Fetal Adipose Tissue Development Research Articles

Maternal Nutrition During Gestation Alters Histochemical Properties, and mRNA and microRNA Expression in Adipose Tissue of Wagyu Fetuses.

We hypothesized that maternal low or high nutrition would give unique effects to morphological and molecular dynamics in adipose tissue of fetus of fatty breed Wagyu (Japanese Black) cattle which produce highly marbled beef. This study aimed to determine the effects of maternal energy intake in Wagyu cows, during gestation on fetal adipose tissue development, histochemical properties, and gene and microRNA (miRNA) expression. Cows were allocated to one of two nutritional energy groups: 120% (HIGH) or 60% nutritional requirements of (LOW). Fetuses (n = 6 per treatment) were removed from pregnant cows by cesarean section at fetal age 260 ± 8 days and euthanized. Subcutaneous adipose tissue (SAT), thoracic cavity visceral adipose tissue (TVAT), and perirenal adipose tissue (PAT) were collected for analysis. In histochemical analysis, in SAT and PAT, HIGH fetuses had greater diameter of adipocytes than LOW fetuses (P<0.05). Only in SAT, LOW fetuses had more Leptin (LEP) mRNA and tended to have more Peroxisome Proliferator-Activated Receptor gamma (PPARG) CCAAT-enhancer-binding proteins alpha (CEBPA) and Glucose transporter (GLUT) 4 mRNA(P<0.10). In all SAT, TVAT, and PAT, LOW fetuses had higher levels of the brown adipose tissue (BAT) biomarkers Uncoupling Protein (UCP) 1 and PPARG coactivator (PGC) 1α mRNA than HIGH fetuses (P<0.08). Meanwhile, in the other adipose tissue, LOW fetuses had lower PPARG, CEBPA, and Zinc Finger Protein (ZFP) 423 (in TVAT and PAT), FASN (in TVAT), LEP and GLUT4 mRNA (in PAT; P<0.10). In particular, in TVAT and PAT, LOW fetuses exhibited lower expression of WAT biomarkers (PPARG and ZFP423). Differential expression of various miRNAs related to adipogenesis between the LOW and HIGH fetuses was detected in an adipose tissue-specific manner (P<0.10). Based on adipose tissue-specific effects of maternal nutrition, these findings suggested that poor maternal nutrition in Wagyu cattle increased BAT development in SAT, TVAT and PAT, while elevated maternal nutrition stimulated fetal SAT development compared with that of TVAT and PAT.

Dietary succinate supplementation to maternal mice improves fetal brown adipose tissue development and thermogenesis of female offspring

Succinic acid widely exists in foods and is used as a food additive. Succinate not only serves as an energy substrate, but also induces protein succinylation. Histone succinylation activates gene transcription. The brown adipose tissue (BAT) is critical for prevention of obesity and metabolic dysfunction, and the fetal stage is pivotal for BAT development. Up to now, the role of maternal succinate supplementation on fetal BAT development and offspring BAT function remains unexamined. To test, female C57BL/6J mice (2-month-old) were separated into 2 groups, received with or without 0.5% succinic acid in drinking water during gestation and lactation. After weaning, female offspring were challenged with high fat diet (HFD) for 12 weeks. Newborn, female weanling, and HFD female offspring mice were analyzed. For neonatal and weaning mice, the BAT weight relative to the whole body weight was significantly increased in the succinate group. The expression of PGC-1α, a key transcription co-activator promoting mitochondrial biogenesis, was elevated in BAT of female neonatal and offspring born to succinate-fed dams. Consistently, maternal succinate supplementation enhanced thermogenesis and the expression of thermogenic genes in offspring BAT. Additionally, maternal succinate supplementation protected female offspring against HFD-induced obesity. Furthermore, in C3H10T1/2 cells, succinate supplementation promoted PGC-1α expression and brown adipogenesis. Mechanistically, succinate supplementation increased permissive histone succinylation and H3K4me3 modification in the Ppargc1a promoter, which correlated with the higher expression of Ppargc1a. In conclusion, maternal succinate supplementation during pregnancy and lactation enhanced fetal BAT development and offspring BAT thermogenesis, which prevented HFD-induced obesity and metabolism dysfunction in offspring.

195 Maternal Impact on Fetal Muscle and Adipose Tissue Development

Abstract Tissues and organs are actively developing during the fetal stage, which is sensitive to nutritional alteration and exerts long-term impacts on offspring performance. Both muscle and adipose tissue are derived from the dermomyotome during the early embryonic stage, and their common origins provide an opportunity to promote myogenic instead of adipogenic differentiation, which enhances the lean/fat ratio of offspring. In previous studies with sheep and cattle, we found that maternal nutrient deficiency reduces fetal myogenesis and the lean/fat ratio of offspring. Stress is common in animals during pregnancy, and we examined the impacts of maternal stress induced by dexamethasone on fetal muscle and adipose development. We found that maternal stress impairs fetal muscle and brown adipose tissue (BAT) development. Mechanistically, we found that maternal stress suppresses mitochondrial biogenesis during fetal muscle and BAT development by elevating DNA methylation in the promoter of peroxisome proliferator-activated receptor-gamma coactivator α (PGC-1α), which persists in offspring muscle and BAT, generating lasting effects on the functions of muscle and adipose tissue. In short, available data clearly show that maternal nutrition and other physiological factors have profound impacts on fetal development, which programs offspring performance. Understanding related mechanisms are important for effective and precise management of animals during gestation in order to enhance production efficiency of offspring.

Excessive Glucocorticoids During Pregnancy Impair Fetal Brown Fat Development and Predispose Offspring to Metabolic Dysfunctions.

Maternal stress during pregnancy exposes fetuses to hyperglucocorticoids, which increases the risk of metabolic dysfunctions in offspring. Despite being a key tissue for maintaining metabolic health, the impacts of maternal excessive glucocorticoids (GC) on fetal brown adipose tissue (BAT) development and its long-term thermogenesis and energy expenditure remain unexamined. For testing, pregnant mice were administered dexamethasone (DEX), a synthetic GC, in the last trimester of gestation, when BAT development is the most active. DEX offspring had glucose, insulin resistance, and adiposity and also displayed cold sensitivity following cold exposure. In BAT of DEX offspring, Ppargc1a expression was suppressed, together with reduced mitochondrial density, and the brown progenitor cells sorted from offspring BAT demonstrated attenuated brown adipogenic capacity. Increased DNA methylation in Ppargc1a promoter had a fetal origin; elevated DNA methylation was also detected in neonatal BAT and brown progenitors. Mechanistically, fetal GC exposure increased GC receptor/DNMT3b complex in binding to the Ppargc1a promoter, potentially driving its de novo DNA methylation and transcriptional silencing, which impaired fetal BAT development. In summary, maternal GC exposure during pregnancy increases DNA methylation in the Ppargc1a promoter, which epigenetically impairs BAT thermogenesis and energy expenditure, predisposing offspring to metabolic dysfunctions.

Maternal n-3 PUFA supplementation promotes fetal brown adipose tissue development through epigenetic modifications in C57BL/6 mice

Brown adipose tissue (BAT) is a crucial regulator of energy expenditure. Emerging evidence suggests that n-3 PUFA potentiate brown adipogenesis in vitro. Since the pregnancy and lactation is a critical time for brown fat formation, we hypothesized that maternal supplementation of n-3 PUFA promotes BAT development in offspring. Female C57BL/6 mice were fed a diet containing n-3 PUFA (3%) derived from fish oil (FO), or an isocaloric diet devoid of n-3 PUFA (Cont) during pregnancy and lactation. Maternal n-3 PUFA intake was delivered to the BAT of neonates significantly reducing the n-6/n-3 ratio. The maternal n-3 PUFA exposure was linked with upregulated brown-specific gene and protein profiles and the functional cluster of brown-specific miRNAs. In addition, maternal n-3 PUFA induced histone modifications in the BAT evidenced by 1) increased epigenetic signature of brown adipogenesis, i.e., H3K27Ac and H3K9me2, 2) modified chromatin-remodeling enzymes, and 3) enriched the H3K27Ac in the promoter region of Ucp1. The offspring received maternal n-3 PUFA nutrition exhibited a significant increase in whole-body energy expenditure and better maintenance of core body temperature against acute cold treatment. Collectively, our results suggest that maternal n-3 PUFA supplementation potentiates fetal BAT development via the synergistic action of miRNA production and histone modifications, which may confer long-lasting metabolic benefits to offspring.

In utero vitamin D deficiency predisposes offspring to long-term adverse adipose tissue effects.

The fetal period represents an important window of susceptibility for later obesity and metabolic disease. Maternal vitamin D deficiency (VDD) during pregnancy is a global concern that may have long-lasting consequences on offspring metabolic health. We sought to determine whether a VDD in utero environment affects fetal adipose tissue development and offspring metabolic disease predisposition in adulthood. Furthermore, we sought to explore the extent to which the VDD intrauterine environment interacts with genetic background or postnatal environment to influence metabolic health. Eight-week-old P0 female C57BL/6J mice were fed either a VDD diet or sufficient diet (VDS) from four weeks before pregnancy (periconception) then bred to male Avy/a mice. Females were maintained on the diets throughout gestation. At weaning, Avy/a and a/a male F1 offspring were randomized to low-fat (LFD) or high-fat diet (HFD) until 19 weeks of age, at which point serum and adipose tissue were harvested for analyses. Mice born to VDD dams weighed less at weaning than offspring born to VDS dams but experienced rapid weight gain in the four weeks post weaning, and acquired a greater ratio of perigonadal (PGAT) to subcutaneous (SQAT) than control offspring. Additionally, these mice were more susceptible to HFD-induced adipocyte hypertrophy. Offspring of VDD dams also had greater expression of Pparg transcript. These novel findings demonstrate that in utero VDD, an easily correctable but highly prevalent health concern, predisposes offspring to long-term adipose tissue consequences and possible adverse metabolic health complications.

Insight Inside: Imaging fetal adipose tissue development with 3D water-fat MRI

Insight Inside: Imaging fetal adipose tissue development with 3D water-fat MRI

The Relationship between Maternal Plasma Leptin and Adiponectin Concentrations and Newborn Adiposity.

Increased maternal blood concentrations of leptin and decreased adiponectin levels, which are common disturbances in obesity, may be involved in offspring adiposity by programming fetal adipose tissue development. The aim of this study was to assess the relationship between maternal leptin and adiponectin concentrations and newborn adiposity. This was a cross-sectional study involving 210 healthy mother-newborn pairs from a public maternity hospital in São Paulo, Brazil. Maternal blood samples were collected after delivery and leptin and adiponectin concentrations were measured by enzyme-linked immunosorbent assay. Newborn body composition was estimated by air displacement plethysmography. The association between maternal leptin and adiponectin concentrations and newborn adiposity (fat mass percentage, FM%) was evaluated by multiple linear regression, controlling for maternal age, socioeconomic status, parity, pre-pregnancy body mass index (BMI), weight gain, gestational age, and newborn age at the time of measurement. No relationship was found between maternal leptin and FM% of male or female newborn infants. Maternal adiponectin (p = 0.001) and pre-pregnancy BMI (p < 0.001; adj. R2 = 0.19) were positively associated with FM% of newborn males, indicating that maternal adiponectin is involved in fetal fat deposition in a sex-specific manner. Large-scale epidemiological, longitudinal studies are necessary to confirm our results.

Fetal development of subcutaneous white adipose tissue is dependent on Zfp423

ObjectiveZfp423 is a multi zinc-finger transcription factor expressed in preadipocytes and mature adipocytes in vivo. Our recent work has revealed a critical role for Zfp423 in maintaining the fate of white adipocytes in adult mice through suppression of the beige cell thermogenic gene program; loss of Zfp423 in mature adipocytes of adult mice results in a white-to-beige phenotypic switch. However, the exact requirements of Zfp423 in the fetal stages of early adipose development in vivo have not been clarified. MethodHere, we utilize two models that confer adipose-specific Zfp423 inactivation during fetal adipose development (Adiponectin-Cre; Zfp423loxP/loxP and Adiponectin-rtTA; TRE-Cre; Zfp423loxP/loxP). We assess the impact of fetal adipose Zfp423 deletion on the initial formation of adipose tissue and evaluate the metabolic consequences of challenging these animals with high-fat diet feeding. ResultsDeletion of Zfp423 during fetal adipose development results in a different phenotype than is observed when deleting Zfp423 in adipocytes of adult mice. Inactivation of Zfp423 during fetal adipose development results in arrested differentiation, specifically of inguinal white adipocytes, rather than a white-to-beige phenotypic switch that occurs when Zfp423 is inactivated in adult mice. This is likely explained by the observation that adiponectin driven Cre expression is active at an earlier stage of the adipocyte life cycle during fetal subcutaneous adipose development than in adult mice. Upon high-fat diet feeding, obese adipose Zfp423-deficient animals undergo a pathological adipose tissue expansion, associated with ectopic lipid deposition and systemic insulin resistance. ConclusionsOur results reveal that Zfp423 is essential for the terminal differentiation of subcutaneous white adipocytes during fetal adipose tissue development. Moreover, our data highlight the striking adverse effects of pathological subcutaneous adipose tissue remodeling on visceral adipose function and systemic nutrient homeostasis in obesity. Importantly, these data reveal the distinct phenotypes that can occur when adiponectin driven transgenes are activated in fetal vs. adult adipose tissue.

Undernutrition and stage of gestation influence fetal adipose tissue gene expression.

Low birthweight is a risk factor for neonatal mortality and adverse metabolic health, both of which are associated with inadequate prenatal adipose tissue development. In the present study, we investigated the impact of maternal undernutrition on the expression of genes that regulate fetal perirenal adipose tissue (PAT) development and function at gestation days 89 and 130 (term=145 days). Singleton fetuses were taken from adolescent ewes that were either fed control (C) intake to maintain adiposity throughout pregnancy or were undernourished (UN) to maintain conception weight but deplete maternal reserves (n=7/group). Fetal weight was independent of maternal intake at day 89, but by day 130, fetuses from UN dams were 17% lighter and had lower PAT mass that contained fewer unilocular adipocytes. Relative PAT expression of IGF1, IGF2, IGF2R and peroxisome proliferator-activated receptor gamma (PPARG) mRNA was lower in UN than in controls, predominantly at day 89. Independent of maternal nutrition, PAT gene expression of PPARG, glycerol-3-phosphate dehydrogenase, hormone sensitive lipase, leptin, uncoupling protein 1 and prolactin receptor increased, whereas IGF1, IGF2, IGF1R and IGF2R decreased between days 89 and 130. Fatty acid synthase and lipoprotein lipase (LPL) mRNAs were not influenced by nutrition or stage of pregnancy. Females had greater LPL and leptin mRNA than males, and LPL, leptin and PPARG mRNAs were decreased in UN at day 89 in females only. PAT gene expression correlations with PAT mass were stronger at day 89 than they were at day 130. These data suggest that the key genes that regulate adipose tissue development and function are active beginning in mid-gestation, at which point they are sensitive to maternal undernutrition: this leads to reduced fetal adiposity by late pregnancy.

Xenotransplantation of human fetal adipose tissue: a model of in vivo adipose tissue expansion and adipogenesis

Obesity during childhood and beyond may have its origins during fetal or early postnatal life. At present, there are no suitable in vivo experimental models to study factors that modulate or perturb human fetal white adipose tissue (WAT) expansion, remodeling, development, adipogenesis, angiogenesis, or epigenetics. We have developed such a model. It involves the xenotransplantation of midgestation human WAT into the renal subcapsular space of immunocompromised SCID-beige mice. After an initial latency period of approximately 2 weeks, the tissue begins expanding. The xenografts are healthy and show robust expansion and angiogenesis for at least 2 months following transplantation. Data and cell size and gene expression are consistent with active angiogenesis. The xenografts maintain the expression of genes associated with differentiated adipocyte function. In contrast to the fetal tissue, adult human WAT does not engraft. The long-term viability and phenotypic maintenance of fetal adipose tissue following xenotransplantation may be a function of its autonomous high rates of adipogenesis and angiogenesis. Through the manipulation of the host mice, this model system offers the opportunity to study the mechanisms by which nutrients and other environmental factors affect human adipose tissue development and biology.

Suboptimal maternal nutrition during early-to-mid gestation in the sheep enhances pericardial adiposity in the near-term fetus.

Manipulation of the maternal diet at defined stages of gestation influences long-term health by inducing changes in fetal adipose tissue development, characterised as possessing brown and white adipocytes. We determined whether suboptimal maternal nutrition in early-to-mid gestation, followed by ad libitum feeding until term, increases adiposity in the pericardial depot of the sheep fetus. Pericardial adipose tissue was sampled from near-term (140 days) fetuses delivered to mothers fed either 100% (C) or 60% (i.e. nutrient restricted (NR)) of their total metabolisable requirements from 28 to 80 days gestation and then fed ad libitum. Adipose tissue mass, uncoupling protein (UCP) 1 and gene expression of brown and white adipogenic genes was measured. Total visceral and pericardial adiposity was increased in offspring born to NR mothers. The abundance of UCP1 was increased, together with those genes involved in brown (e.g. BMP7 and C/EBPβ) and white (e.g. BMP4 and C/EBPα) adipogenesis, whereas insulin receptor gene expression was downregulated. In conclusion, suboptimal maternal nutrition between early-to-mid gestation followed by ad libitum feeding enhances pericardial adiposity near to term. A combination of raised UCP1 and adipose tissue mass could improve survival following cold exposure at birth. In the longer term, this enhanced adipogenic potential could predispose to greater pericardial adiposity.

Spontaneous intra-uterine growth restriction modulates the endocrine status and the developmental expression of genes in porcine fetal and neonatal adipose tissue

Low birth weight is correlated with low adiposity at birth, a phenotype that influences neonatal survival and later adiposity. A better understanding of events affecting the fetal adipose tissue development and its functionality around birth is thus needed. This study was undertaken to examine the impact of spontaneous intra-uterine growth restriction (IUGR) on circulating concentrations of hormones and nutrients together with the developmental expression patterns of various genes in subcutaneous adipose tissue of pig fetus during the last third of pregnancy and just after birth. At 71 and 112days post-conception and 2days postnatal, pairs of same-sex piglets were chosen within litters to have either a medium (MBW) or a low (LBW) weight (n=6 pairs at each stage). The results indicate that IUGR counteracts the temporal fall of DLK1 gene expression in developing adipose tissue across gestation. It also attenuates the time-dependent increase in expression levels of many genes promoting adipocyte differentiation (PPARG, CEBPA) and lipogenesis (LPL, SREBF1, FASN, FABP4). Opposite responses to IUGR were observed for the IGF system, so that IGF1 mRNA levels were lower (P<0.001) but IGF2 mRNA levels were greater in adipose tissue of LBW piglets compared with MBW piglets. The plasma insulin concentration and the mRNA levels of insulin receptor (INSR) and insulin-responsive glucose transporter (GLUT4) in adipose tissue were also greater in LBW piglets at day 2 postnatal. The data indicate that IUGR delays the normal ontogeny of adipose tissue across gestation and affects the insulin and IGF axes around birth.

An in vivo model for human fetal adipose tissue development

Adipogenesis in the developing fetus is a key determinant of postnatal adiposity and, by extension, the risk of developing obesity‐related disease later in life. A variety of environmental factors, including toxicants and maternal diet, can influence fetal adipogenesis. To study the effects of environmental factors on fetal adipogenesis, we have developed a xenotransplantation model. Mid‐gestation human fetal white adipose tissue (WAT), obtained from cases of spontaneous fetal loss, was implanted into immunocompromised rodents using the renal subcapsular site. In multiple experiments (7 fetal samples ranging in gestation from 20 to 22 weeks), we observed an initial loss of adipocytes within the first week. This was followed by development of obvious fat pads. Expansion of these fat pads continued for up to 6 months. Immunohistochemical analyses revealed the WAT foci to contain viable adipocytes that were heterogeneous in size, an indication of active adipogenesis. Staining for the endothelial cell marker CD31 demonstrated rich vascularity of the implants and invasion of vessels from the implant into the host kidney parenchyma. These results demonstrate that transplantation of human fetal WAT into immunocompromised mice is a model for marked healthy WAT expansion and remodeling. This model can be utilized to study the direct effect of nutrient manipulation and obesogens on fetal white adipose tissue.

Developmental programming of fetal skeletal muscle and adipose tissue development.

All important developmental milestones are accomplished during the fetal stage, and nutrient fluctuation during this stage produces lasting effects on offspring health, so called fetal programming or developmental programming. The fetal stage is critical for skeletal muscle development, as well as adipose and connective tissue development. Maternal under-nutrition at this stage affects the proliferation of myogenic precursor cells and reduces the number of muscle fibers formed. Maternal over-nutrition results in impaired myogenesis and elevated adipogenesis. Because myocytes, adipocytes and fibrocytes are all derived from mesenchymal stem cells, molecular events which regulate the commitment of stem cells to different lineages directly impact fetal muscle and adipose tissue development. Recent studies indicate that microRNA is intensively involved in myogenic and adipogenic differentiation from mesenchymal stem cells, and epigenetic changes such as DNA methylation are expected to alter cell lineage commitment during fetal muscle and adipose tissue development.

Prepartum dietary energy source fed to beef cows: II. Effects on progeny postnatal growth, glucose tolerance, and carcass composition1

Mature Angus-cross beef cows (n = 228) were used to evaluate effects of prepartum dietary energy source on postnatal growth and carcass composition of progeny in a 2-yr study. Starting at approximately 160 d of gestation, cows were fed diets consisting of 1 of 3 primary energy sources: grass hay (HY), corn (CN), or dried corn distillers grains with solubles (DG). The CN and DG diets were limit-fed to achieve similar energy intakes as cows fed HY. Following parturition, cows were fed a common diet and managed as a single group. Calves were weaned at an average of 185 ± 6 d of age and backgrounded for 28 d. A subset of progeny (n = 134) was individually fed a common finishing diet until slaughter, when each calf reached 1.2 ± 0.05 cm of backfat. A glucose tolerance test (GTT) was conducted in year 2 on 4 calves/treatment after 41 and 111 d on the finishing diet (DOF). Calf birth weights were greater (P = 0.002) in calves from cows fed CN and DG than calves from cows fed HY, and weaning BW (P = 0.08) was less for calves from cows fed HY vs. CN. Receiving BW, final BW, and HCW did not differ (P ≥ 0.16) among treatments. No difference (P ≥ 0.28) in ADG, morbidity, and mortality from birth to slaughter was observed among treatments. In response to a GTT, increased DOF resulted in greater (P ≤ 0.005) fasting insulin, faster glucose disappearance rate, and greater insulin:glucose area under the curve ratio. Glucose disappearance rate was greater (P = 0.01) in calves from cows fed CN than in calves from cows fed HY or DG. A greater initial insulin response (P = 0.005) was observed in calves from cows fed CN or DG than in calves from cows fed HY. Carcass traits used to measure yield grade did not differ (P ≥ 0.19) among treatments. Calves from dams fed CN had the lowest marbling score (P = 0.03) and intramuscular fat content (P = 0.07). These results indicate that prepartum maternal dietary energy source can alter fetal adipose tissue development and insulin sensitivity resulting in long-term effects on progeny's intramuscular fat deposition. Moreover, present findings suggest that increasing the number of days on a corn-based finishing diet increases insulin resistance in beef cattle.

Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep

The global incidence of human obesity has more than doubled over the past three decades. An ovine model of obesity was developed to determine effects of maternal obesity and arginine supplementation on maternal, placental, and fetal parameters of growth, health, and well being. One-hundred-twenty days prior to embryo transfer, ewes were fed either ad libitum (n = 10) to induce obesity or 100% National Research Council-recommended nutrient requirements (n = 10) as controls. Embryos from superovulated ewes with normal body condition were transferred to the uterus of control-fed and obese ewes on day 5.5 post-estrus to generate genetically similar singleton pregnancies. Beginning on day 100 of gestation, obese ewes received intravenous administration of saline or L-arginine-HCl three times daily (81 mg arginine/kg body weight/day) to day 125, whereas control-fed ewes received saline. Fetal growth was assessed at necropsy on day 125. Maternal obesity increased (1) percentages of maternal and fetal carcass lipids and (2) concentrations of leptin, insulin, glucose, glutamate, leucine, lysine and threonine in maternal plasma while reducing (1) concentrations of progesterone, glycine and serine in maternal plasma and (2) amniotic and allantoic fluid volumes. Administration of L-arginine to obese ewes increased arginine and ornithine concentrations in maternal and fetal plasma, amniotic fluid volume, protein content in maternal carcass, and fetal brown adipose tissue (+60%), while reducing maternal lipid content and circulating leptin levels. Fetal or placental weight did not differ among treatments. Results indicate that arginine treatment beneficially reduces maternal adiposity and enhances fetal brown adipose tissue development in obese ewes.

In UteroProgramming of Later Adiposity: The Role of Fetal Growth Restriction

Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation.

Arginine nutrition and fetal brown adipose tissue development in nutrient-restricted sheep

Intrauterine growth restriction is a significant problem worldwide, resulting in increased rates of neonatal morbidity and mortality, as well as increased risks for metabolic and cardiovascular disease. The present study investigated the role of maternal undernutrition and L-arginine administration on fetal growth and development. Embryo transfer was utilized to generate genetically similar singleton pregnancies. On Day 35 of gestation, ewes were assigned to receive either 50 or 100% of their nutritional requirements. Ewes received i.v. injections of either saline or L-arginine three times daily from Day 100 to Day 125. Fetal growth was assessed at necropsy on Day 125. Maternal dietary manipulation altered circulating concentrations of leptin, progesterone, and amino acids in maternal plasma. Fetal weight was reduced in nutrient-restricted ewes on Day 125 compared with 100% fed ewes. Compared with saline-treated underfed ewes, maternal L-arginine administration did not affect fetal weight but increased weight of the fetal pancreas by 32% and fetal peri-renal brown adipose tissue mass by 48%. These results indicate that L-arginine administration enhanced fetal pancreatic and brown adipose tissue development. The postnatal effects of increased pancreatic and brown adipose tissue growth warrant further study.

RUMINANT NUTRITION SYMPOSIUM: OPTIMIZING PERFORMANCE OF THE OFFSPRING: Nourishing and managing the dam and postnatal calf for optimal lactation, reproduction, and immunity1,2

For several mammalian species, it has been shown that fetal and early postnatal nutrition has a role in long-term lipid and glucose metabolism of the offspring, and it thus also may have consequences on milk yield in the dairy cow. For instance, high-energy diets during the last weeks of pregnancy may result in increased glycemia, which in turn, may alter fetal adipose tissue development. However, most research efforts on management and nutrition of dry cows have focused on minimizing metabolic disorders of the postpartum cow without devoting much attention to potential consequences for the offspring. Similarly, nutritional needs for proper placental development and early fetal growth have received little attention, despite the fact that alterations in placental and fetal development may alter expression of genes participating in homeorhesis of the offspring. Therefore, nutrition of the pregnant cow, both while lactating and dry, should also consider aspects of placental and fetal development that may affect health and performance of the progeny. Similarly, newborn calves and young heifers are fed to ensure a particular growth target without compromising mammary development, although data linking postnatal growth targets with future milk yield are scarce. However, milk yield not only depends on mammary development, but also on nutrient partitioning, which is regulated by the endocrine milieu. There are some periods of time during development where nutrition may have long-lasting effects on metabolic function and milk production. For instance, the first months of postnatal life seem to be critical because recent data from both retrospective and controlled studies indicate that increased growth rate or plane of nutrition during this phase is positively associated with future milk production. Postnatal growth rate depends on nutrition (a necessary but not sufficient condition) and management (i.e., grouping strategies and housing systems), and thus optimal rearing programs should be designed considering long-term consequences on milk yield.