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BACKGROUND: Intrauterine growth restriction (IUGR) is an obstetrical condition where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has been used to assess fetal myelin water fraction (MWF) and might potentially assess myelination changes associated with IUGR. PURPOSE: To quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. STUDY TYPE: Prospective animal model. ANIMAL MODEL: Dunkin-Hartley GP model of spontaneous IUGR (mean ± SD: 60 ± 1.2 days gestation; 19 IUGR, 52 control). FIELD STRENGTH/SEQUENCE: Eight spoiled gradient-recalled (SPGR) gradient echo volumes (flip angles [α]: 2°-16°), and two sets of eight balanced steady-state free precession (bSSFP) gradient echo volumes (α: 8° - 64°), at 0° and 180° phase increments, at 3.0 T. ASSESSMENT: MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1 /T2 (mcDESPOT). MWF was quantified in the fetal corpus callosum (CC), fornix (FOR), parasagittal white matter (PSW), and whole fetal brain. STATISTICAL TESTS: Linear regression was performed between five fetal IUGR markers (body volume, body-to-pregnancy volume ratio, brain-to-liver volume ratio, brain-to-placenta volume ratio, and brain-to-body volume ratio) and MWF (coefficient of determination, R2 ). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs (significance was determined at α < 0.05). RESULTS: The MWF of the control fetuses are (mean ± SD): 0.23 ± 0.02 (CC), 0.31 ± 0.02 (FOR), 0.28 ± 0.02 (PSW), and 0.20 ± 0.01 (whole brain). The MWF of the IUGR fetuses are (mean ± SD): 0.19 ± 0.02 (CC), 0.27 ± 0.01 (FOR), 0.24 ± 0.03 (PSW), and 0.16 ± 0.01 (whole brain). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every comparison. DATA CONCLUSION: The mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.
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Maternal obesity and gestational diabetes mellitus (GDM) are linked with impaired placental function and early onset of non-communicable cardiometabolic diseases in offspring. Previous studies have highlighted that the dietary non-esterified fatty acids (NEFAs) palmitate (PA) and oleate (OA), key dietary metabolites associated with maternal obesity and GDM, are potential modulators of placental lipid processing. Using the BeWo cell line model, the current study integrated transcriptomic (mRNA microarray), metabolomic, and lipidomic readouts to characterize the underlying impacts of exogenous PA and OA on placental villous trophoblast cell metabolism. Targeted gas chromatography and thin-layer chromatography highlighted that saturated and monounsaturated NEFAs differentially impact BeWo cell lipid profiles. Furthermore, cellular lipid profiles differed when exposed to single and multiple NEFA species. Additional multi-omic analyses suggested that PA exposure is associated with enrichment in ß-oxidation pathways, while OA exposure is associated with enrichment in anti-inflammatory and antioxidant pathways. Overall, this study further demonstrated that dietary PA and OA are important regulators of placental lipid metabolism. Encouraging appropriate dietary advice and implementing dietary interventions to maintain appropriate placental function by limiting excessive exposure to saturated NEFAs remain crucial in managing at-risk obese and GDM pregnancies.
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INTRODUCTION: We determined the impact of gestational diabetes (GDM) and pre-existing diabetes (DM) on birth/placental weight and cord oxygen values with implications for placental efficiency and fetal-placental growth and development. METHODS: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA >34 weeks (N = 69,854). Oxygen saturation was calculated from the cord PO2 and pH data, while fetal O2 extraction was calculated from the oxygen saturation data. The effect of diabetic status on birth/placental weight and cord oxygen values was examined adjusting for covariates. RESULTS: Birth/placental weights were stepwise decreased in GDM and DM compared to non-diabetics with placentas disproportionally larger indicating decreasing placental efficiency. Umbilical vein oxygen was marginally increased in GDM but decreased in DM attributed to the previously reported hyper-vascularization in diabetic placentas with absorbing surface area of capillaries initially increased, but then constrained by increasing distance from maternal blood within the intervillous space. Umbilical artery oxygen was unchanged in GDM and DM, with fetal O2 extraction decreased in DM indicating that fetal O2 delivery must be increased relative to O2 consumption and likely due to increased umbilical blood flow. DISCUSSION: Increased villous density/hyper-vascularization in GDM and DM with placentas disproportionately larger and umbilical blood flow increased, are postulated to normalize umbilical artery oxygen despite increased birth weights and growth-related O2 consumption. These findings have implications for mechanisms signaling fetal-placental growth and development in diabetic pregnancies and differ from that reported with maternal obesity.
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Diabetes Gestacional , Placenta , Embarazo , Femenino , Humanos , Placenta/irrigación sanguínea , Oxígeno , Placentación , Cordón Umbilical , Peso al NacerRESUMEN
Pre-existing and gestationally-developed diabetes mellitus have been linked with impairments in placental villous trophoblast cell metabolic function, that are thought to underlie the development of metabolic diseases early in the lives of the exposed offspring. Previous research using placental cell lines and ex vivo trophoblast preparations have highlighted hyperglycemia is an important independent regulator of placental function. However, it is poorly understood if hyperglycemia directly influences aspects of placental metabolic function, including nutrient storage and mitochondrial respiration, that are altered in term diabetic placentae. The current study examined metabolic and mitochondrial function as well as nutrient storage in both undifferentiated cytotrophoblast and differentiated syncytiotrophoblast BeWo cells cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the direct impacts of placental hyperglycemic exposure. Hyperglycemic-exposed BeWo trophoblasts displayed increased glycogen and triglyceride nutrient stores, but real-time functional readouts of metabolic enzyme activity and mitochondrial respiratory activity were not altered. However, specific investigation into mitochondrial dynamics highlighted increased expression of markers associated with mitochondrial fission that could indicate high glucose-exposed trophoblasts are transitioning towards mitochondrial dysfunction. To further characterize the impacts of independent hyperglycemia, the current study subsequently utilized a multi-omics approach and evaluated the transcriptomic and metabolomic signatures of BeWo cytotrophoblasts. BeWo cytotrophoblasts exposed to hyperglycemia displayed increased mRNA expression of ACSL1, HSD11B2, RPS6KA5, and LAP3 and reduced mRNA expression of CYP2F1, and HK2, concomitant with increased levels of: lactate, malonate, and riboflavin metabolites. These changes highlighted important underlying alterations to glucose, glutathione, fatty acid, and glucocorticoid metabolism in BeWo trophoblasts exposed to hyperglycemia. Overall, these results demonstrate that hyperglycemia is an important independent regulator of key areas of placental metabolism, nutrient storage, and mitochondrial function, and these data continue to expand our knowledge on mechanisms governing the development of placental dysfunction.
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Hiperglucemia , Trofoblastos , Embarazo , Femenino , Humanos , Trofoblastos/metabolismo , Placenta/metabolismo , Multiómica , Hiperglucemia/metabolismo , Glucosa/farmacología , Glucosa/metabolismo , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Intrauterine growth restriction (IUGR) exerts a negative impact on developing cardiomyocytes and emerging evidence suggests activation of oxidative stress pathways plays a key role in this altered development. Here, we provided pregnant guinea pig sows with PQQ, an aromatic tricyclic o-quinone that functions as a redox cofactor antioxidant, during the last half of gestation as a potential antioxidant intervention for IUGR-associated cardiomyopathy. METHODS: Pregnant guinea pig sows were randomly assigned to receive PQQ or placebo at mid gestation and fetuses were identified as spontaneous IUGR (spIUGR) or normal growth (NG) near term yielding four cohorts: NG ± PQQ and spIUGR ± PQQ. Cross sections of fetal left and right ventricles were prepared and cardiomyocyte number, collagen deposition, proliferation (Ki67) and apoptosis (TUNEL) were analyzed. RESULTS: Cardiomyocyte endowment was reduced in spIUGR fetal hearts when compared to NG; however, PQQ exerted a positive effect on cardiomyocyte number in spIUGR hearts. Cardiomyocytes undergoing proliferation and apoptosis were more common in spIUGR ventricles when compared with NG animals, which was significantly reduced with PQQ supplementation. Similarly, collagen deposition was increased in spIUGR ventricles and was partially rescued in PQQ-treated spIUGR animals. CONCLUSION: The negative influence of spIUGR on cardiomyocyte number, apoptosis, and collagen deposition during parturition can be suppressed by antenatal administration of PQQ to pregnant sows. These data identify a novel therapeutic intervention for irreversible spIUGR-associated cardiomyopathy.
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Retardo del Crecimiento Fetal , Miocitos Cardíacos , Animales , Femenino , Cobayas , Embarazo , Antioxidantes , Retardo del Crecimiento Fetal/tratamiento farmacológico , Retardo del Crecimiento Fetal/metabolismo , Oxidación-Reducción , Cofactor PQQ/farmacología , Cofactor PQQ/uso terapéuticoRESUMEN
PURPOSE: Fetal tracheal occlusion (TO) reverses the pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. 'Omic' readouts capture metabolic and lipid processing function, which aid in understanding CDH and TO metabolic mechanisms. METHODS: CDH was created in fetal rabbits at 23 days, TO at 28 days and lung collection at 31 days (Term â¼32 days). Lung-body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. In a cohort, left and right lungs were collected, weighed, and samples homogenized, and extracts collected for non-targeted metabolomic and lipidomic profiling via LC-MS and LC-MS/MS, respectively. RESULTS: LBWR was significantly lower in CDH while CDH + TO was similar to controls (p = 0.003). MTBD was significantly higher in CDH fetuses and restored to control and sham levels in CDH + TO (p < 0.001). CDH and CDH + TO resulted in significant differences in metabolome and lipidome profiles compared to sham controls. A significant number of altered metabolites and lipids between the controls and CDH groups and the CDH and CDH + TO fetuses were identified. Significant changes in the ubiquinone and other terpenoid-quinone biosynthesis pathway and the tyrosine metabolism pathway were observed in CDH + TO. CONCLUSION: CDH + TO reverses pulmonary hypoplasia in the CDH rabbit, in association with a specific metabolic and lipid signature. A synergistic untargeted 'omics' approach provides a global signature for CDH and CDH + TO, highlighting cellular mechanisms among lipids and other metabolites, enabling comprehensive network analysis to identify critical metabolic drivers in disease pathology and recovery. TYPE OF STUDY: Basic Science, Prospective. LEVEL OF EVIDENCE: II.
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Hernias Diafragmáticas Congénitas , Animales , Conejos , Hernias Diafragmáticas Congénitas/patología , Lipidómica , Estudios Prospectivos , Cromatografía Liquida , Espectrometría de Masas en Tándem , Pulmón/patología , Lípidos , Tráquea/metabolismo , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: Fetal myelination assessment is important for understanding neurodevelopment and neurodegeneration. Myelin water imaging (MWI) quantifies myelin water fraction (MWF), a validated marker for myelin content, and has been used to assess brain myelin in children and neonates. PURPOSE: To demonstrate that MWI can quantify MWF in fetal guinea pigs (GPs). STUDY TYPE: Animal model. ANIMAL MODEL: Nine pregnant, Dunkin-Hartley GPs with 31 fetuses (mean ± standard deviation = 60 ± 1.5 days gestation). FIELD STRENGTH/SEQUENCE: 3D spoiled gradient echo and balanced steady-state free precession sequences at 3.0 T. ASSESSMENT: MWF maps were reconstructed for maternal and fetal GP brains using the multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) approach. Myelin basic protein (MBP) stain provided histological validation of the MWF. Regions of interest were placed in the maternal corpus callosum (CC), maternal fornix (FOR), fetal CC, and fetal FOR in MWF maps and MBP stains. STATISTICAL TESTS: Linear regression between MWF and MBP stain intensity (SI) of all four regions (coefficient of determination, R2 ). A paired t-test compared the MWF of maternal and mean fetal CC, MBP SI of maternal and mean fetal CC, MWF of maternal and mean fetal FOR, MBP SI of maternal and mean fetal FOR. A paired t-test with a linear mixed model compared the MWF of fetal CC and fetal FOR, and MBP SI of fetal CC and fetal FOR. A P value < 0.0083 was considered statistically significant. RESULTS: The mean MWF of the analyzed regions are as follows (mean ± standard deviation): 0.338 + 0.016 (maternal CC), 0.340 ± 0.017 (maternal FOR), 0.214 ± 0.016 (fetal CC), and 0.305 ± 0.025 (fetal FOR). MWF correlated with MBP SI in all regions (R2 = 0.81). Significant differences were found between MWF and MBP SI of maternal and fetal CC, and MWF and MBP SI of fetal CC and fetal FOR. DATA CONCLUSION: This study demonstrated the feasibility of MWI in assessing fetal brain myelin content. EVIDENCE LEVEL: 2 Technical Efficacy: Stage 1.
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Vaina de Mielina , Agua , Embarazo , Femenino , Cobayas , Animales , Vaina de Mielina/metabolismo , Estudios de Factibilidad , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
BACKGROUND: We determined the effect of fetal sex on birth/placental weight and umbilical vein and artery oxygen values with implications for placental efficiency and regulatory mechanisms underlying fetal-placental growth differences. METHODS: A hospital database was used to obtain birth/placental weight, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 weeks (N = 69,836). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of fetal sex on birth/placental weight, cord PO2, O2 saturation, and fractional O2 extraction was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. RESULTS: Birth/placental weights were lower in females indicating decreased placental efficiency. Umbilical vein oxygen values were higher in females attributed to increased uterine blood flow, while artery oxygen values were lower in females attributed to decreased hemoglobin and umbilical blood flow, and increased oxygen consumption. Fetal O2 extraction was increased in females confirming increased O2 consumption relative to delivery. CONCLUSIONS: Sex-related differences in uterine/umbilical blood flows, placental development, and fetal O2 consumption can be linked to the differences observed in cord oxygen. The lower umbilical artery oxygen in females as a measure of systemic oxygenation signaling growth could account for their decreased birth weights, while slower development in female placentae could account for their lower placental weights, which could be differentially effected contributing to their lower birth/placental weights.
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Oxígeno , Placenta , Peso al Nacer , Femenino , Sangre Fetal , Humanos , Placenta/irrigación sanguínea , Embarazo , Arterias Umbilicales , Cordón UmbilicalRESUMEN
Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of ß-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.
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Fructosa/efectos adversos , Metabolismo de los Lípidos/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Proteómica/métodos , Animales , Cromatografía Liquida , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Ácidos Grasos Monoinsaturados/sangre , Femenino , Cobayas , Humanos , Masculino , Mitocondrias Hepáticas/efectos de los fármacos , Fosforilación Oxidativa/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/sangre , Especies Reactivas de Oxígeno/metabolismo , Espectrometría de Masas en Tándem , Triglicéridos/metabolismo , DesteteRESUMEN
BACKGROUND: We determined the impact of gestational age (GA) from near term to term to post-term on birth/placental weight ratio and cord oxygen values with implications for placental transport efficiency for oxygen, fetal O2 consumption relative to delivery or fractional O2 extraction, and oxygen margin of safety. MATERIALS AND METHODS: A hospital database was used to obtain birth/placental weight ratios, cord PO2 and other information on patients delivering between Jan 1, 1990 and Jun 15, 2011 with GA > 34 completed weeks (N = 69,852). Oxygen saturation was calculated from the cord PO2 and pH data, while fractional O2 extraction was calculated from the oxygen saturation data. The effect of GA grouping on birth/placental weight ratio, cord PO2, O2 saturation, and fractional O2 extraction values, was examined in all patients adjusting for pregnancy and labor/delivery covariates, and in a subset of low-risk patients. RESULTS: Birth/placental weight ratio and umbilical venous O2 values increased with advancing GA, supporting the conjecture of increasing placental transport efficiency for oxygen. However, umbilical arterial O2 values decreased while fractional O2 extraction increased with successive GA groupings, indicating that fetal O2 consumption must be increasing relative to delivery. CONCLUSIONS: Fetal O2 consumption can be seen as ever 'outgrowing' O2 delivery over the last weeks of pregnancy and leading to a continued lowering in systemic oxygen levels. While this lowering in oxygen may trigger feedback mechanisms with survival benefit, the 'oxygen margin of safety' will also be lowered increasing perinatal morbidity and mortality which appear to be hypoxia related.
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Oxígeno , Placenta , Peso al Nacer , Femenino , Sangre Fetal , Edad Gestacional , Humanos , Parto , Embarazo , Cordón UmbilicalRESUMEN
BACKGROUND: Intrauterine growth restriction and low birth weight (LBW) have been widely reported as an independent risk factor for adult hypercholesterolaemia and increased hepatic cholesterol in a sex-specific manner. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. METHODS: Hepatic cholesterol, transcriptome, cholesterol homoeostasis regulatory proteins, and antioxidant markers were studied in UPI-induced LBW and normal birth weight (NBW) male and female guinea pigs at 150 days. RESULTS: Hepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "cholesterol metabolism" was an enriched pathway in LBW males but not in females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. CONCLUSIONS: UPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. IMPACT: Low birth weight (LBW) is a risk factor for increased hepatic cholesterol. Uteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. UPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. These changes, at the current age studied, were sex-specific, only being observed in LBW males and not in LBW females. These programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age.
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Antioxidantes , Hepatopatías , Animales , Peso al Nacer , Colesterol , Sistema Enzimático del Citocromo P-450 , Femenino , Cobayas , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , MasculinoRESUMEN
There is a strong relationship between low birth weight (LBW) and an increased risk of developing cardiovascular disease (CVD). In postnatal life, LBW offspring are becoming more commonly exposed to the additional independent CVD risk factors, such as an obesogenic diet. However, how an already detrimentally programmed LBW myocardium responds to a secondary insult, such as an obesogenic diet (western diet; WD), during postnatal life is ill defined. Herein, we aimed to determine in a pre-clinical guinea pig model of CVD, both the independent and interactive effects of LBW and a postnatal WD on the molecular pathways that regulate cardiac growth and metabolism. Uterine artery ablation was used to induce placental insufficiency (PI) in pregnant guinea pigs to generate LBW offspring. Normal birth weight (NBW) and LBW offspring were weaned onto either a Control diet or WD. At Ë145 days after birth (young adulthood), male and female offspring were humanely killed, the heart weighed and left ventricle tissue collected. The mRNA expression of signalling molecules involved in a pathological hypertrophic and fibrotic response was increased in the myocardium of LBW male, but not female offspring, fed a WD as was the mRNA expression of transcription factors involved in fatty acid oxidation. The mRNA expression of glucose transporters was downregulated by LBW and WD in male, but not female hearts. This study has highlighted a sexually dimorphic cardiac pathological hypertrophic and fibrotic response to the secondary insult of postnatal WD consumption in LBW offspring.
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Enfermedades Cardiovasculares , Insuficiencia Placentaria , Adulto , Animales , Peso al Nacer/fisiología , Dieta Occidental/efectos adversos , Femenino , Fibrosis , Cobayas , Humanos , Masculino , Placenta , Embarazo , ARN Mensajero , Adulto JovenRESUMEN
Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar "Western" diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose-tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male "lean" offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism, as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high-fat/high-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism, promoting mitochondrial overload.
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Fenómenos Fisiológicos Nutricionales de los Animales , Dieta Occidental/efectos adversos , Insulina/sangre , Mitocondrias/metabolismo , Músculo Esquelético/irrigación sanguínea , Animales , Animales Recién Nacidos , Peso al Nacer , Glucemia/metabolismo , Carnitina/análogos & derivados , Carnitina/sangre , Modelos Animales de Enfermedad , Femenino , Retardo del Crecimiento Fetal , Cobayas , Metabolismo de los Lípidos , Masculino , Insuficiencia Placentaria , Embarazo , Transducción de SeñalRESUMEN
INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is characterised by accumulation of triglycerides and cholesterol within the liver and dysregulation of specific hepatic cytochrome P450 (CYPs) activity. CYPs are involved in the metabolism of endogenous and exogenous chemicals. Hepatic CYP activity is dysregulated in human studies and animal models of a Western diet (WD) or low birth weight (LBW) independently, but the additive effects of LBW and postnatal WD consumption are unknown. As such, the aim of this study was to determine the independent and combined effect of birthweight and postnatal diet on hepatic CYP activity in a guinea pig model. METHODS: LBW was generated via uterine artery ablation at mid gestation (term = 70 days gestation). Normal birthweight (NBW) and LBW pups were allocated either a control diet (CD) or WD at weaning. After 4 months of dietary intervention, guinea pigs were humanely killed, and liver tissue collected for biochemical and functional hepatic CYP activity analyses. RESULTS: Independent of birthweight, functional activity of CYP3A was significantly reduced in female and male WD compared to CD animals (female, P < 0.0001; male, P = 0.004). Likewise, CYP1A2 activity was significantly reduced in male WD compared to CD animals (P = 0.020) but this same reduction was not observed in females. CONCLUSION: Diet, but not birthweight, significantly altered hepatic CYP activity in both sexes, and the effect of diet appeared to be greater in males. These findings may have clinical implications for the management of NAFLD and associated co-morbidities between the sexes.
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Peso al Nacer/fisiología , Sistema Enzimático del Citocromo P-450/fisiología , Dieta Alta en Grasa/efectos adversos , Dieta Occidental/efectos adversos , Hígado/enzimología , Enfermedad del Hígado Graso no Alcohólico/enzimología , Animales , Femenino , Cobayas , Masculino , Enfermedad del Hígado Graso no Alcohólico/etiología , EmbarazoRESUMEN
One of the greatest challenges to the development and implementation of pregnancy therapeutics is the ability to rigorously test treatments in clinically relevant animal models. Guinea pigs offer a unique advantage in studying the placenta, fetal development, and reproductive health as they have similar developmental milestones to humans, both throughout gestation and following birth. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane. Here, we describe a methodology to efficiently and accurately time mate guinea pigs, and provide a picture representation of changes to the guinea pig vaginal membrane throughout the estrus cycle. Utilization of this monitoring enabled a 100% pregnancy success rate on the first mating attempt in a cohort of five guinea pigs. This approach, along with early pregnancy ultrasounds as a secondary method to confirm pregnancy, offers a reliable approach to timed mating in the guinea pig.
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Migratory birds experience bouts of muscle growth and depletion as they prepare for, and undertake prolonged flight. Our studies of migratory bird muscle physiology in vitro led to the discovery that sanderling (Calidris alba) muscle satellite cells proliferate more rapidly than other normal cell lines. Here we determined the proliferation rate of muscle satellite cells isolated from five migratory species (sanderling; ruff, Calidris pugnax; western sandpiper, Calidris mauri; yellow-rumped warbler, Setophaga coronata; Swainson's thrush, Catharus ustulatus) from two families (shorebirds and songbirds) and with different migratory strategies. Ruff and sanderling satellite cells exhibited rapid proliferation, with population doubling times of 9.3 ± 1.3 and 11.4 ± 2 h, whereas the remaining species' cell doubling times were greater than or equal to 24 h. The results indicate that the rapid proliferation of satellite cells is not associated with total migration distance but may be related to flight bout duration and interact with lifespan.
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Charadriiformes , Pájaros Cantores , Migración Animal , Animales , Proliferación Celular , Humanos , MúsculosRESUMEN
Intrauterine growth restriction (IUGR) of the fetus, resulting from placental insufficiency (PI), is characterized by low fetal oxygen and nutrient concentrations that stunt growth rates of metabolic organs. Numerous animal models of IUGR recapitulate pathophysiological conditions found in human fetuses with IUGR. These models provide insight into metabolic dysfunction in skeletal muscle and liver. For example, cellular energy production and metabolic rate are decreased in the skeletal muscle and liver of IUGR fetuses. These metabolic adaptations demonstrate that fundamental processes in mitochondria, such as substrate utilization and oxidative phosphorylation, are tempered in response to low oxygen and nutrient availability. As a central metabolic organelle, mitochondria coordinate cellular metabolism by coupling oxygen consumption to substrate utilization in concert with tissue energy demand and accretion. In IUGR fetuses, reducing mitochondrial metabolic capacity in response to nutrient restriction is advantageous to ensure fetal survival. If permanent, however, these adaptations may predispose IUGR fetuses toward metabolic diseases throughout life. Furthermore, these mitochondrial defects may underscore developmental programming that results in the sequela of metabolic pathologies. In this review, we examine how reduced nutrient availability in IUGR fetuses impacts skeletal muscle and liver substrate catabolism, and discuss how enzymatic processes governing mitochondrial function, such as the tricarboxylic acid cycle and electron transport chain, are regulated. Understanding how deficiencies in oxygen and substrate metabolism in response to placental restriction regulate skeletal muscle and liver metabolism is essential given the importance of these tissues in the development of later lifer metabolic dysfunction.
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Retardo del Crecimiento Fetal/etiología , Mitocondrias/fisiología , Enfermedades Mitocondriales/complicaciones , Animales , Ciclo del Ácido Cítrico/fisiología , Femenino , Retardo del Crecimiento Fetal/metabolismo , Humanos , Recién Nacido , Hígado/metabolismo , Hígado/patología , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Fosforilación Oxidativa , Oxígeno/metabolismo , Insuficiencia Placentaria/etiología , Insuficiencia Placentaria/metabolismo , Insuficiencia Placentaria/patología , EmbarazoRESUMEN
BACKGROUND: Alterations in glycolysis are central to the increasing incidence of non-alcoholic fatty liver disease (NAFLD), highlighting a need for in vivo, non-invasive technologies to understand the development of hepatic metabolic aberrations. PURPOSE: To use hyperpolarized magnetic resonance spectroscopy (MRS) and proton density fat fraction (PDFF) magnetic resonance imaging (MRI) techniques to investigate the effects of a chronic, life-long exposure to the Western diet (WD) in an animal model resulting in NAFLD; to investigate the hypothesis that exposure to the WD will result in NAFLD in association with altered pyruvate metabolism. STUDY TYPE: Prospective. ANIMAL MODEL: Twenty-eight male guinea pigs weaned onto a control diet (N = 14) or WD (N = 14). FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted gradient echo, T2-weighted spin-echo, three-dimensional gradient multi-echo fat-water separation (IDEAL-IQ), and broadband point-resolved spectroscopy (PRESS) chemical-shift sequences. ASSESSMENT: Median PDFF was calculated in the liver and hind limbs. [1-13 C]pyruvate dynamic MRS in the liver was quantified by the time-to-peak (TTP) for each metabolite. Animals were euthanized and tissue was analyzed for lipid and cholesterol concentration and enzyme level and activity. STATISTICAL TESTS: Unpaired Student's t-tests were used to determine differences in measurements between the two diet groups. The Pearson correlation coefficient was calculated to determine correlations between measurements. RESULTS: Life-long WD consumption resulted in significantly higher liver PDFF and elevated triglyceride content in the liver. The WD group exhibited a decreased TTP for lactate production, and ex vivo analysis highlighted increased liver lactate dehydrogenase (LDH) activity. DATA CONCLUSION: PDFF MRI results suggest differential fat deposition patterns occurring in animals fed a life-long WD characteristic of lean, or lacking excessive subcutaneous fat, NAFLD. The decreased liver lactate TTP and increased ex vivo LDH activity suggest lipid accumulation occurs in association with a shift from oxidative metabolism to anaerobic glycolytic metabolism in WD-exposed livers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.
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Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Occidental , Cobayas , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Estudios Prospectivos , Protones , Ácido Pirúvico , Reproducibilidad de los ResultadosRESUMEN
Advanced imaging techniques are enhancing research capacity focussed on the developmental origins of adult health and disease (DOHaD) hypothesis, and consequently increasing awareness of future health risks across various subareas of DOHaD research themes. Understanding how these advanced imaging techniques in animal models and human population studies can be both additively and synergistically used alongside traditional techniques in DOHaD-focussed laboratories is therefore of great interest. Global experts in advanced imaging techniques congregated at the advanced imaging workshop at the 2019 DOHaD World Congress in Melbourne, Australia. This review summarizes the presentations of new imaging modalities and novel applications to DOHaD research and discussions had by DOHaD researchers that are currently utilizing advanced imaging techniques including MRI, hyperpolarized MRI, ultrasound, and synchrotron-based techniques to aid their DOHaD research focus.
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Investigación Biomédica/tendencias , Diagnóstico por Imagen/métodos , Enfermedades Fetales/diagnóstico , Feto/patología , Femenino , Enfermedades Fetales/diagnóstico por imagen , Feto/diagnóstico por imagen , Humanos , Embarazo , Sociedades CientíficasRESUMEN
Placental villous trophoblast mitochondrial respiratory function is critical for a successful pregnancy and environmental influences such as maternal obesity have been associated with respiratory impairment at term. More recently, a gestational high fat diet independent of maternal body composition, has been highlighted as a potential independent regulator of placental mitochondrial metabolism. The current study aimed to characterize the direct impact of a prolonged and isolated exposure to the dietary fatty acids Palmitate (PA) and Oleate (OA) upon placental cell mitochondrial respiratory function. BeWo cytotrophoblast (CT) and syncytiotrophoblast (SCT) cells were treated for 72 h with 100 µM PA, OA or PA+OA (P/O). Live-cell metabolic function was analyzed via the Seahorse XF Mito and Glycolysis Stress tests. Immunoblots and spectrophotometric activity assays were utilized to examine the protein expression and function of electron transport chain (ETC) complexes and key mitochondrial regulatory enzymes. Syncytialization of BeWo cells resulted reduced respiratory activity in conjunction with altered complex I and II activity and decreased pyruvate dehydrogenase (PDH) protein expression and activity. PA and P/O treatments were associated with increased basal and maximal respiratory activities in BeWo CT cells without alterations in protein expression or activity of individual ETC complexes and mitochondrial substrate regulators. The metabolic suppression in BeWo SCTs was consistent with that previously observed in primary human trophoblast cell cultures, while the observed increases in respiratory activity in PA-treated BeWo CTs may be indicative of an early timepoint of specific dietary saturated fat-mediated placental cell mitochondrial dysfunction.