139 Wettemann Graduate Scholar in Physiology: Maternal nutrition alters concentrations of nutrients in fetal fluids and expression of genes impacting production efficiencies in bovine fetal liver, muscle, and cerebrum during the first 50

AbstractEvidence suggests that sub-optimal maternal nutrition has implications for the developing offspring. We have previously shown that exposure to a low-protein diet during gestation was associated with upregulation of genes associated with cholesterol transport and packaging within the placenta. This study aimed to elucidate the effect of altering maternal dietary linoleic acid (LA; omega-6) to alpha-linolenic acid (ALA; omega-6) ratios as well as total fat content on placental expression of genes associated with cholesterol transport. The potential for maternal body mass index (BMI) to be associated with expression of these genes in human placental samples was also evaluated. Placentas were collected from 24 Wistar rats at 20-day gestation (term = 21–22-day gestation) that had been fed one of four diets containing varying fatty acid compositions during pregnancy, and from 62 women at the time of delivery. Expression of 14 placental genes associated with cholesterol packaging and transfer was assessed in rodent and human samples by quantitative real time polymerase chain reaction. In rats, placental mRNA expression of ApoA2, ApoC2, Cubn, Fgg, Mttp and Ttr was significantly elevated (3–30 fold) in animals fed a high LA (36% fat) diet, suggesting increased cholesterol transport across the placenta in this group. In women, maternal BMI was associated with fewer inconsistent alterations in gene expression. In summary, sub-optimal maternal nutrition is associated with alterations in the expression of genes associated with cholesterol transport in a rat model. This may contribute to altered fetal development and potentially programme disease risk in later life. Further investigation of human placenta in response to specific dietary interventions is required.

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Maternal overnutrition suppresses the phosphorylation of 5′-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90492.2008 ◽

2008 ◽

Vol 295 (6) ◽

pp. R1982-R1990 ◽

Cited By ~ 17

Author(s):

L. K. Philp ◽

B. S. Muhlhausler ◽

A. Janovska ◽

G. A. Wittert ◽

J. A. Duffield ◽

...

Keyword(s):

Skeletal Muscle ◽

Maternal Nutrition ◽

Fetal Liver ◽

Glucose Production ◽

Later Life ◽

Quadriceps Muscle ◽

Epidemiological Studies ◽

Postnatal Life ◽

Increased Risk ◽

Maternal Overnutrition

Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or ∼55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139–141 days gestation ( n = 14) and lambs at 30 days of postnatal age ( n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPKα1 and AMPKα2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKα and phospho-AMPKα (P-AMPKα) was determined by Western blot analysis, and the proportion of the total AMPKα pool that was phosphorylated in each sample (%P-AMPKα) was determined. The ratio of AMPKα2 to AMPKα1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKα was lower in both fetuses and lambs in the Overfed group and %P-AMPKα in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth ( r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPKα or P-AMPKα abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKα responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.

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Maturation stage–specific regulation of megakaryopoiesis by pointed-domain Ets proteins

Blood ◽

10.1182/blood-2006-04-019760 ◽

2006 ◽

Vol 108 (7) ◽

pp. 2198-2206 ◽

Cited By ~ 52

Author(s):

Liyan Pang ◽

Hai-Hui Xue ◽

Gabor Szalai ◽

Xun Wang ◽

Yuhuan Wang ◽

...

Keyword(s):

Transcription Factor ◽

Fetal Liver ◽

Maturation Stage ◽

Platelet Factor ◽

Ets Proteins ◽

Expression Of Genes ◽

Friend Leukemia ◽

Specific Regulation

Abstract Numerous megakaryocyte-specific genes contain signature Ets-binding sites in their regulatory regions. Fli-1 (friend leukemia integration 1), an Ets transcription factor, is required for the normal maturation of megakaryocytes and controls the expression of multiple megakaryocyte-specific genes. However, in Fli-1–/– mice, early megakaryopoiesis persists, and the expression of the early megakaryocyte-specific genes, αIIb and cMpl, is maintained, consistent with functional compensation by a related Ets factor(s). Here we identify the Ets protein GABPα (GA-binding protein α) as a regulator of early megakaryocyte-specific genes. Notably, GABPα preferentially occupies Ets elements of early megakaryocyte-specific genes in vitro and in vivo, whereas Fli-1 binds both early and late megakaryocyte-specific genes. Moreover, the ratio of GABPα/Fli-1 expression declines throughout megakaryocyte maturation. Consistent with this expression pattern, primary fetal liver–derived megakaryocytes from Fli-1–deficient murine embryos exhibit reduced expression of genes associated with late stages of maturation (glycoprotein [GP] Ibα, GPIX, and platelet factor 4 [PF4]), whereas GABPα-deficient megakaryocytes were mostly impaired in the expression of early megakaryocyte-specific genes (αIIb and cMpl). Finally, mechanistic experiments revealed that GABPα, like Fli-1, can impart transcriptional synergy between the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 (friend of GATA-1). In concert, these data reveal disparate, but overlapping, functions of Ets transcription factors at distinct stages of megakaryocyte maturation.

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Maternal nutrition alters the expression of insulin-like growth factors in fetal sheep liver and skeletal muscle

Journal of Endocrinology ◽

10.1677/joe.0.1670429 ◽

2000 ◽

Vol 167 (3) ◽

pp. 429-437 ◽

Cited By ~ 78

Author(s):

JM Brameld ◽

A Mostyn ◽

J Dandrea ◽

TJ Stephenson ◽

JM Dawson ◽

...

Keyword(s):

Skeletal Muscle ◽

Growth Hormone Receptor ◽

Maternal Nutrition ◽

Fetal Liver ◽

Mrna Abundance ◽

Nutrient Restriction ◽

Fetal Sheep ◽

Gestation Age ◽

Igf I ◽

Metabolisable Energy

We investigated the influence of maternal dietary restriction between days 28 and 80 of gestation followed by re-feeding to the intake of well-fed ewes up to 140 days of gestation (term is 147 days) in sheep, on expression of mRNA for insulin-like growth factor (IGF)-I, IGF-II and growth hormone receptor (GHR) in fetal liver and skeletal muscle. Singleton bearing ewes either consumed 3.2-3.8 MJ/day of metabolisable energy (ME) (i.e. nutrient restricted - approximately 60% of ME requirements, taking into account requirements for both ewe maintenance and growth of the conceptus) or 8.7-9.9 MJ/day (i.e. well fed - approximately 150% of ME requirements) between days 28 and 80 of gestation. All ewes were then well fed (150% of ME requirements) up to day 140 of gestation and consumed 8-10.9 MJ/day. At days 80 and 140 of gestation, five ewes were sampled from each group and fetal tissues taken. There was no difference in fetal body weight or liver weights between groups at either sampling date, or skeletal muscle (quadriceps) weight at 140 days. IGF-I mRNA abundance was lower in livers of nutrient-restricted fetuses at day 80 of gestation (nutrient restricted 2.35; well fed 3.70 arbitrary units), but was higher than well-fed fetuses at day 140 of gestation, after 60 days of re-feeding (restricted/re-fed 4.27; well fed 2.83;s.e.d. 0.98 arbitrary units, P=0.061 for dietxage interaction). IGF-II mRNA abundance was consistently higher in livers of nutrient-restricted fetuses (80 days: nutrient restricted 7.78; well fed 5.91; 140 days: restricted/re-fed 7.23; well fed 6.01;s.e.d. 1.09 arbitrary units, P=0.061 for diet). Nutrient restriction had no effect on hepatic GHR mRNA abundance, but re-feeding of previously nutrient-restricted fetuses increased GHR mRNA compared with continuously well-fed fetuses (80 days: nutrient restricted 70.6; well fed 75.1; 140 days: restricted/re-fed 115.7; well fed 89.4;s.e.d. 10.13 arbitrary units, P=0.047 for dietxage interaction). In fetal skeletal muscle, IGF-I mRNA abundance was not influenced by maternal nutrition and decreased with gestation age (P<0.01). IGF-II mRNA abundance was higher in skeletal muscle of nutrient-restricted fetuses compared with well-fed fetuses at day 80 of gestation (nutrient restricted 16.72; well fed 10.53 arbitrary units), but was lower than well-fed fetuses after 60 days of re-feeding (restricted/re-fed 7.77; well fed 13.72;s.e.d. 1.98 arbitrary units, P<0.001 for dietxage interaction). There was no effect of maternal nutrition or gestation age on fetal skeletal muscle GHR expression. In conclusion, maternal nutrient restriction in early to mid gestation with re-feeding thereafter results in alterations in hepatic and skeletal muscle expression of IGF-I, IGF-II and/or GHR in the fetus which may subsequently relate to altered organ and tissue function.

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Coordinated regulation of c-Myc and Max in rat liver development

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00545.2004 ◽

2006 ◽

Vol 290 (1) ◽

pp. G145-G155 ◽

Cited By ~ 5

Author(s):

Jennifer A. Sanders ◽

Philip A. Gruppuso

Keyword(s):

Liver Regeneration ◽

Fetal Development ◽

Potential Role ◽

Fetal Liver ◽

Expression Patterns ◽

Hepatocyte Proliferation ◽

Liver Development ◽

Adult Liver ◽

Expression Of Genes ◽

Growth Metabolism

The processes of liver development and regeneration involve regulation of a key network of transcription factors, the c -myc/ max/ mad network. This network regulates the expression of genes involved in hepatocyte proliferation, growth, metabolism, and differentiation. In previous studies on the expression and localization of c-Myc in the fetal and adult liver, we made the unexpected observation that c-Myc content was similar in the two. However, c-Myc was localized predominantly to the nucleolus in the adult liver. On the basis of this finding, we went on to characterize the expression patterns of the other members of the network, max and mad, comparing their regulation during late fetal development with the proliferation of mature hepatocytes that is seen in liver regeneration. We found that Max content, rather than being constitutive, as predicted by other studies, was elevated in the fetal liver compared with the adult liver. Its content correlated with hepatocyte proliferation during the perinatal transition. In contrast, mad4 expression was decreased in the fetal liver compared with the adult liver. Nucleolar localization of c-Myc coincided with changes in Max content. To explore this relationship, we overexpressed Max in cultured adult hepatocytes. High levels of Max resulted in a shift in c-Myc localization from nucleolar to diffuse nuclear. In contrast, liver regeneration was associated with an increase in c-Myc content but no change in Max content. We conclude that the regulation of Max content during liver development and its potential role in determining c-Myc localization are means by which Max may control the biological activity of the c-Myc/Max/Mad network during liver development.

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Effects of maternal dietary omega-3 polyunsaturated fatty acids and methionine during late gestation on fetal growth, DNA methylation, and mRNA relative expression of genes associated with the inflammatory response, lipid metabolism and DNA methylation in placenta and offspring’s liver in sheep

Journal of Animal Science and Biotechnology ◽

10.1186/s40104-020-00513-7 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Milca Rosa Velazquez ◽

Fernanda Batistel ◽

Juan Manuel Pinos Rodriguez ◽

Alejandro Enrique Relling

Keyword(s):

Dna Methylation ◽

Fatty Acids ◽

Fatty Acid ◽

Inflammatory Response ◽

Fetal Growth ◽

Fetal Liver ◽

Late Gestation ◽

Omega 3 ◽

Relative Expression ◽

Expression Of Genes

Abstract Background Omega-3 PUFA or methionine (Met) supply during gestation alters offspring physiology. However, the effect of both nutrients on fetal development has not been explored. Our objective was to determine the effects of supplementation of these two nutrients during late gestation on fetal growth, DNA methylation, and mRNA expression of genes associated with the inflammatory response, and DNA methylation. Ewes (n = 5/treatment) were fed from day 100 to 145 of gestation one of the following treatments: 1) basal diet (NS) without fatty acids (FS) or methionine (MS) supplementation; 2) FS (10 g/kg Ca salts, source omega-3 PUFA); 3) MS (1 g/kg rumen protected methionine); and 4) FS and MS (FS-MS). On day 145, ewes were euthanized, and data from dams and fetus was recorded. Placenta (cotyledon), fetal liver, and blood samples were collected. Results A treatments interaction on fetal liver weight, ewe body weight and body condition score (BCS) was observed; FS-MS were heavier (P < 0.01) than FS and MS, and FS-MS ewes had a better (P = 0.02) BCS than NS. Methionine increased (P = 0.03) ewe plasma glucose concentration. Fetal liver global DNA methylation increased (P < 0.01) in FS and MS. Dietary treatments modify the mRNA relative expression on some of the genes evaluated. In the fetal liver, FS increased (P = 0.04) the mRNA relative expression of arachidonate-5-lipoxygenase-activating-protein and tended to decrease (P = 0.06) methionine-adenosyltransferase-1A. Moreover, MS decreased (P = 0.04) DNA-methyltransferase-1 and tended to decrease (P = 0.08) free-fatty-acid-receptor-1 mRNA relative expression. Furthermore, FS-MS decreased mRNA relative expression of tumor-necrosis-factor-alpha (P = 0.05), peroxisome-proliferator-activated-receptor-delta (P = 0.03) and gamma (P = 0.04), tended to decrease (P ≤ 0.09) interleukin-6, fatty-acid-transport-protein-1, and delta-5-desaturase, and increased adenosylhomocysteinase (P = 0.04) mRNA relative expression. In cotyledon, FS tended to decrease fatty acid binding protein 4 (P = 0.09) mRNA relative expression. Conclusion Omega-3 PUFA and Met supplementation improves dam’s performance in late gestation, which was positively correlated with an increase in offspring’s liver development. Moreover, FS-MS decreased mRNA relative expression of proinflammatory cytokines, and lipogenic genes, and increased the expression on an enzyme that has an important role in methylation.

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In utero glucocorticoid exposure reduces fetal skeletal muscle mass in rats independent of effects on maternal nutrition

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00466.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. R1143-R1152 ◽

Cited By ~ 14

Author(s):

Ganga Gokulakrishnan ◽

Irma J. Estrada ◽

Horacio A. Sosa ◽

Marta L. Fiorotto

Keyword(s):

Skeletal Muscle ◽

Food Intake ◽

Maternal Nutrition ◽

Muscle Protein ◽

Fetal Liver ◽

Muscle Growth ◽

Tyrosine Aminotransferase ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Ad Libitum

Maternal stress and undernutrition can occur together and expose the fetus to high glucocorticoid (GLC) levels during this vulnerable period. To determine the consequences of GLC exposure on fetal skeletal muscle independently of maternal food intake, groups of timed-pregnant Sprague-Dawley rats ( n = 7/group) were studied: ad libitum food intake (control, CON); ad libitum food intake with 1 mg dexamethasone/l drinking water from embryonic day (ED)13 to ED21 (DEX); pair-fed (PF) to DEX from ED13 to ED21. On ED22, dams were injected with [3H]phenylalanine for measurements of fetal leg muscle and diaphragm fractional protein synthesis rates (FSR). Fetal muscles were analyzed for protein and RNA contents, [3H]phenylalanine incorporation, and MuRF1 and atrogin-1 (MAFbx) mRNA expression. Fetal liver tyrosine aminotransferase (TAT) expression was quantified to assess fetal exposure to GLCs. DEX treatment reduced maternal food intake by 13% ( P < 0.001) and significantly reduced placental mass relative to CON and PF dams. Liver TAT expression was elevated only in DEX fetuses ( P < 0.01). DEX muscle protein masses were 56% and 70% than those of CON ( P < 0.01) and PF ( P < 0.05) fetuses, respectively; PF muscles were 80% of CON ( P < 0.01). Muscle FSR decreased by 35% in DEX fetuses ( P < 0.001) but were not different between PF and CON. Only atrogin-1 expression was increased in DEX fetus muscles. We conclude that high maternal GLC levels and inadequate maternal food intake impair fetal skeletal muscle growth, most likely through different mechanisms. When combined, the effects of decreased maternal intake and maternal GLC intake on fetal muscle growth are additive.

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Suboptimal maternal nutrition, during early fetal liver development, promotes lipid accumulation in the liver of obese offspring

Reproduction ◽

10.1530/rep-10-0325 ◽

2011 ◽

Vol 141 (1) ◽

pp. 119-126 ◽

Cited By ~ 35

Author(s):

M A Hyatt ◽

D S Gardner ◽

S Sebert ◽

V Wilson ◽

N Davidson ◽

...

Keyword(s):

Gene Expression ◽

Lipid Accumulation ◽

Glucocorticoid Receptors ◽

Maternal Nutrition ◽

Fetal Liver ◽

Uncoupling Protein ◽

Acid Oxidation ◽

Gene Expressions ◽

Triglyceride Accumulation ◽

Pregnant Sheep

Maternal nutrition during the period of early organ development can modulate the offspring's ability to metabolise excess fat as young adults when exposed to an obesogenic environment. This study examined the hypothesis that exposing offspring to nutrient restriction coincident with early hepatogenesis would result in endocrine and metabolic adaptations that subsequently lead to increased ectopic lipid accumulation within the liver. Pregnant sheep were fed either 50 or 100% of total metabolisable energy requirements from 30 to 80 days gestation and 100% thereafter. At weaning, offspring were made obese, and at ∼1 year of age livers were sampled. Lipid infiltration and molecular indices of gluconeogenesis, lipid metabolism and mitochondrial function were measured. Although hepatic triglyceride accumulation was not affected by obesityper se, it was nearly doubled in obese offspring born to nutrient-restricted mothers. This adaptation was accompanied by elevated gene expression for peroxisome proliferator-activated receptor γ (PPARG) and its co-activator PGC1α, which may be indicative of changes in the rate of hepatic fatty acid oxidation. In contrast, maternal diet had no influence on the stimulatory effect of obesity on gene expression for a range of proteins involved in glucose metabolism and energy balance including glucokinase, glucocorticoid receptors and uncoupling protein 2. Similarly, although gene expressions for the insulin and IGF1 receptors were suppressed by obesity they were not influenced by the prenatal nutritional environment. In conclusion, excess hepatic lipid accumulation with juvenile obesity is promoted by suboptimal nutrition coincident with early development of the fetal liver.

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345 The effects of maternal nutrient restriction followed by re-alimentation on offspring growth and metabolism in sheep

Journal of Animal Science ◽

10.1093/jas/skz258.202 ◽

2019 ◽

Vol 97 (Supplement_3) ◽

pp. 98-98

Author(s):

Brandon I Smith ◽

Manuel A Vásquez-Hidalgo ◽

Kimberly A Vonnahme ◽

Kendall C Swanson ◽

Anna T Grazul-Bilska ◽

...

Keyword(s):

Maternal Nutrition ◽

Management Practice ◽

Fetal Liver ◽

Control Diet ◽

Liver Lipid ◽

Nutrient Restriction ◽

Triceps Brachii ◽

Liver Growth ◽

Offspring Growth ◽

Negative Impacts

Abstract The duration and timing of inadequate maternal nutrition can have detrimental effects on metabolism and organogenesis in the offspring. Re-alimentation, a common management practice that involves feeding full nutrient requirements following a period of nutrient restriction, may reduce the negative impacts of maternal nutrient restriction. To determine the effects of maternal nutrient restriction and re-alimentation on offspring growth,48 primiparous ewes, confirmed pregnant with singletons, were fed a control diet consisting of100% NRC requirements (CON) starting on day25 of gestation. On day50 of gestation, ewes (n = 7) were euthanized and fetal liver, muscle, and blood samples were collected. The remaining animals were fed either CON or60% NRC requirements (RES). On day90 of gestation, a portion of ewes were euthanized (n = 7 per treatment) and fetal samples and weights were collected. Remaining ewes were maintained on the current diet (CON-CON, n = 6; RES-RES, n = 7) or switched to the alternative diet (CON-RES, RES-CON; n = 7/treatment). On day130 of gestation, all remaining ewes were euthanized. All fetal BW, liver, longissimus muscle, semitendinosus, and triceps brachii weights were determined for each day of gestation. Fetal BW’s were not different between treatment groups (P = 0.29; P = 0.83). Fetal liver weights decreased12.89% in RES-RES compared with CON-CON at day130 (P = 0.049), but were not different at day90 (P = 0.69). There was a tendency for decreased semitendinosus weight in RES group compared with CON at day90 (P = 0.055). Liver lipid droplet accumulation was analyzed for day90 and130 using histochemistry and an effect of maternal nutrition was not observed (P = 0.562). In summary, maternal nutrient restriction reduces offspring muscle and liver growth. To gain insight into the effects of maternal nutrient restriction and re-alimentation on liver development and metabolism, analysis of liver morphology, gene expression, and global metabolomics are needed. Supported by USDA-AFRI grant2016-67016-24884

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