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Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats.

ABSTRACT: Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted during the last week of gestation. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased. This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Restoration of autophagy with rapamycin but not with glucagon, indicated no defect in autophagy machinery per se, but in signals triggered by glucagon. Taken together, these results support the notion that hyperinsulinemia is an important mechanism by which mobilization of liver glycogen by autophagy is defective in food-restricted animals. This early alteration in the hormonal control of liver glycogen autophagy may influence the risk of developing metabolic diseases later in life.

SUBMITTER: de Toro-Martin J

PROVIDER: S-EPMC7573689 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats.

de Toro-Martín Juan J Fernández-Marcelo Tamara T González-Rodríguez Águeda Á Escrivá Fernando F Valverde Ángela M ÁM Álvarez Carmen C Fernández-Millán Elisa E

Scientific reports 20201019 1

Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted du ...[more]

PMID: 33077861

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Project description:BackgroundFetal growth restriction (FGR) has been associated with adverse perinatal outcomes and epigenetic modifications that impact gene expression leading to permanent changes of fetal metabolic pathways and thereby influence development of disease in childhood and adult life. In this study, we investigated the result of maternal food restriction on liver protein expression in Wistar male newborn pups.Materials & methodsTen (n = 10) timed pregnant Wistar rats on their 14th day of gestation were randomly assigned to either control (n = 4) or food restricted group (n = 6). The control group had ad libitum access to food. In the food restricted group, maternal diet was limited in a moderate fashion (50%) from day 15 of pregnancy until delivery. All rats delivered spontaneously on day 21 and newborn pups were immediately weighed. Pups born to normally nourished mothers were considered as controls, while pups born to food restricted mothers were subdivided into two groups, based on their birth weight: growth restricted (FGR) and appropriately grown (non-FGR). Rats were euthanized immediately after birth and liver tissues of 11 randomly selected male offspring (FGR n = 4, non-FGR n = 4, control n = 3) were collected and analyzed using quantitative proteomics.ResultsIn total 6,665 proteins were profiled. Of these, 451 and 751 were differentially expressed in FGR and non-FGR vs. control, respectively, whereas 229 proteins were commonly expressed. Bioinformatics analysis of the differentially expressed proteins (DEPs) in FGR vs. control revealed induction of the super-pathway of cholesterol biosynthesis and inhibition of thyroid hormone metabolism, fatty acid beta oxidation and apelin liver signaling pathway. Analysis of DEPs in non-FGR vs. control groups showed inhibition of thyroid hormone metabolism, fatty acid beta oxidation, and apelin liver signaling pathway.ConclusionThis study demonstrates the impact of prenatal food restriction on the proteomic liver profile of FGR and non-FGR offspring underlying the importance of both prenatal adversities and birth weight on liver-dependent postnatal disease.

Project description:Background: Accumulating evidence suggests a connection between the gut microbiota and neonatal diseases. Hypoxia may play an important role in the intestinal lesions in neonates. Objective: This study aims to determine whether the gut microbiota differs between intrauterine hypoxic rats and healthy controls and to identify the factors that influence the changes in the gut microbiota. Methods: We constructed an intrauterine hypoxia model in rats and collected the intestinal contents of intrauterine hypoxic newborn rats and normal newborn rats within 4 h and on the seventh day after birth. They were divided them into the intrauterine hypoxia first-day group (INH1), intrauterine hypoxia seventh-day group (INH7), normal first-day group (NOR1), and normal seventh-day group (NOR7). The contents of the intestines were sequenced with 16S rRNA sequencing, the sequencing results were analyzed for biological information, and the differences in the diversity, richness, and individual taxa among the groups were analyzed. Results: The abundance of the gut microbiota of neonatal rats with intrauterine hypoxia was higher than that of the control group rats. Intrauterine hypoxia altered the structural composition of the gut microbiota in neonatal rats. The INH1 group showed increased species richness, phylogenetic diversity, and β-diversity, and altered relative abundance in several taxa compared to those in the control group. The differences in the microbiota among the four groups were significantly higher than those within the group, and the differences in the abundance and diversity of the INH7 and NOR7 groups decreased after 7 days of suckling. Functional analysis based on the Cluster of Orthologous Groups (COG) suggested that 23 functional COG categories. There was no significant difference in the functional categories between the hypoxia group and the normal group. Conclusion: Intrauterine hypoxia changed the initial colonization of the gut microbiota in neonatal rats. It could increase the species richness and β-diversity of the gut microbiota, and altered relative abundances of several taxa.

Project description:Epidemiological studies report an inverse association between birth weight and risk for kidney disease that may differ between males and females, but studies investigating this association are limited. This study tested the hypothesis that male intrauterine growth-restricted offspring in a model of low birth weight induced by placental insufficiency in the rat exhibit enhanced renal injury in response to a persistent secondary renal insult while female growth-restricted offspring are protected. For this study, control offspring from sham-operated dams and growth-restricted offspring from reduced uterine perfusion dams underwent uninephrectomy or a sham procedure at 18 months of age. One month later, urinary markers of renal injury, renal function, and histological damage were measured. Results were analyzed using 2-way ANOVA. Male and female offspring were assessed separately. Proteinuria and urinary neutrophil gelatinase-associated lipocalin were significantly elevated in male growth-restricted offspring exposed to uninephrectomy when compared to male uninephrectomized control. Urinary kidney injury marker-1 was elevated in male uninephrectomized growth-restricted offspring relative to male sham growth-restricted but not to male uninephrectomized controls. Likewise, urinary neutrophil gelatinase-associated lipocalin was elevated in female uninephrectomized growth-restricted offspring but only when compared to female sham growth-restricted offspring. Markers of renal function including glomerular filtration rate and serum creatinine were impaired after uninephrectomy in female offspring regardless of birth weight. Histological parameters did not differ between control and growth-restricted offspring. Collectively, these studies suggest that both male and female growth-restricted offspring demonstrate susceptibility to renal injury following uninephrectomy; however, only male growth-restricted offspring exhibited an increase in renal markers of injury in response to uninephrectomy relative to same-sex control counterparts. These findings further suggest that urinary excretion of protein, kidney injury marker-1, and neutrophil gelatinase-associated lipocalin may be early markers of kidney injury in growth-restricted offspring exposed to a secondary renal insult such as reduction in renal mass.

Project description:Parasitic helminths polarize immune response of their vertebrate hosts towards anti-inflammatory Th2 type and therefore it is hypothesized that they may suppress the inflammatory conditions in autoimmune disorders. The present study was undertaken to investigate in vivo immunomodulatory and therapeutic potential of somatic antigens (Ag) of liver infecting digenetic trematodes [Fasciola gigantica (Fg) and Gigantocotyle explanatum (Ge)] in collagen-induced arthritic (CIA) Wistar rats. The CIA rats were administered subcutaneously with different doses (50 μg, 100 μg and 150 μg) of somatic antigens of Fg and Ge, daily for 21 days, the time period required to establish infection in natural host (Bubalus bubalis). Thereafter, the control, diseased and treated rats were compared for different parameters viz. hind paw thickness; serum interleukins, IL-4 and IL-10, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); expression level of matrix metalloproteinases (MMPs) -2, -9, -13 and nitric oxide (NO) in knee joints and patellar morphology. The CIA rats treated with different antigens, Fg-Ag and Ge-Ag, show significant amelioration of the disease by down regulation of serum TNF-α and IFN-γ (p< 0.05) and upregulation of IL-4 and IL-10 cytokines (p< 0.05); inhibition (p< 0.05) of MMPs (-2,-9,-13) and NO in knee joints and improved patellar morphology with decreased synovial hypertrophy and reduced infiltration of ploymorphonuclear cells. The activity of pro as well as active MMPs (-2 and -9) and active MMP-13 in knee joints of CIA rats was very high compared to the control and treatment groups, suggesting the extent of collagen degradation in CIA rats. Interestingly, the highest dose (150 μg) of Ge-Ag almost wiped out MMP-13 expression. The overall findings suggest that the somatic proteins of Ge-Ag appeared to be therapeutically more effective than Fg-Ag, reflecting interspecific molecular differences which could contribute to the ability of these worms to successfully ameliorate the pathology of CIA.

Project description:BackgroundFetal growth restriction (FGR) has been associated with a higher risk of developing adverse perinatal outcomes and distinct neurodevelopmental and neurobehavioral disorders. The aim of the present study was to investigate the impact of prenatal food restriction on the brain proteome in both FGR and appropriately grown rats and to identify potential pathways connecting maternal malnutrition with altered brain development.MethodsTen time-dated pregnant Wistar rats were housed individually at their 12th day of gestation. On the 15th day of gestation, the rats were randomly divided into two groups, namely the food restricted one (n = 6) and the control group (n = 4). From days 15 to 21 the control group had unlimited access to food and the food restricted group was given half the amount of food that was on average consumed by the control group, based on measurements taken place the day before. On the 21st day of gestation, all rats delivered spontaneously and after birth all newborn pups of the food restricted group were weighed and matched as appropriately grown (non-FGR) or growth restricted (FGR) and brain tissues were immediately collected. A multiplex experiment was performed analyzing brain tissues from 4 FGR, 4 non-FGR, and 3 control male offspring. Differentially expressed proteins (DEPs) were subjected to bioinformatics analysis in order to identify over-represented processes.ResultsProteomic analysis resulted in the profiling of 3,964 proteins. Gene ontology analysis of the common DEPs using DAVID (https://david.ncifcrf.gov/) showed significant enrichment for terms related to cellular morphology, learning, memory and positive regulation of NF-kappaB signaling. Ingenuity Pathway Analysis showed significant induction of inflammation in FGR pups, whereas significant induction of cell migration and cell spreading were observed in non-FGR pups.ConclusionThis study demonstrated that in both FGR and non-FGR neonates, a range of adaptive neurodevelopmental processes takes place, which may result in altered cellular morphology, chronic stress, poor memory and learning outcomes. Furthermore, this study highlighted that not only FGR, but also appropriately grown pups, which have been exposed to prenatal food deprivation may be at increased risk for impaired cognitive and developmental outcomes.

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Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats.

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Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats.

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