ELISA kit for rts (Mercodi, Uppsl, Sweden). Leptin nd diponectin were ssyed in plsm smples using specific enzyme immunossy (EIA) kit for rts (Biovendor, Brno, Czech Repulic, nd Millipore, Bedford, MA, resp.). Estimtes of insulin resistnce were clculted s previously descried [15, 25] y determintion of the following indexes from the 24 h fsting plsm glucose nd insulin vlues: homeostsis model ssessment of insulin resistnce (HOMA-IR) nd insulin sensitivity index (ISI). The HOMA- IR ws clculted s the product of the fsting plsm glucose (FPG) nd insulin (FPI) divided y constnt, FPI ws expressed in microunits per milliliter nd FPG s millimoles per liter [26]. The ISI ws clculted s the rtio 2/[(FPI FPG) + 1], expressing FPI nd FPG in micromoles per liter [15]. Additionlly, estimtes of insulin sensitivity were lso clculted in fed-stte s previously descried [25] y determintion of the rtio etween glucose levels (in milligrms per deciliter) nd insulin vlues (in microunits per milliliter). Finlly, plsm liquots were lso used to determine the oxidtive stress stte. The concentrtion of mlondildehyde (MDA) in plsm ws mesured s mrker of lipid peroxidtion using the method previously descried [27], y mesuring the fluorescence of MDA-thiorituric cid (TBA) complexes t 515 nm/553 nm excittion/emission wvelengths. Further, the dvnced oxidtion protein products (AOPP) in plsm were determined s protein oxidtive stress iomrker using the spectrophotometric technique previously descried [28, 29]. The AOPP concentrtions were expressed s μmol/l of chlormine-t equivlents Sttisticl Anlysis. Results were expressed s men ± SE. Tretment effects were nlyzed y one-wy ANOVA. When tretment effects were significntly different (P < 5), mens were tested y the Tukey multiple rnge test, using computer progrm SSPS (version 15). When the vrince ws not homogeneous, post hoc Tmhne test ws performed. 3. Results 3.1. Ingestion of 10% wt/vol Fructose Solution throughout Gesttion Affects Leptinemi in Mle Progeny. As shown in Tle 1, neither fructose nor glucose intke throughout pregnncy produced ltertions in the ody weight of the mle nd femle progeny.

3 Journl of Nutrition nd Metolism 3 Tle 1: Body weight nd plsm nlytes in fed 90-dy-old progeny from fructose- or glucose-supplemented mothers. Mle Body weight (g) ± ± ± 21.3 Glucose (mg/dl) ± ± ± 1.0 Insulin (μg/l) 0.53 ± ± ± 8 Glucose/insulin rtio 10.4 ± ± ± 1.4 Triglycerides (mg/dl) 95.6 ± ± ± 5.7 NEFA (mm) 0.45 ± ± ± 7 Glycerol (mg/dl) 2.87 ± ± ± 0.18 Adiponectin (μg/ml) 18.9 ± ± ± 1.8 Leptin (ng/ml) 6.35 ± ± ± 0.92 Femle Body weight (g) ± ± ± 4.2 Glucose (mg/dl) ± ± ± 1.8 Insulin (μg/l) 0.54 ± ± ± 5 Glucose/insulin rtio 10.7 ± ± ± 1.0 Triglycerides (mg/dl) 57.2 ± ± ± 4.3 NEFA (mm) 0.48 ± ± ± 4 Glycerol (mg/dl) 2.81 ± ± ± 0.14 Adiponectin (μg/ml) 43.9 ± ± ± 3.8 Leptin (ng/ml) 5.27 ± ± ± 0.17 Dt re mens ± SE; n = nimls from four litters. Where two or three pups from one litter were studied, their dt were verged. Different letters indicte significnt differences etween the groups (P < 5). Plsm NEFA, glycerol, nd triglycerides concentrtions were similr in the mle rts from crohydrtefed mothers with respect to control vlues (Tle 1). Mle rts from crohydrte-fed mothers showed higher levels of plsm diponectin levels. Although glycemi nd insulinemi showed no differences etween the three groups (Tle 1), glucose/insulin rtio tended to e lower in the mle nimls from fructose-fed mothers compred to the nimls from control nd glucose-supplemented rts (Tle 1). Interestingly, mle descendents from fructose-supplemented rts turnedouttoeclerlyhyperleptinemic(tle 1). On the other hnd, since insulinemi nd glycemi were similr in the femle rts from crohydrte-fed mothers with respect to control vlues, glucose/insulin rtio ws found toesimilrforthefemleprogenyofcontrol,fructosefed, nd glucose-fed pregnnt rts (Tle 1). Similr findings were recorded for plsm diponectin levels. However, plsm NEFA, glycerol, nd triglycerides concentrtions were lowerinfemlenimlsfromglucose-fedpregnntrtsin comprison to the other two groups (Tle 1). In contrst to mles, femle descendents from fructose-supplemented rts showed similr vlues in their leptinemi to the nimls from control nd glucose-supplemented mothers (Tle 1) Ingestion of 10% wt/vol Fructose Solution throughout Gesttion Affects Insulin Sensitivity in Fsted Mle Progeny. To confirm possile disturnce in glucose homeostsis in Tle 2: Plsm nlytes in fsted 91-dy-old progeny from fructose- or glucose-supplemented mothers. Mle Glucose (mg/dl) 89.3 ± ± ± 5.7 Insulin (μg/l) 44 ± ± ± 06 Triglycerides (mg/dl) 52.1 ± ± ± 4.1 NEFA (mm) 1.66 ± ± ± 6 Glycerol (mg/dl) 5.04 ± ± ± 0.15 Adiponectin (μg/ml) 29.9 ± ± ± 1.0 Ketone odies (mm) 0.64 ± ± ± 6 Femle Glucose (mg/dl) ± ± ± 7.4 Insulin (μg/l) ± ± ± 04 Triglycerides (mg/dl) 26.4 ± ± ± 4.6 NEFA (mm) 1.49 ± ± ± 4 Glycerol (mg/dl) 4.62 ± ± ± 0.58 Adiponectin (μg/ml) 47.8 ± ± ± 5.3 Ketone odies (mm) 0.63 ± ± ± 0.20 Dt re mens ± SE; n = nimls from four litters. Where two or three pups from one litter were studied, their dt were verged. Different letters indicte significnt differences etween the groups (P < 5). mle, ut not in femle, rts orn of mothers supplemented throughout pregnncy with liquid fructose, we sujected the progeny of the three experimentl groups to 24 h fsting nd mesured plsm prmeters relted to insulin resistnce. After 24-hour fsting, plsm glucose, NEFA, glycerol, ketone odies, nd triglycerides concentrtions did not show ny differences in the mle rts from crohydrte-fed mothers with respect to control vlues (Tle 2). Similr findings were recorded for plsm diponectin levels. However, insulinemi ws significntly higher in mle nimls from fructose-fed pregnnt rts in comprison to the other two groups (Tle 2). Thus, HOMA-IR nd ISI rtios were significntly different in the mle nimls from fructose-fed motherscompredtothemlenimlsfromcontrolnd glucose-supplemented rts (Figures 1()-1()), nd, therefore, these findings confirmed tht n insulin resistnt stte exists in mle progeny of fructose-fed mothers. In ccordnce with this result, mle descendents from fructose-supplemented rts showed cler increse in their plsm leptin concentrtions (Figure 1(c)). After 24-hour fsting, plsm glucose, NEFA, glycerol, ketone odies, diponectin, nd triglycerides levels were similr in the femle rts from crohydrte-fed mothers with respect to the control vlues (Tle 2). However, insulinemi ws lower in femle nimls from crohydrte-fed pregnnt rts in comprison to the control group (Tle 2). Thus, HOMA-IR nd ISI rtios were significntly different in the femle nimls from crohydrte-supplemented mothers compred to the femle nimls from control rts (Figures 1()-1()), these eing more pronounced in the group from the glucose-fed mothers. Thus, not only did femle rts from fructose-fed mothers not show n insulin

4 4 Journl of Nutrition nd Metolism Mle HOMA Femle HOMA () Mle insulin sensitivity index Femle insulin sensitivity index () Mle leptin (ng/ml) Femle leptin (ng/ml) (c) Figure 1: Fructose in pregnncy produces insulin resistnce nd hyperleptinemi in progeny. Mle nd femle () HOMA-IR nd () ISI rtios nd (c) leptinemi of 24-hour fsted 90-dy-old progeny from control, fructose-fed, nd glucose-fed pregnnt rts. Dt re mens ± SE; n=10 12 nimls from four litters. Different letters indicte significnt differences etween the groups (P < 5).

5 Journl of Nutrition nd Metolism Mle MDA (μm) Femle MDA (μm) () Mle AOPP (μm) Femle AOPP (μm) () Figure 2: Fructose in pregnncy influences plsm oxidtive stress in progeny. Mle nd femle() plsm MDA() nd AOPP vlues of 90-dy-old progeny from control, fructose-fed, nd glucose-fed pregnnt rts. Dt re mens ± SE; n = nimls from four litters. Different letters indicte significnt differences etween the groups (P < 5). resistnt stte s seen in mle progeny, ut femle rts from crohydrte-fed mothers showed improved insulin sensitivity. In fsted femle descendents from fructose-supplemented rts, lthough plsm leptin concentrtions tended to e higher thn in the other two groups, the effect ws not significnt (Figure 1(c)) Ingestion of 10% wt/vol Fructose Solution throughout Gesttion Affects Plsm Oxidtive Stress in Mle Progeny. Since fructose intke during pregnncy seems to produce insulin resistnce nd hyperleptinemi in the mle progeny, prmeters which hve een relted to metolic syndrome, we lso checked whether other fetures relted to tht disturnce could e ffected. Thus, s shown in Figure 2, plsm MDA nd AOPP, which would indicte lipid nd protein oxidtion, respectively, tended to e ugmented in the mle rts from fructose-fed mothers in comprison to the nimls from control nd glucose-fed pregnnt rts, ecoming significnt for AOPP levels. In contrst, plsm AOPP, ut not MDA, were diminished in the femle progeny of crohydrte-fed mothers (Figure 2), this effect eing significntly different in theprogenyfromglucose-fedmothers. Interestingly, mle rts from fructose-supplemented mothers showed higher uricemi (3.4 ± 0.5; 5.4 ± 0.3; nd 3.4 ± 0.4 mg/dl, for mles orn from control, fructose-fed, nd glucose-fed mothers, resp., P < 5). In comprison, femles from crohydrte-fed mothers showed lower levels of plsm uric cid thn the control group, this effect eing significntly different in the progeny from glucose-fed mothers (4.1 ± 0.3; 3.4 ± 0.3;nd2.3 ± 0.2 mg/dl, for femle progeny from control, fructose-fed, nd glucose-fed mothers, resp., P < 5). 4. Discussion In our previous study [25], we reported n impired heptic trnsduction of the leptin signl in the fetuses from fructosefed, ut not glucose-fed, pregnnt rts nd relted it to diminished leptin response to fsting nd refeeding oserved in their mothers. Since it hs een proposed tht period of reltive hypoleptinemi (or, in our cse, leptin resistnce)

6 6 Journl of Nutrition nd Metolism during development my induce some metolic dpttions tht underlie developmentl progrmming [30], we speculted whether the findings found in our previous study [25] could e responsile for developmentl progrmming of those progeny nd produce some metolic disturnces, when dult. Thus, mle progeny orn of fructose-fed rts presented higher leptinemi versus the other two groups, nd tht hyperleptinemi ws oserved in oth fed nd fsting conditions. In ccordnce with this finding, fsting insulinemi ws higher in the mle progeny from fructose-fed mothers, ll these results eing consistent with the insulin resistnt stte found in these nimls (mesured s HOMA nd ISI rtios). The presence of hyperinsulinemi in fsted mle fructosefed progeny long with hyperleptinemi could lso indicte leptin resistnce t the level of pncretic islets [31]. Since insulin stimultes dipogenesis nd leptin production in dipocytes wheres leptin inhiits the production of insulin in pncretic β-cells, prolonged elevtion of plsm leptin levels would result in dysregultion of the dipoinsulr xis nd corresponding filure to suppress insulin secretion [32]. In fct, in the present study, lthough the mle progeny from fructose-fed mothers ws hyperleptinemic in oth fed nd fsted conditions, fsting produced lower impct on insulin levels in comprison to the other two groups (12.1-, 4.3-, nd 15.2-fold reduction, for control, fructose, nd glucose groups, resp.).inreltiontothis,ithseenreportedthtdipocytes from mle offspring of lctting mothers consuming fructose spontneously relesed more leptin thn control rt-derived dipocytes nd lso displyed impired response to insulin stimultion [4]. Since the progeny from fructose-fed mothers were lredy leptin resistnt when they were fetuses [25], the mle progeny of fructose-fed pregnnt rts could present vicious circle (leptin resistnce, hypersecretion of insulin, nd incresing insulin resistnce) [23, 33]. On the other hnd, it hs een demonstrted tht fructose is much more rective thn glucose with respect to prticiption in glycosyltion rections, which represent n importnt source of free rdicls. In ccordnce with this fct, rts fed fructose (25% wt/vol) exhiited significnt increse in lipid peroxidtion products, compred with rts fed the sme mount of glucose or sucrose nd those given pure wter [34]. Moreover, it hs een reported tht short-term dministrtion of fructose-rich diet to norml rts promotes n increse in severl glycoxidtive stress mrkers [16, 35]. Further, s reducing sugr, fructose rects with protein molecules to form toxic dvnced glyction end-products (AGEs) nd lso induces protein oxidtion possily through the formtion of hydroxyl rdicls [36]. Both AGEs nd AOPP pper to e involved in the pthogenesis of inflmmtion, dietes complictions, nd crdiovsculr diseses. In the present work, the mle progeny from fructose-fed dms showed incresed plsm levels of protein oxidtion products, mesured s AOPP. It is worthwhile to mention tht AOPP levels hve een ssocited with metolic syndrome, sincehighlevelsofaopphveeenpositivelycorrelted with insulin nd HOMA levels [37].Given tht it hs een proposed tht AGEs could ccumulte indefinitely on longlived molecules such s collgen nd DNA [38], it might e speculted tht fructose intke during pregnncy could promote oxidtion products formtion in fetuses nd these toxic compounds would ccumulte, lter ppering in the plsm of progeny. Reltedtothtincreseinplsmoxidtivestressof progeny from fructose-fed rts, we lso determined uricemi nd, surprisingly, mle rts orn to fructose-fed mothers turned out to e hyperuricemic. Some uthors consider hyperuricemi in metolic syndrome to e the consequence of elevted serum insulin levels, which hve een shown to stimulte renl resorption of uric cid. In fct, thizolidinediones which improve insulin sensitivity nd lower insulin levels reduce the level of serum uric cid in dietic ptients. Conversely, Nkgw et l. (2006) demonstrted tht the reductionofuriccidlevelswithxnthineoxidseinhiitor improved insulin sensitivity. Accordingly, in the present study, fructose-fed mle progeny presented hyperuricemi long with insulin resistnce. Interestingly, the xnthine oxidse pthwy, which is relted to uric cid production, hs een shown to generte oxidnts [39]. Our findings would gree with this result since the hyperuricemic mle progeny lso presents n increse in plsm oxidtive stress. In fct, recentstudyhsshownclosereltionshipetweenfructose, hyperuricemi, oxidtive stress, nd dietes [40]. The most prominent result found here is tht the intke of just smll mount of fructose (10%) throughout gesttion produces cler impirment in the insulin ction, hyperleptinemi, nd other fetures of metolic syndrome such s high vlues of oxidtive stress iomrkers nd uricemi in mle progeny. However, femle progeny orn of fructose-fed mothers did not show ny of these chrcteristics of metolic syndrome. Nevertheless, s hs een descried, femles orn to mothers sujected to undernutrition expressed progrmmed phenotype only in the presence of high-ft diet, wheres the mle progeny could mnifest it independently of postntl nutrition [30]. Therefore, it is possile tht postntl hypercloric nutrition could mplify ll these metolic normlities induced y the fructose-fed fetl progrmming, nd this deserves further investigtion. Finlly, since the crohydrte ws dministered only during gesttion, we cn ssume tht the effects of fructose intke would occur during intruterine development. As previously reported [25], fetuses from fructose-fed mothers presented leptin resistnce. Leptin hs een implicted in the regultion of insulin secretion y islets nd, in fct, leptin my influence the norml prolifertion of pncretic β-cells which occurs in the neontl period [30]. If it is ssumed tht n interrelted endocrine insulin-leptin feedck system exists, we could speculte tht the dipoinsulr xis hs een ffected y fructose intke throughout pregnncy. 5. Conclusion Mternl fructose intke seems to provoke fetures of metolic syndrome, nmely, insulin resistnce, hyperleptinemi, hyperuricemi, nd plsm oxidtive stress in mle, ut not femle, progeny.

7 Journl of Nutrition nd Metolism 7 Conflict of Interests The uthors declre tht there is no conflict of interests regrding the puliction of this pper. Acknowledgments The uthors thnk Jose M. Grrido for his help in hndling the rts nd Brin Crilly for his editoril help. This work ws supported y grnt from Pln Ncionl de Investigción Científic, Desrrollo e Innovción Tecnológic (I+D+i), Instituto de Slud Crlos III-Sudirección Generl de Evlución y Fomento de l Investigción (PI-09/02192), Europen Community FEDER, nd Fundción Universitri Sn Plo CEU (PC 09/2012). Silvi Rodrigo is FUSP-CEU fellowship. References [1] G. J. Howie, D. M. Slood, T. Kml, nd M. H. Vickers, Mternl nutritionl history predicts oesity in dult offspring independent of postntl diet, The Journl of Physiology, vol. 587, no. 4, pp , [2] B. Koletzko, I. Broekert, H. Demmelmir et l., Protein intke inthefirstyeroflife:riskfctorforlteroesity?thee.u. childhood oesity project, Advnces in Experimentl Medicine nd Biology,vol.569,pp.69 79,2005. [3] B. Beck, S. Richy, Z. A. Archer, nd J. G. Mercer, Ingestion of crohydrte-rich supplements during gesttion progrms insulin nd leptin resistnce ut not ody weight gin in dult rt offspring, Frontiers in Physiology, vol. 3, rticle224, [4] A. Alzmendi, D. Cstrogiovnni, R. C. Gillrd, E. Spinedi, nd A. Giovmttist, Incresed mle offspring s risk of metolic-neuroendocrine dysfunction nd overweight fter fructose-rich diet intke y the lctting mother, Endocrinology,vol.151,no.9,pp ,2010. [5] L. Šedová, O. Šed, L. Kzdová et l., Sucrose feeding during pregnncy nd lcttion elicits distinct metolic response in offspring of n inred genetic model of metolic syndrome, The Americn Journl of Physiology Endocrinology nd Metolism,vol.292,no.5,pp.E1318 E1324,2007. [6] P. J. Hvel, Dietry fructose: implictions for dysregultion of energy homeostsis nd lipid/crohydrte metolism, Nutrition Reviews,vol.63,no.5,pp ,2005. [7] L. Tppy nd K.-A. Lê, Metolic effects of fructose nd the worldwide increse in oesity, Physiologicl Reviews, vol. 90, no. 1, pp , [8]R.J.Johnson,M.S.Segl,Y.Sutinetl., Potentilroleof sugr (fructose) in the epidemic of hypertension, oesity nd the metolic syndrome, dietes, kidney disese, nd crdiovsculr disese, The Americn Journl of Clinicl Nutrition, vol.86,no.4,pp ,2007. [9] R.J.Johnson,S.E.Perez-Pozo,Y.Y.Sutinetl., Hypothesis: could excessive fructose intke nd uric cid cuse type 2 dietes? Endocrine Reviews,vol.30,no.1,pp ,2009. [10] C. H. Tghiiglou, A. Crpentier, S. C. vn Iderstine et l., Mechnisms of heptic very low-density lipoprotein overproduction in insulin resistnce, The Journl of Biologicl Chemistry,vol.275,no.12,pp ,2000. [11] N. Roglns, L. Vilà, M. Frré et l., Impirment of heptic STAT-3 ctivtion nd reduction of PPARα ctivity in fructosefed rts, Heptology, vol. 45, no. 3, pp , [12] K. L. Stnhope, J. M. Schwrz, N. L. Keim et l., Consuming fructose-sweetened, not glucose-sweetened, everges increses viscerl diposity nd lipids nd decreses insulin sensitivity in overweight/oese humns, Journl of Clinicl Investigtion,vol.119,no.5,pp ,2009. [13] K. L. Stnhope, A. A. Bremer, V. Medici et l., Consumption of fructose nd high fructose corn syrup increse postprndil triglycerides, LDL-cholesterol, nd polipoprotein-b in young men nd women, TheJournlofCliniclEndocrinologynd Metolism,vol.96,no.10,pp.E1596 E1605,2011. [14] L. de Koning, V. S. Mlik, M. D. Kellogg, E. B. Rimm, W. C. Willett, nd F. B. Hu, Sweetened everge consumption, incident coronry hert disese, nd iomrkers of risk in men, Circultion,vol.125,no.14,pp ,2012. [15] L. Vilà, N. Roglns, V. Pern et l., Liver AMP/ATP rtio nd fructokinse expression re relted to gender differences in AMPK ctivity nd glucose intolernce in rts ingesting liquid fructose, Journl of Nutritionl Biochemistry,vol.22,no.8,pp , [16] J. Busserolles, A. Mzur, E. Gueux, E. Rock, nd Y. Ryssiguier, Metolic syndrome in the rt: femles re protected ginst the pro-oxidnt effect of high sucrose diet, Experimentl Biology nd Medicine,vol.227,no.9,pp ,2002. [17] K.-A. Lê, D. Feh, R. Stettler et l., A 4-wk high-fructose diet lters lipid metolism without ffecting insulin sensitivity or ectopic lipids in helthy humns, The Americn Journl of Clinicl Nutrition,vol.84,no.6,pp ,2006. [18] S. A. Byol, B. H. Simi, J. A. Bertrnd, nd N. C. Sticklnd, Offspring from mothers fed junk food diet in pregnncy nd lcttion exhiit excerted diposity tht is more pronounced in femles, TheJournlofPhysiology,vol.586,no.13,pp , [19] A. Sori, A. Chicco, N. Mocchiutti et l., A sucrose-rich diet ffects triglyceride metolism differently in pregnnt nd nonpregnnt rts nd hs negtive effects on fetl growth, Journl of Nutrition,vol.126,no.10,pp ,1996. [20] M. A. Munill nd E. Herrer, Mternl hypertriglyceridemi during lte pregnncy does not ffect the increse in circulting triglycerides cused y the long-term consumption of sucroserich diet y rts, Journl of Nutrition,vol.130,no.12,pp , [21] K.-L. C. Jen, C. Rochon, S. Zhong, nd L. Whitcom, Fructose nd sucrose feeding during pregnncy nd lcttion in rts chnges mternl nd pup fuel metolism, JournlofNutrition,vol.121,no.12,pp ,1991. [22] R. H. H. Ching, L. O. Y. Yeung, I. M. Y. Tse, W.-H. Sit, nd E.T.S.Li, Supplementtionofittermelontortsfed high-fructose diet during gesttion nd lcttion meliortes fructose-induced dyslipidemi nd heptic oxidtive stress in mle offspring, Journl of Nutrition, vol. 141, no. 9, pp , [23] S.Rwn,K.Clrk,S.Zhong,A.Buison,S.Chckunkl,nd K.-L. C. Jen, Low dose fructose ingestion during gesttion nd lcttion ffects crohydrte metolism in rt dms nd their offspring, Journl of Nutrition, vol. 123, no. 12, pp , 1993.

8 8 Journl of Nutrition nd Metolism [24] M. H. Vickers, Z. E. Clyton, C. Yp, nd D. M. Slood, Mternl fructose intke during pregnncy nd lcttion lters plcentl growth nd leds to sex-specific chnges in fetl nd neontl endocrine function, Endocrinology, vol. 152, no. 4, pp , [25] L. Rodríguez, M. I. Pndero, N. Roglns et l., Fructose during pregnncy ffects mternl nd fetl leptin signling, The Journl of Nutritionl Biochemistry, vol. 24, no. 10, pp , [26] R. Muniypp, S. Lee, H. Chen, nd M. J. Quon, Current pproches for ssessing insulin sensitivity nd resistnce in vivo: dvntges, limittions, nd pproprite usge, The Americn Journl of Physiology Endocrinology nd Metolism,vol. 294, no. 1, pp. E15 E26, [27]S.H.Y.Wong,J.A.Knight,S.M.Hopfer,O.Zhri,C. N. Lech Jr., nd F. W. Sundermn Jr., Lipoperoxides in plsm s mesured y liquid-chromtogrphic seprtion of mlondildehyde-thiorituric cid dduct, Clinicl Chemistry,vol.33,no.2,prt1,pp ,1987. [28] V.Witko-Srst,M.Friedlnder,T.N.Khoetl., Advnced oxidtion protein products s novel meditors of inflmmtion nd monocyte ctivtion in chronic renl filure, Journl of Immunology, vol. 161, no. 5, pp , [29] B. Anderstm, B.-H. Ann-Christin, A. Vlli, P. Stenvinkel, B. Lindholm, nd M. E. Sulimn, Modifiction of the oxidtive stress iomrker AOPP ssy: ppliction in uremic smples, Clinic Chimic Act,vol.393,no.2,pp ,2008. [30] M.H.Vickers,P.D.Gluckmn,A.H.Covenyetl., Neontl leptin tretment reverses developmentl progrmming, Endocrinology,vol.146,no.10,pp ,2005. [31] M. Srinivsn, C. Dodds, H. Ghnim et l., Mternl oesity nd fetl progrmming: effects of high-crohydrte nutritionl modifiction in the immedite postntl life of femle rts, The Americn Journl of Physiology Endocrinology nd Metolism,vol.295,no.4,pp.E895 E903,2008. [32] M. H. Vickers, S. Reddy, B. A. Ikensio, nd B. H. Breier, Dysregultion of the dipoinsulr xis mechnism for the pthogenesis of hyperleptinemi nd dipogenic dietes induced y fetl progrmming, Journl of Endocrinology, vol. 170, no. 2, pp , [33] A.Shpiro,W.Mu,C.Roncl,K.-Y.Cheng,R.J.Johnson,nd P. J. Scrpce, Fructose-induced leptin resistnce excertes weight gin in response to susequent high-ft feeding, The Americn Journl of Physiology Regultory Integrtive nd Comprtive Physiology,vol.295,no.5,pp.R1370 R1375,2008. [34] B. Levi nd M. J. Wermn, Long-term fructose consumption ccelertes glyction nd severl ge-relted vriles in mle rts, Journl of Nutrition,vol.128,no.9,pp ,1998. [35] M.C.Cstro,M.L.Mss,H.delZotto,J.J.Gglirdino,ndF. Frncini, Rt liver uncoupling protein 2: chnges induced y fructose-rich diet, Life Sciences,vol.89,no.17-18,pp , [36] Y. Tkgi, A. Kshiwgi, Y. Tnk, T. Ashin, R. Kikkw, nd Y. Shiget, Significnce of fructose-induced protein oxidtion nd formtion of dvnced glyction end product, Journl of Dietes nd Its Complictions,vol.9,no.2,pp.87 91,1995. [37] G. G. Korkmz, E. Altinoglu, S. Civelek et l., The ssocition of oxidtive stress mrkers with conventionl risk fctors in the metolic syndrome, Metolism: Clinicl nd Experimentl, vol. 62, no. 6, pp , [38] A. R. Gy, Adverse effects of dietry fructose, Alterntive Medicine Review,vol.10,no.4,pp ,2005. [39] T. Nkgw, H. Hu, S. Zhrikov et l., A cusl role for uric cid in fructose-induced metolic syndrome, Americn Journl of Physiology Renl Physiology, vol.290,no.3,pp. F625 F631, [40] R. J. Johnson, T. Nkgw, L. G. Snchez-Lozd et l., Sugr, uric cid, nd the etiology of dietes nd oesity, Dietes,vol. 62, no. 10, pp , 2013.

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