H2S, a gasotransmitter that can be produced both via the transsulfuration pathway and non-enzymatically, plays a key role in vasodilation and angiogenesis during pregnancy. In fact, the involvement of H2S production on plasma levels of sFLT1, PGF, and other molecules related to preeclampsia has been demonstrated. Interestingly, we have found that maternal fructose intake (a common component of the Western diet) affects tissular H2S production. However, its consumption is allowed during pregnancy. Thus, (1) to study whether maternal fructose intake affects placental production of H2S in the offspring, when pregnant; and (2) to study if fructose consumption during pregnancy can increase the risk of preeclampsia, pregnant rats from fructose-fed mothers (10% w/v) subjected (FF) or not (FC) to a fructose supplementation were studied and compared to pregnant control rats (CC). Placental gene expression, H2S production, plasma sFLT1, and PGF were determined. Descendants of fructose-fed mothers (FC) presented an increase in H2S production. However, if they consumed fructose during their own gestation (FF), this effect was reversed so that the increase disappeared. Curiously, placental synthesis of H2S was mainly non-enzymatic. Related to this, placental expression of Cys dioxygenase, an enzyme involved in Cys catabolism (a molecule required for non-enzymatic H2S synthesis), was significantly decreased in FC rats. Related to preeclampsia, gene expression of sFLT1 (a molecule with antiangiogenic properties) was augmented in both FF and FC dams, although these differences were not reflected in their plasma levels. Furthermore, placental expression of PGF (a molecule with angiogenic properties) was decreased in both FC and FF dams, becoming significantly diminished in plasma of FC versus control dams. Both fructose consumption and maternal fructose intake induce changes in molecules that contribute to increasing the risk of preeclampsia, and these effects are not always mediated by changes in H2S production.

The role of fructose consumption in the development of obesity, MetS, and CVD epidemic has been widely documented. Notably, among other effects, fructose consumption has been demonstrated to induce cardiac hypertrophy. Moreover, fructose intake during pregnancy can cause hypertrophy of the maternal heart. Our previous research has demonstrated that maternal fructose intake has detrimental effects on fetuses, which persist into adulthood and are exacerbated upon re-exposure to fructose. Additionally, we found that maternal fructose consumption produces changes in female progeny that alter their own pregnancy. Despite these findings, fructose intake during pregnancy is not currently discouraged. Given that cardiac hypertrophy is a prognostic marker for heart disease and heart failure, this study aimed to determine whether metabolic changes occurring during pregnancy in the female progeny of fructose-fed mothers could provoke a hypertrophic heart. To test this hypothesis, pregnant rats from fructose-fed mothers, with (FF) and without (FC) fructose supplementation, were studied and compared to pregnant control rats (CC). Maternal hearts were analyzed. Although both FF and FC mothers exhibited heart hypertrophy compared to CC rats, cardiac DNA content was more diminished in the hearts of FF dams than in those of FC rats, suggesting a lower number of heart cells. Accordingly, changes associated with cardiac hypertrophy, such as HIF1α activation and hyperosmolality, were observed in both the FC and FF dams. However, FF dams also exhibited higher oxidative stress, lower autophagy, and decreased glutamine protection against hypertrophy than CC dams. In conclusion, maternal fructose intake induces changes in female progeny that alter their own pregnancy, leading to cardiac hypertrophy, which is further exacerbated by subsequent fructose intake.

We previously demonstrated that treatment with BemA (bempedoic acid), an inhibitor of ATP citrate lyase, significantly reduces fatty liver in a model of liver steatosis (HFHFr—female Sprague-Dawley rat fed a high-fat high-fructose diet). Since the hepatic production of the gasotransmitter H2S is impaired in liver disorders, we were interested in determining if the production of H2S was altered in our HFHFr model and whether the administration of BemA reversed these changes. We used stored liver samples from a previous study to determine the total and enzymatic H2S production, as well as the expression of CBS (cystathionine β-synthase), CSE (cystathionine γ-lyase), and 3MST (3-mercaptopiruvate sulfurtransferase), and the expression/activity of FXR (farnesoid X receptor), a transcription factor involved in regulating CSE expression. Our data show that the HFHFr diet reduces the total and enzymatic production of liver H2S, mainly by decreasing the expression of CBS and CSE. Furthermore, BemA treatment restored H2S production, increasing the expression of CBS and CSE, providing evidence for the involvement of FXR transcriptional activity and the mTORC1 (mammalian target of rapamycin1)/S6K1 (ribosomal protein S6 kinase beta-1)/PGC1α (peroxisome proliferator receptor gamma coactivator1α) pathway.

Fructose consumption has been associated with the development of metabolic syndrome. It has also been shown that fructose intake during pregnancy can cause detrimental effects on offspring (1). In addition, other authors have described how nutrition can affect the function of thyroid hormones, which are involved in various metabolic diseases. Therefore, we determined the effect of maternal fructose consumption during pregnancy on the metabolism of thyroid hormones in their offspring and the effects of the supplementation with different diets (fructose, tagatose, fructose with cholesterol) in the offspring. Tagatose increased plasma free T4 levels and hepatic DIO1 expression only in the offspring of fructose-fed mothers. However, the hepatic expression of UCP2 showed a profile more similar to that of THRa. In ileum and TAL, the expression profiles for DIO1 and UCP are correlated and affected by fructose consumption (effect dependent on maternal intake). The addition of cholesterol to the diet potentiated the effect of fructose in ileum (for DIO1 and UCP2). Thus, maternal fructose consumption affects the metabolism of thyroid hormones in the offspring, both in response to a fructose rich diet and a combination of fructose and cholesterol (“Western diet”). This work aims to alert the population, especially pregnant women, of the relevant role of nutrition, leading to possible negative consequences for the health of their children.

Fructose-rich beverages and foods consumption correlates with the epidemic rise in cardiovascular disease, diabetes and obesity. Severity of COVID-19 has been related to these metabolic diseases. Fructose-rich foods could place people at an increased risk for severe COVID-19. We investigated whether maternal fructose intake in offspring affects hepatic and ileal gene expression of proteins that permit SARS-CoV2 entry to the cell. Carbohydrates were supplied to pregnant rats in drinking water. Adult and young male descendants subjected to water, liquid fructose alone or as a part of a Western diet, were studied. Maternal fructose reduced hepatic SARS-CoV2 entry factors expression in older offspring. On the contrary, maternal fructose boosted the Western diet-induced increase in viral entry factors expression in ileum of young descendants. Maternal fructose intake produced a fetal programming that increases hepatic viral protection and, in contrast, exacerbates fructose plus cholesterol-induced diminution in SARS-CoV2 protection in small intestine of progeny.

Fructose consumption has increased during the last decades, while a simultaneous rise in the incidence of pathologies such as type 2 diabetes and metabolic syndrome has also taken place. Although there is evidence that fructose can cause alterations in the offspring related to the development of the aforementioned diseases, exposure to fructose during pregnancy is not contraindicated for women. This effect is explained by the concept of foetal programming, which suggests that changes that occur during the embryogenic and foetal stages are permanent in the adult, due to maternal health, diet and other environmental factors. Therefore, the effect of fructose on cholesterol metabolism in the offspring of mothers fed with or without fructose during gestation was studied. In addition, the progeny also received different diets: fructose (with and without supplementation of cholesterol) or tagatose solutions. Tagatose increased non-HDL cholesterol in the offspring of water-fed mothers, whereas fructose consumption during gestation dampened this effect, indicating foetal programming. In addition, fructose and tagatose feeding increased atherogenic indices by decreasing HDL-cholesterol concentration and increasing triglycerides levels. On the other hand, the addition of cholesterol to fructose consumption caused an increase in total cholesterol and a change in its distribution: higher concentration of non-HDL cholesterol and lower concentration of HDL cholesterol, independently of maternal feeding. This also caused an increase in atherogenic indices. Ultimately, the results indicate that cholesterol metabolism is influenced by both maternal fructose consumption, and the subsequent intake of fructose (alone or in combination with cholesterol) and tagatose in the offspring.

INTRODUCTION:Fructose, alone or in combination with glucose, has been used as a source of added sugars to manufacture sugary drinks and processed foods. High consumption of simple sugars, mainly fructose, has been demonstrated to be one of the causes of developing metabolic diseases. Maternal nutrition is a key factor in the health of the progeny when adult. However, ingestion of fructose-containing foods is still permitted during gestation. Hydrogen sulphide (H2S) is a gasotransmitter produced in the transsulfuration pathway with proved beneficial effects to combat metabolic diseases.METHODS:Carbohydrates were supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation, and the pregnant rats, their foetuses, and adult male descendants were studied. Later, adult male progeny from control, fructose- and glucose-fed mothers were subjected to liquid fructose, and were compared to the control group. Liver H2S production was determined.RESULTS:This study shows that, in pregnancy, either a fructose-rich diet per se or situations that produce an impaired insulin sensitivity such as an excessive intake of glucose, decrease hepatic and placental production of H2S. Furthermore, this effect was also observed in the liver of male offspring (both in foetal and adult stages). Interestingly, when these adult descendants were subjected to a high fructose intake, decreases in H2S synthesis in liver and adipose tissue due to this fructose intake were maternal consumption dependent.CONCLUSIONS:Given H2S is a protective agent against diseases such as diabetes, obesity, cardiovascular diseases, and metabolic syndrome, the fact that carbohydrate consumption reduces H2S synthesis both in pregnancy and in their progeny could have clear and relevant clinical implications.

The role of fructose in the global obesity and metabolic syndrome epidemic is widely recognized. However, its consumption is allowed during pregnancy. We have previously demonstrated that maternal fructose intake in rats induces detrimental effects in fetuses. However, these effects only appeared in adult descendants after a re-exposure to fructose. Pregnancy is a physiological state that leads to profound changes in metabolism and hormone response. Therefore, we wanted to establish if pregnancy in the progeny of fructose-fed mothers was also able to provoke an unhealthy situation. Pregnant rats from fructose-fed mothers (10% w/v) subjected (FF) or not (FC) to a fructose supplementation were studied and compared to pregnant control rats (CC). An OGTT was performed on the 20th day of gestation, and they were sacrificed on the 21st day. Plasma and tissues from mothers and fetuses were analyzed. Although FF mothers showed higher AUC insulin values after OGTT in comparison to FC and CC rats, ISI was lower and leptinemia was higher in FC and FF rats than in the CC group. Accordingly, lipid accretion was observed both in liver and placenta in the FC and FF groups. Interestingly, fetuses from FC and FF mothers also showed the same profile observed in their mothers on lipid accumulation, leptinemia, and ISI. Moreover, hepatic lipid peroxidation was even more augmented in fetuses from FC dams than those of FF mothers. Maternal fructose intake produces in female progeny changes that alter their own pregnancy, leading to deleterious effects in their fetuses.

ScopeFructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases (CVD). However, consumption of beverages containing fructose is allowed during gestation. Homocysteine (Hcy) is a well‐known risk factor for CVD while hydrogen sulfide (H2S), a product of its metabolism, has been proved to exert opposite effects to Hcy.Methods and resultsFirst, it is investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H2S synthesis of the progeny. Carbohydrates are supplied to pregnant rats in drinking water (10% wt/vol) throughout gestation. Adult female descendants from fructose‐fed, control or glucose‐fed mothers are studied. Females from fructose‐fed mothers have elevated homocysteinemia, hepatic H2S production, cystathionine γ‐lyase (CSE) (the key enzyme in H2S synthesis) expression and plasma H2S, versus the other two groups. Second, it is studied how adult female progeny from control (C/F), fructose‐ (F/F), and glucose‐fed (G/F) mothers responded to liquid fructose and compared them to the control group (C/C). Interestingly, hepatic CSE expression and H2S synthesis are diminished by fructose intake, this effect being more pronounced in F/F females.ConclusionMaternal fructose intake produces a fetal programming that increases hepatic H2S production and, in contrast, exacerbates its fructose‐induced drop in female progeny.

Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome. Nevertheless, consumption of beverages sweetened with fructose is allowed in gestation. We have studied how adult male progeny from control (C/F), fructose- (F/F) and glucose-fed (G/F) mothers respond to liquid fructose (10% wt/vol), and compared them to the control group (C/C). Interestingly, plasma levels of fibroblast growth factor 21 (FGF21) were augmented in fructose-fed males, mainly in F/F group. FGF21 has proven to be a protective agent against steatosis and oxidative stress. Accordingly, FGF21 protected against fructose-induced lipid accumulation in livers of C/F and F/F males, but not in G/F. However, fructose-induced lipid oxidation was found in the adipose tissue of F/F males due to an impaired response of their antioxidant system. Maternal carbohydrate intake does influence the adult male offspring’s response to liquid fructose presumably by affecting the FGF21 function.

Balloon catheter endothelial denudation in New Zealand white rabbits fed high cholesterol diet is a validated atherosclerosis model. Well-characterized in terms of atherosclerosis induction and progression, the metabolic changes associated with the atherosclerosis progression remain indeterminate. Non-targeted metabolomics permits to develop such elucidation and allows to evaluate the metabolic consequences of colchicine treatment, an anti-inflammatory drug that could revert these changes. 16 rabbits underwent 18 weeks of atherosclerosis induction by diet and aortic denudation. Thereafter animals were randomly assigned to colchicine treatment or placebo for 18 weeks while on diet. Plasma samples were obtained before randomization and at 36 weeks. Multiplatform (GC/MS, CE/MS, RP-HPLC/MS) metabolomics was applied. Plasma fingerprints were pre-processed, and the resulting matrixes analyzed to unveil differentially expressed features. Different chemical annotation strategies were accomplished for those significant features. We found metabolites associated with either atherosclerosis progression, or colchicine treatment, or both. Atherosclerosis was profoundly associated with an increase in circulating bile acids. Most of the changes associated with sterol metabolism could not be reverted by colchicine treatment. However, the variations in lysine, tryptophan and cysteine metabolism among others, have shown new potential mechanisms of action of the drug, also related to atherosclerosis progression, but not previously described.

Endoplasmic reticulum (ER) homeostasis is crucial to appropriate cell functioning, and when disturbed, a safeguard system called unfolded protein response (UPR) is activated. Fructose consumption modifies ER homeostasis and has been related to metabolic syndrome. However, fructose sweetened beverages intake is allowed during gestation. Therefore, we investigate whether maternal fructose intake affects the ER status and induces UPR. Thus, administrating liquid fructose (10% w/v) to pregnant rats partially activated the ER-stress in maternal and fetal liver and placenta. In fact, a fructose-induced increase in the levels of pIRE1 (phosphorylated inositol requiring enzyme-1) and its downstream effector, X-box binding protein-1 spliced form (XBP1s), was observed. XBP1s is a key transcription factor, however, XBP1s nuclear translocation and the expression of its target genes were reduced in the liver of the carbohydrate-fed mothers, and specifically diminished in the fetal liver and placenta in the fructose-fed mothers. These XBP1s target genes belong to the ER-associated protein degradation (ERAD) system, used to buffer ER-stress and to restore ER-homeostasis. It is known that XBP1s needs to form a complex with diverse proteins to migrate into the nucleus. Since methylglyoxal (MGO) content, a precursor of advanced glycation endproducts (AGE), was augmented in the three tissues in the fructose-fed mothers and has been related to interfere with the functioning of many proteins, the role of MGO in XBP1s migration should not be discarded. In conclusion, maternal fructose intake produces ER-stress, but without XBP1s nuclear migration. Therefore, a complete activation of UPR that would resolve ER-stress is lacking. A state of fructose-induced oxidative stress is probably involved.

Fructose consumption from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. We have investigated whether maternal fructose intake produces subsequent changes in cholesterol metabolism of progeny. Carbohydrates were supplied to pregnant rats in drinking water (10% w/v solution) throughout gestation. Adult male and female descendants from fructose-fed, control or glucose-fed mothers were studied. Male offspring from fructose-fed mothers had elevated plasma HDL-cholesterol levels, whereas female progeny from fructose-fed mothers presented lower levels of non-HDL cholesterol vs. the other two groups. Liver X-receptor (LXR), an important regulator of cholesterol metabolism, and its target genes such as scavenger receptor B1, ATP-binding cassette (ABC)G5 and cholesterol 7-alpha hydroxylase showed decreased gene expression in males from fructose-fed mothers and the opposite in the female progeny. Moreover, the expression of a number of LXRα target genes related to lipogenesis paralleled to that for LXRα expression. In accordance with this, LXRα gene promoter methylation was increased in males from fructose-fed mothers and decreased in the corresponding group of females. Surprisingly, plasma folic acid levels, an important methyl-group donor, were augmented in males from fructose-fed mothers and diminished in female offspring. Maternal fructose intake produces a fetal programming that influences, in a gender-dependent manner, the transcription factor LXRα epigenetically, and both hepatic mRNA gene expression and plasma parameters of cholesterol metabolism in adult progeny. Changes in the LXRα promoter methylation might be related to the availability of the methyl donor folate.

Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and related events. Nevertheless, consumption of beverages sweetened with fructose is not regulated in gestation. Previously, we found that maternal fructose intake produces in the progeny, when fetuses, impaired leptin signaling and hepatic steatosis and then impaired insulin signaling and hypoadiponectinemia in adult male rats. Interestingly, adult females from fructose-fed mothers did not exhibit any of these disturbances. However, we think that, actually, these animals keep a programmed phenotype hidden. Fed 240-day-old female progeny from control, fructose- and glucose-fed mothers were subjected for 3weeks to a fructose supplementation period (10% wt/vol in drinking water). Fructose intake provoked elevations in insulinemia and adiponectinemia in the female progeny independently of their maternal diet. In accordance, the hepatic mRNA levels of several insulin-responsive genes were similarly affected in the progeny after fructose intake. Interestingly, adult progeny of fructose-fed mothers displayed, in response to the fructose feeding, augmented plasma triglyceride and NEFA levels and hepatic steatosis versus the other two groups. In agreement, the expression and activity for carbohydrate response element binding protein (ChREBP), a lipogenic transcription factor, were higher after the fructose period in female descendants from fructose-fed mothers than in the other groups. Furthermore, liver fructokinase expression that has been indicated as one of those responsible for the deleterious effects of fructose ingestion was preferentially augmented in that group. Maternal fructose intake does influence the adult female offspring's response to liquid fructose and so exacerbates fructose-induced dyslipidemia and hepatic steatosis.

SCOPE:One of the features of metabolic syndrome caused by liquid fructose intake is an impairment of redox status. We have investigated whether maternal fructose ingestion modifies the redox status in pregnant rats and their fetuses.METHODS AND RESULTS:Fructose (10% wt/vol) in the drinking water of rats throughout gestation, leads to maternal hepatic oxidative stress. However, this change was also observed in glucose-fed rats and, in fact, both carbohydrates produced a decrease in antioxidant enzyme activity. Surprisingly, mothers fed carbohydrates displayed low plasma lipid oxidation. In contrast, fetuses from fructose-fed mothers showed elevated levels of plasma lipoperoxides versus fetuses from control or glucose-fed mothers. Interestingly, a clearly augmented oxidative stress was observed in placenta of fructose-fed mothers, accompanied by a lower expression of the transcription factor Nuclear factor-erythroid 2-related factor-2 (Nrf2) and its target gene, heme oxygenase-1 (HO-1), a potent antioxidant molecule. Moreover, histone deacetylase 3 (HDAC3) that has been proposed to upregulate HO-1 expression by stabilizing Nrf2, exhibited a diminished expression in placenta of fructose-supplemented mothers.CONCLUSIONS:Maternal fructose intake provoked an imbalanced redox status in placenta and a clear diminution of HO-1 expression, which could be responsible for the augmented oxidative stress found in their fetuses.

Purpose Fructose intake from added sugars correlates with the epidemic rise in metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. Recently, we found that an intake of fructose (10 % wt/vol) throughout gestation produces impaired fetal leptin signaling and hepatic steatosis. Therefore, we have investigated whether fructose intake during pregnancy produces subsequent changes in the progeny, when adult. Methods Fed 261-day-old male and female descendants from fructose-fed, control or glucose-fed mothers were used. Plasma was used to analyze glucose, insulin, leptin, and adiponectin. Hepatic expression of proteins related to insulin signaling was determined. Results Fructose intake throughout pregnancy did not produce alterations in the body weight of the progeny. Adult male progeny of fructose-fed mothers had elevated levels of insulin without a parallel increase in phosphorylation of protein kinase B. However, they displayed an augmented serine phosphorylation of insulin receptor substrate-2, indicating reduced insulin signal transduction. In agreement, adiponectin levels, which have been positively related to insulin sensitivity, were lower in male descendants from fructose-fed mothers than in the other two groups. Furthermore, mRNA levels for insulin-responsive genes were not affected (phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) or they were decreased (sterol response element-binding protein-1c) in the livers of male progeny from fructose-supplemented rats. On the contrary, adult female rats from fructose-fed mothers did not exhibit any of these disturbances. Conclusion Maternal fructose, but not glucose, intake confined to the prenatal stage provokes impaired insulin signal transduction, hyperinsulinemia, and hypoadiponectinemia in adult male, but not female, progeny.