1. Investigación

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.

Scope: fructose consumption from added sugars correlates with the epidemic rise in MetS and CVD. Maternal fructose intake has been described to program metabolic diseases in progeny. However, consumption of fructose-containing beverages is allowed during gestation. Cholesterol is also a well-known risk factor for CVD. Therefore, it is essential to study Western diets which combine fructose and cholesterol and how maternal fructose can influence the response of progeny to these diets. Methods and results: a high-cholesterol (2%) diet combined with liquid fructose (10%), as a model of an unhealthy Western diet, was administered to descendants from control and fructose-fed mothers. Gene (mRNA and protein) expression and plasma, fecal and tissue parameters of cholesterol metabolism were measured. Interestingly, progeny from fructose-fed dams consumed less liquid fructose and cholesterol-rich chow than males from control mothers. Moreover, descendants of fructose-fed mothers fed a Western diet showed an increased cholesterol elimination through bile and feces than males from control mothers. Despite these mitigating circumstances to develop a proatherogenic profile, the same degree of hypercholesterolemia and severity of steatosis were observed in all descendants fed a Western diet, independently of maternal intake. An increased intestinal absorption of cholesterol, synthesis, esterification, and assembly into lipoprotein found in males from fructose-fed dams consuming a Western diet could be the cause. Moreover, an augmented GLP2 signalling seen in these animals would explain this enhanced lipid absorption. Conclusions: maternal fructose intake, through a fetal programming, makes a Western diet considerably more harmful in their descendants than in the offspring from control mothers.

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.

La DMG es una enfermedad multifactorial, por lo que existe controversia en cuanto a los mecanismos implicados en su patogénesis. Nos preguntamos si el estilo de vida y los hábitos alimenticios influyen en la aparición y patogenia de la DMG. Para explorar este tema, el objetivo del presente estudio fue analizar las características de la dieta y el estilo de vida en el embarazo temprano y su influencia en el desarrollo de DMG en mujeres normoglucémicas y evaluar si los conocimientos previos y adquiridos mediante consultas de educación nutricional sobre un correcto manejo del control glucémico en mujeres con diagnóstico de DMG influyen y mejoran la obtención de resultados perinatales maternos y fetales óptimos. El estudio se realizó en el Hospital Universitario La Paz y fue aprobado por el comité de bioética del hospital. Se dividió en dos partes, la primera incluyó a 103 mujeres embarazadas que completaron un cuestionario sobre conocimientos nutricionales, estilo de vida y hábitos alimenticios a través del cual se obtuvo información sobre el estilo de vida pregestacional. La segunda parte incluyó a 51 mujeres con diagnóstico de DMG, las cuales completaron un cuestionario sobre conocimientos nutricionales implicados en el control glucémico y estilo de vida. En ambos grupos de estudio se realizó seguimiento del embarazo, obteniéndose resultados perinatales y bioquímicos, los cuales se compararon entre las mujeres normoglucémicas y aquellas que desarrollaron DMG. Los resultados obtenidos demuestran que existe una relación entre la dieta materna y estilo de vida en la aparición de DMG en mujeres normoglucémicas. Los conocimientos dietéticos y sobre el estilo de vida influyen en el control metabólico en mujeres con diagnóstico de DMG. Por lo que, la educación nutricional es fundamental al inicio de la gestación para que las mujeres adquieran hábitos dietéticos que puedan influir en la prevención del desarrollo de DMG o un correcto manejo glucémico en caso de diagnóstico y de esta manera intentar evitar las complicaciones que esta puede conllevar. El estudio demuestra la importancia de la educación nutricional antes y durante el embarazo.

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.

Pregnancy and lactation are considered critical periods in a female’s life. Thus, the maternal diet must provide sufficient energy and nutrients to meet the mother’s higher than usual requirements as well as the needs of the growing fetus. The maternal diet must enable the mother to provide stores of nutrients required for adequate fetal development, and good health and quality of life in infancy and later adulthood. Among the food and beverage groups, milk and dairy products can play a very important role in achieving these targets due to their high nutrient density and bioavailability, as well as their availability and widespread consumption. The objective of this study was to evaluate the influence of maternal milk and dairy consumption on pregnancy and lactation outcomes in healthy women. This report mainly focuses on the effects of the mother’s intake of dairy products on infant birth weight and length, fetal femur length, head circumference, gestational weight gain, preterm birth, spontaneous abortion, breast milk consumption, and human milk nutritional value. A systematic review of available studies published up toMay 2018 was conducted. A preliminary broad search of the literature yielded 5,695 citations. Four of the investigators independently selected studies for inclusion according to predefined eligibility criteria. Thirty-seven full-text articles were evaluated for potential inclusion, and 17 studies were finally included. Six were prospective cohort studies, 3 were intervention studies, 3 were retrospective cohort studies, 3 were cross-sectional studies, and 2 were case-control studies. Although the number and types of studies prevent definite conclusions, there appears to be a trend that maternal milk intake during pregnancy is positively associated with infant birth weight and length. The lack of studies prevents any conclusions being drawn related to preterm deliveries, spontaneous abortion, and lactation. Adv Nutr 2019;10:S74–S87.

Las patologías del embarazo, tales como diabetes gestacional (DG) o preeclampsia, suponen un riesgo tanto materno como fetal, a corto y largo plazo. Nuestra hipótesis apunta a que determinadas variaciones genéticas, a nivel materno y placentario, podrían predisponer a la mujer a desarrollar patologías del embarazo, generando cambios en las estructuras embrionarias que modifiquen las condiciones del entorno intrauterino y el correcto desarrollo fetal. El objetivo general del estudio está encaminado a ampliar el conocimiento de los factores involucrados en el desarrollo de patologías del embarazo, así como identificar posibles biomarcadores de estas patologías permitiendo su abordaje temprano. Así se han identificado los polimorfismos, rs1387153 y rs10830963 (MTNR1B), como potenciales biomarcadores de DG de aparición temprana, y el hsa-miR-206 circulante como potencial biomarcador de DG. Además, observamos un comportamiento diferencial entre las caras de la placenta que permite acomodar los recursos a la demanda energética fetal, en las gestaciones gemelares. En placentas con preeclampsia se observan cambios en la expresión de transportadores, enzimas del metabolismo lipídico y factores reguladores de angiogénesis, diferencial según el momento de aparición de la patología, fundamentalmente en la cara fetal de la placenta, debidos posiblemente a mecanismos adaptativo que asegure la disponibilidad de ATP feto-placentario.

To study the effect of prolonged diabetes on protein synthesis and on the activities of initiation factors elF-2 and elF-2B in the liver, female rats were treated with streptozotocin. Some animals were mated and studied on day 20 of pregnancy, whereas others were kept virgin and studied in parallel. The protein synthesis rate was measured with an 'in vitro' cellfree system, and was lower in diabetic pregnant and virgin animals than in pregnant and virgin controls (30-60%). The fetuses of diabetic rats had a lower protein synthesis rate than those from controls, although they always showed a higher protein synthesis rate than their mothers or virgin rats. Protein synthesis rate, RNA concentration, and initiation factor 2 activity were higher in pregnant than in virgin rats. Both activity and level of elF-2 factor changed in parallel to the protein synthesis rate, although no differences could be detected between control and diabetic animals. The eIF-2B activity in tissue extracts from diabetic virgin rats and fetuses was lower than in extracts from their controls, whereas no differences could be detected between pregnant and virgin control rats nor between pregnant control and pregnant diabetic animals. The percentage of the phosphorylated form of eIF-2 factor, eIF-2(uP), was slightly lower in virgin than in pregnant rats but was unaffected by the diabetic condition, while in diabetic fetuses this parameter was lower than in their corresponding controls. The cyclic adenosine monophosphate dependent protein kinase level was lower in diabetic rats than in controls, whereas no changes in the activity of casein kinase II were found. The isoelectric forms of the 13 subunit of eIF-2 factor, eIF-213, were different in the diabetic and the control animals, indicating that insulin deficiency modifies the phosphorylation of specific substrates. Since no differences were detected in RNA or eIF-2 content between control and diabetic rats, translation may, at least partly, be inhibited in the liver by an impairment of peptide chain initiation caused by the decreased eIF-2B activity which nevertheless is independent of eIF2u phosphorylation.

Fibrates are peroxisome proliferator-activated receptor alpha (PPARa) ligands used to normalize lipid and glucose parameters and exert anti-inflammatory effects. The acute-phase response (APR) is an important inflammatory process. One of the most important acute-phase proteins in rats is a2-macroglobulin (A2Mg). Whereas normal adult rats present low serum levels, pregnant rats display high amounts. Therefore, we used pregnant rats to detect the effect of fenofibrate on hepatic A2Mg expression by RT-PCR and Northern blot. Virgin rats were used as controls. The expression of other APR genes, a known fibrate-responder gene, gamma-chain fibrinogen (g-Fib), and one gene from the same family as A2Mg, complement component 3 (C3), were also measured in liver. In order to determine whether the fibrateeffects were mediated by PPARa, wild-type mice and PPARa-null mice were also used and treated with WY-14,643 (WY) or di-2-ethylhexyl phthalate (DEHP). Fenofibrate depressed A2Mg expression in virgin rats, but expression was decreased more sharply in pregnant rats. Expression of C3 and g-Fib was diminished after treatment only in pregnant rats. On the other hand, WY, but not DEHP, reduced A2Mg and g-Fib expression in the livers of wild-type mice, without any effect in PPARa-null mice. WY or DEHP did not affect C3 expression. Therefore, A2Mg expression is modified by PPARa agonists not only in pregnant rats under augmented APR protein synthesis, but also in virgin rats and mice under basal conditions. Interestingly, our results also identify A2Mg as a novel PPARa agonist-regulated gene.

To study insulin/glucose relationship during gestation, rats were studied on days 6, 12, 15, 18, 20 or 21 of presnancy and the results were compared to values in sex.matched virgin control rats. Blood glucose levels were decreased on days 20 and 21 of gestation whereas plasma insulin levels appeared decreased on days 6 and 12, unchanged on day 15 and enhanced on days 18. 20 and 2L of gestation. Total pancreas insulin content was already augmented on day 6 of gestation and continued to increase with gestational time. \Vith the exception of an increase in tbe 6-day.pregnant rats 22.5 min after an oral glucose toad, blood glucose levels did not differ between 6• or 12-day.pregnant rats and virgin controls although plasma insulin levels reached higher values on these days. However. in the 15-day-pregnam rats, glucose tolera!lce after the glucose load was enhanced while plasma insulin levels did not differ from those in virgin rats during the first 30 mjn. In the IS-day-pregnant rat blood glucose was more increased but plasma insulin did not differ after the glucose load when compared to virgin rats, whereas 20. or 21-day-pregnant rats showed a gJucose tolerance similar to that of virgin rats but their insulin levels shonly after the glucose load were higher. The hY'I.»" glycemic response lo a high intravenous dose of insulin was decreased in 12-, 18-. 20- and 21-day-pregnant rats. TI,erefore, whereas in both the 6- and 12-day-pregnant rats there is an enhanced 13-,celJ response to the glucose insulinotropic effect and insulin responsiveness is reduced in J 2. day-pregnant rats. the 15-day pregnam rat is in a transitory stage where both insulin sensitivity and the J},-ccll response return to non pregnant vaJ. ues. Ho\•.revcr. from 18 da)'S of gcslation on, there is an intense insulin• resistanl condition which is only partially compensated by an enormous accumulation of insuJin in the pancreas followed by a faster and larger insulin release after a glucose load.