Bempedoic Acid Restores Liver H2S Production in a Female Sprague-Dawley Rat Dietary Model of Non-Alcoholic Fatty Liver.

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 ß-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.

Fish oil diet in pregnancy and lactation reduces pup weight and modifies newborn hepatic metabolic adaptations in rats.

PURPOSE: To determine the effects of a diet containing fish oil (FD) during pregnancy and lactation in rats on the metabolic adaptations made by the offspring during early extrauterine life and to compare it to an olive oil diet (OD). METHODS: Rats were mated and randomly allocated to OD or FD containing 10 % of the corresponding oil. During lactation, litters were adjusted to eight pups per dam. Fetuses of 20 days and pups of 0, 1, 10, 20 and 30 days of age were studied. RESULTS: Body weight and length were lower in pups of the FD group from birth. The diet, milk, pups' plasma and liver of FD group had higher proportions of n-3 LCPUFA, but the content of arachidonic acid (ARA) was lower. Plasma glucose was higher, but unesterified fatty acids, triacylglycerols (TAG), 3-hydroxybutyrate and liver TAG in 1-day-old pups were lower in the FD group, and differences in some of these variables were also found in pups up to 30 days old. Liver lipoprotein lipase activity and mRNA expression, and the expression of carnitine palmitoyl transferase I, acyl-CoA oxidase and 3-hydroxy 3-methyl glutaryl-CoA synthase increased more at birth in pups of the FD group, but the expression of sterol regulatory element binding protein-1c and Δ6-desaturase mRNA was lower in the FD group. CONCLUSIONS: Maternal intake of high n-3 LCPUFA retards postnatal development, which could be the result of impaired ARA synthesis, and affects hepatic metabolic adaptations to extrauterine life.

Fructose only in pregnancy provokes hyperinsulinemia, hypoadiponectinemia, and impaired insulin signaling in adult male, but not female, progeny.

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.

Cardiac Hypertrophy in Pregnant Rats, Descendants of Fructose-Fed Mothers, an Effect That Worsens with Fructose Supplementation.

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.

Fructose Consumption Affects Placental Production of H2S: Impact on Preeclampsia-Related Parameters.

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.

Assessing addiction vulnerability with different rat strains and place preference procedures: the role of the cocaine and amphetamine-regulated transcript.

Validated biomarkers of addiction vulnerability are unavailable despite their potential value in diagnostics and therapeutics. As cocaine and amphetamine-regulated transcript (CART) peptides can be considered candidates for such biomarkers, we have studied the acute regulation of CART gene expression in the nucleus accumbens of rats with different drug-seeking behaviors. Two subgroups of Sprague-Dawley rats with different persistences of cocaine-induced and morphine-induced place preference showed a similar regulation of CART mRNA irrespective of their behavioral differences: CART gene expression was unaffected by acute cocaine and downregulated by acute morphine to a similar extent in both subgroups. Fischer 344 and Lewis rats, known to exhibit very different drug-seeking behaviors, showed lower basal expression of CART when compared with Sprague-Dawley rats, being almost undetectable in the case of the Lewis strain. Acute morphine downregulated CART in Fischer 344 rats as it did in Sprague-Dawley rats. The results tend to show that CART mRNA regulation by acute morphine or cocaine in the nucleus accumbens does not seem predictive of addiction vulnerability. However, in the particular case of Lewis rats, the pronounced hypoactivity of the CART system could contribute to the high vulnerability of this strain to develop drug-seeking behaviors.

Maternal fructose boosts the effects of a Western-type diet increasing SARS-COV-2 cell entry factors in male offspring.

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.

Mitochondrial Dysfunction in Lung Resident Mesenchymal Stem Cells from Idiopathic Pulmonary Fibrosis Patients.

Idiopathic pulmonary fibrosis (IPF) is characterized by an aberrant repair response with uncontrolled turnover of extracellular matrix involving mesenchymal cell phenotypes, where lung resident mesenchymal stem cells (LRMSC) have been supposed to have an important role. However, the contribution of LRMSC in lung fibrosis is not fully understood, and the role of LRMSC in IPF remains to be elucidated. Here, we performed transcriptomic and functional analyses on LRMSC isolated from IPF and control patients (CON). Both over-representation and gene set enrichment analyses indicated that oxidative phosphorylation is the major dysregulated pathway in IPF LRMSC. The most relevant differences in biological processes included complement activation, mesenchyme development, and aerobic electron transport chain. Compared to CON LRMSC, IPF cells displayed impaired mitochondrial respiration, lower expression of genes involved in mitochondrial dynamics, and dysmorphic mitochondria. These changes were linked to an impaired autophagic response and a lower mRNA expression of pro-apoptotic genes. In addition, IPF TGFß-exposed LRMSC presented different expression profiles of mitochondrial-related genes compared to CON TGFß-treated cells, suggesting that TGFß reinforces mitochondrial dysfunction. In conclusion, these results suggest that mitochondrial dysfunction is a major event in LRMSC and that their occurrence might limit LRMSC function, thereby contributing to IPF development.

Pregnancy Is Enough to Provoke Deleterious Effects in Descendants of Fructose-Fed Mothers and Their Fetuses.

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.

Liquid carbohydrate intake modifies transsulfuration pathway both in pregnant rats and in their male descendants.

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.

Maternal Fructose Intake Increases Liver H2 S Synthesis but Exarcebates its Fructose-Induced Decrease in Female Progeny.

SCOPE: Fructose 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 (H2 S), a product of its metabolism, has been proved to exert opposite effects to Hcy. METHODS AND RESULTS: First, it is investigated whether maternal fructose intake produces subsequent changes in Hcy metabolism and H2 S 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 H2 S production, cystathionine γ-lyase (CSE) (the key enzyme in H2 S synthesis) expression and plasma H2 S, 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 H2 S synthesis are diminished by fructose intake, this effect being more pronounced in F/F females. CONCLUSION: Maternal fructose intake produces a fetal programming that increases hepatic H2 S production and, in contrast, exacerbates its fructose-induced drop in female progeny.

Pharmacological and gene modification-based models for studying the impact of perinatal metabolic disturbances in adult life.

Genetic modification approaches or pharmacological interventions may be useful for understanding the molecular mechanisms by which nutrient derivatives and metabolites exert their effects in the perinatal period and how they may influence longterm metabolism in adults. Examples for such experimental settings in rodents are targeted disruption of the gene for peroxisome proliferator-activated receptor (PPAR)-a, a lipid sensor and master regulator of lipid catabolism, or maternal treatment with agonists of PPARgamma, a master regulator of adipogenesis and target of insulin sensitizing drugs in adults. All these interventions show differential effects in the perinatal period compared to adults and indicate that altered activity of master regulators of metabolism results in profound metabolic alterations in the perinatal period that may influence adult metabolism.

Effects of Maternal Fructose Intake on Perinatal ER-Stress: A Defective XBP1s Nuclear Translocation Affects the ER-stress Resolution.

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.

Nutrigenómica y funcionamiento de las hormonas tiroideas, un efecto dependiente de la ingesta materna de fructosa / Nutrigenomics and thyroid hormone functioning, a dependent effect of maternal fructose intake

El consumo de fructosa se ha asociado con el desarrollo de síndrome metabólico. También se ha demostrado que la ingesta de fructosa durante la gestación puede provocar efectos perjudiciales en los descendientes (1). Además, otros autores han descrito cómo la nutrición puede afectar al funcionamiento de las hormonas tiroideas, las cuales están implicadas en diversas enfermedades metabólicas.Por ello, se determinaron el efecto del consumo materno de fructosa durante la gestación sobre el metabolismo de las hormonas tiroideas en sus descendientes, y los efectos de la suplementación de los descendientes con distintas dietas (fructosa, tagatosa, fructosa con colesterol).La tagatosa aumentó los niveles plasmáticos de T4 libre y la expresión hepática de DIO1 solamente en descendientes de madres fructosa. Sin embargo, la expresión hepática de UCP2 mostró un perfil más similar a la de THRa.En íleon y TAL los perfiles de expresión para DIO1 y UCP están correlacionados y se ven afectados por el consumo de fructosa (efecto dependiente de la ingesta materna). La adición de colesterol a la dieta potenció el efecto de la fructosa en íleon (para DIO1 y UCP2).Por tanto, el consumo materno de fructosa afecta al metabolismo de las hormonas tiroideas de la descendencia, tanto en respuesta a una dieta rica en fructosa como a la asociación de fructosa y colesterol (“Western diet”).Este trabajo pretende alertar a la población, en especial mujeres embarazadas del papel relevante que ejerce la nutrición, con posibles consecuencias negativas para la salud de sus hijos.(AU)

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.(AU)

Maternal fructose induces gender-dependent changes in both LXRα promoter methylation and cholesterol metabolism in progeny.

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.

Role of insulin receptor substrate-1 serine 307 phosphorylation and adiponectin in adipose tissue insulin resistance in late pregnancy.

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.

Morphine differentially regulates hsp90beta expression in the nucleus accumbens of Lewis and Fischer 344 rats.

We have comparatively studied hsp90beta gene and protein expression in the nucleus accumbens of Lewis and Fischer 344 (F344) rats, two inbred strains that exhibit prominent behavioural differences in drug-seeking behaviours. Phenotypical studies confirmed that Lewis rats developed a higher preference for morphine-paired environments after conditioning. RT-PCR assays did not reveal strain-related differences in hsp90beta gene expression in basal conditions; however, acute morphine treatment provoked an increase of hsp90beta mRNA 2h after injection only in the case of Lewis rats. We also found a significant upregulation of the Hsp90beta protein in both strains 8h after morphine injection, this increase being significantly higher in Lewis rats. Taking into account the suggested roles for Hsp90 in the brain, the data suggest that Lewis and F344 strain differences concerning opioid-seeking behaviours could be related to differential sensitivity to opioid-induced neuronal plasticity within the brain reward system, an effect that could be mediated (at least partially) by stress proteins.

La ingesta materna de fructosa modula el metabolismo del colesterol en respuesta a una dieta occidental en la descendencia / Maternal fructose intake modulates cholesterol metabolism in response to a western diet in the offspring

El consumo de fructosa ha aumentado en las últimas décadas, en paralelo a la incidencia de síndrome metabólico y diabetes tipo 2. Múltiples evidencias sugieren que la ingesta materna de fructosa provoca alteraciones en la descendencia favoreciendo el desarrollo de síndrome metabólico. Sin embargo, la ingesta de fructosa durante el embarazo no está contraindicada. Este efecto se produce a través de la programación fetal, según la cual cambios como la dieta materna y ambientales durante las etapas embrionaria y fetal conducen a alteraciones en la etapa adulta de la descendencia. Con estos antecedentes, estudiamos el efecto de la ingesta materna de fructosa sobre el metabolismo del colesterol en la descendencia. Además, la progenie también se sometió a diferentes tratamientos dietéticos: fructosa, fructosa con colesterol y tagatosa.La tagatosa provocó un aumento del colesterol no HDL en la descendencia de madres control, mientras que el consumo materno de fructosa amortiguó este efecto, sugiriendo una programación fetal. Además, la suplementación con fructosa y con tagatosa provocaron un aumento de los índices aterogénicos disminuyendo la concentración de colesterol HDL y aumentando la de triglicéridos.Además, la suplementación con colesterol y fructosa provocó un aumento en los niveles plasmáticos de colesterol total y colesterol no HDL y una disminución del colesterol HDL, independientemente de la alimentación materna, provocando un aumento de los índices aterogénicos.En definitiva, los resultados indican que el metabolismo del colesterol está influenciado tanto por el consumo materno de fructosa como por los tratamientos dietéticos posteriores de la descendencia: fructosa, fructosa con colesterol y tagatosa. (AU)

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. (AU)

La ingesta materna de fructosa modula el metabolismo del colesterol en respuesta a una dieta occidental en la descendencia / Maternal fructose intake modulates cholesterol metabolism in response to a western diet in the offspring

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. (AU)

El consumo de fructosa ha aumentado en las últimas décadas, en paralelo a la incidencia de síndrome metabólico y diabetes tipo 2. Múltiples evidencias sugieren que la ingesta materna de fructosa provoca alteraciones en la descendencia favoreciendo el desarrollo de síndrome metabólico. Sin embargo, la ingesta de fructosa durante el embarazo no está contraindicada. Este efecto se produce a través de la programación fetal, según la cual cambios como la dieta materna y ambientales durante las etapas embrionaria y fetal conducen a alteraciones en la etapa adulta de la descendencia. Con estos antecedentes, estudiamos el efecto de la ingesta materna de fructosa sobre el metabolismo del colesterol en la descendencia. Además, la progenie también se sometió a diferentes tratamientos dietéticos: fructosa, fructosa con colesterol y tagatosa.La tagatosa provocó un aumento del colesterol no HDL en la descendencia de madres control, mientras que el consumo materno de fructosa amortiguó este efecto, sugiriendo una programación fetal. Además, la suplementación con fructosa y con tagatosa provocaron un aumento de los índices aterogénicos disminuyendo la concentración de colesterol HDL y aumentando la de triglicéridos.Además, la suplementación con colesterol y fructosa provocó un aumento en los niveles plasmáticos de colesterol total y colesterol no HDL y una disminución del colesterol HDL, independientemente de la alimentación materna, provocando un aumento de los índices aterogénicos.En definitiva, los resultados indican que el metabolismo del colesterol está influenciado tanto por el consumo materno de fructosa como por los tratamientos dietéticos posteriores de la descendencia: fructosa, fructosa con colesterol y tagatosa. (AU)

Englitazone administration to late pregnant rats produces delayed body growth and insulin resistance in their fetuses and neonates.

The level of maternal circulating triacylglycerols during late pregnancy has been correlated with the mass of newborns. PPARgamma (peroxisome-proliferator-activated receptor gamma) ligands, such as TZDs (thiazolidinediones), have been shown to reduce triacylglycerolaemia and have also been implicated in the inhibition of tissue growth and the promotion of cell differentiation. Therefore TZDs might control cell proliferation during late fetal development and, by extension, body mass of pups. To investigate the response to EZ (englitazone), a TZD, on perinatal development, 0 or 50 mg of englitazone/kg of body mass was given as an oral dose to pregnant rats daily from day 16 of gestation until either day 20 for the study of their fetuses, or until day 21 of gestation for the study of neonates. EZ decreased maternal triacylglycerol levels at day 20 of gestation and neonatal mass, but not fetal mass. Fetuses and neonates from EZ-treated mothers exhibited high levels of insulin and were found to be hyperglycaemic. The apparent insulin-resistant state in neonates from EZ-treated pregnant rats was corroborated, since they showed higher plasma NEFA [non-esterified ('free') fatty acid] levels, ketonaemia and liver LPL (lipoprotein lipase) activity and lower plasma IGF-I (type 1 insulin-like growth factor) levels, in comparison with those from control mothers. Moreover, at the molecular level, an increase in Akt phosphorylation was found in the liver of neonates from EZ-treated mothers, which confirms that the insulin pathway was negatively affected. Thus the response of fetuses and neonates to maternal antidiabetic drug treatment is the opposite of what would be expected, and can be justified by the scarce amount of adipose tissue impeding a normal response to PPARgamma ligands and by hyperinsulinaemia as being responsible for a major insulin-resistant condition.