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US populations have seen dramatic increases in the prevalence of chronic disease over the past three generations. Rapid increases in type 2 diabetes and obesity have occurred in all the states but have been particularly striking in the Deep South. These increases have contributed to decreases in life expectancy and to painful elevations in health care costs. The causes of worsening population health are complex and incompletely understood. However, there is strong evidence that vulnerability to chronic conditions is determined in early life. Most chronic diseases are developmentally driven. There are specific stressors experienced in early life that influence epigenetic and structural changes during development. These include malnutrition, severe levels of social stress, toxic chemicals, and low oxygen levels. Most US populations have experienced a decrease in the quality of the food they consume as industrial foods have replaced garden-grown foods. Thus, the consumption of too few nutrients before and during pregnancy and during lactation influences the growth of the placenta and fetal organs and their level of resilience when faced with stresses in postnatal life and particularly as adults. Animal studies have shown that the effects of poor nutrition can be passed on to future generations. The most powerful way that the current epidemics of obesity and insulin resistance can be reversed is by providing key nutrients to prospective mothers and those already pregnant. [ABSTRACT FROM AUTHOR]

Prepregnancy maternal obesity is associated with adverse outcomes for the offspring, including increased incidence of neonatal bacterial sepsis and necrotizing enterocolitis. We recently reported that umbilical cord blood (UCB) monocytes from babies born to obese mothers generate a reduced IL-6/TNF-α response to TLR 1/2 and 4 ligands compared to those collected from lean mothers. These observations suggest altered development of the offspring's immune system, which in turn results in dysregulated function. We therefore investigated transcriptional and epigenetic differences within UCB monocytes stratified by prepregnancy maternal body mass index. We show that UCB monocytes from babies born to obese mothers generate a dampened response to LPS stimulation compared with those born to lean mothers, at the level of secreted immune mediators and transcription. Because gene expression profiles of resting UCB monocytes from both groups were comparable, we next investigated the role of epigenetic differences. Indeed, we detected stark differences in methylation levels within promoters and regulatory regions of genes involved in TLR signaling in resting UCB monocytes. Interestingly, the DNA methylation status of resting cells was highly predictive of transcriptional changes post-LPS stimulation, suggesting that cytosine methylation is one of the dominant mechanisms driving functional inadequacy in UCB monocytes obtained from babies born to obese mothers. These data highlight a potentially critical role of maternal pregravid obesity-associated epigenetic changes in influencing the function of an offspring's monocytes at birth. These findings further our understanding of mechanisms that explain the increased risk of infection in neonates born to mothers with high prepregnancy body mass index.

There is limited knowledge about the metabolic reprogramming induced by cancer therapies and how this contributes to therapeutic resistance. Here we show that although inhibition of PI3K-AKT-mTOR signaling markedly decreased glycolysis and restrained tumor growth, these signaling and metabolic restrictions triggered autophagy, which supplied the metabolites required for the maintenance of mitochondrial respiration and redox homeostasis. Specifically, we found that survival of cancer cells was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to sustain fatty acid oxidation and oxidative phosphorylation. Consistent with this, we observed significantly increased lipid droplets, with subsequent mobilization to mitochondria. These changes were abrogated in cells deficient for the essential autophagy gene ATG5 Accordingly, inhibition of PLA2 significantly decreased lipid droplets, decreased oxidative phosphorylation, and increased apoptosis. Together, these results describe how treatment-induced autophagy provides nutrients for cancer cell survival and identifies novel cotreatment strategies to override this survival advantage.

An international summit focusing on the difficult challenge of providing adequate nutrition for adolescent girls and young women in low- and middle-income countries was held in Portland, Oregon in 2015. Sixty-seven delegates from 17 countries agreed on a series of recommendations that would make progress toward improving the nutritional status of girls and young women in countries where their access to nutrition is compromised. Delegate recommendations include: (1) elevate the urgency of nutrition for girls and young women to a high international priority, (2) raise the social status of girls and young women in all regions of the world, (3) identify major knowledge gaps in the biology of adolescence that could be filled by robust research efforts, (4) and improve access to nutrient-rich foods for girls and young women. Attention to these recommendations would improve the health of young women in all nations of the world.

BackgroundMeasurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models.ObjectivesThe goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3- and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum.DesignForty-one healthy pregnant women with prepregnancy body mass index (in kg/m(2)) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (Db) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37-38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment.ResultsSystematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW(VRJ), 3-compartment, Db(VRJ), BIA, air displacement plethysmography body density, and SFT ranging from a mean ± SD of 29.5 ± 13.2 kg via 4-compartment to 39.1 ± 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via Db(VRJ)and 3-compartment methods had the highest precision; BIA had the lowest.ConclusionsADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714.

In preterm neonates unable to obtain sufficient oral nutrition, intravenous lipid emulsion is life-saving. The contribution of post-conceptional level of maturation to pathology that some neonates experience is difficult to untangle from the global pathophysiology of premature birth. In the present study, we determined fetal physiological responses to intravenous lipid emulsion. Fetal sheep were given intravenous Intralipid 20® (n = 4 females, 7 males) or Lactated Ringer's Solution (n = 7 females, 4 males) between 125 ± 1 and 133 ± 1 d of gestation (term = 147 d). Manufacturer's recommendation for premature human infants was followed: 0.5--1 g/kg/d initial rate, increased by 0.5--1 to 3 g/kg/d. Hemodynamic parameters and arterial blood chemistry were measured, and organs were studied postmortem. Red blood cell lipidomics were analyzed by LC-MS. Intravenous Intralipid did not alter hemodynamic or most blood parameters. Compared with controls, Intralipid infusion increased final day plasma protein (P=0.004; 3.5 ± 0.3 vs. 3.9 ± 0.2 g/dL), albumin (P = 0.031; 2.2 ± 0.1 vs. 2.4 ± 0.2 g/dL), and bilirubin (P<0.001; conjugated: 0.2 ± 0.1 vs. 0.6 ± 0.2 mg/dL; unconjugated: 0.2 ± 0.1 vs. 1.1 ± 0.4 mg/dL). Circulating IGF-1 decreased following Intralipid infusion (P<0.001; 66 ± 24 vs. 46 ± 24 ng/mL). Compared with control Oil Red O liver stains (median score 0), Intralipid-infused fetuses scored 108 (P=0.0009). Lipidomic analysis revealed uptake and processing of infused lipids into red blood cells, increasing abundance of saturated fatty acids. The near-term fetal sheep tolerates intravenous lipid emulsion well, although lipid accumulates in the liver. Increased levels of unconjugated bilirubin may reflect increased red blood cell turnover or impaired placental clearance. Whether Intralipid is less well tolerated earlier in gestation remains to be determined. [ABSTRACT FROM AUTHOR]

Angiotensin II (Ang II) is an important regulator of cardiovascular function in adult vertebrates. Although its role in regulating the adult system has been extensively investigated, the cardiovascular response to Ang II in embryonic vertebrates is relatively unknown. We investigated the potential of Ang II as a regulator of cardiovascular function in embryonic chickens, which lack central nervous system control of cardiovascular function throughout the majority of incubation. The cardiovascular response to Ang II in embryonic chickens was investigated over the final 50% of their development. Ang II produced a dose-dependent increase in arterial pressure on each day of development studied, and the response increased in intensity as development progressed. The Ang II type-1 receptor nonspecific competitive peptide antagonist [Sar1 ile8] Ang II blocked the cardiovascular response to subsequent injections of Ang II on day 21 only. The embryonic pressure response to Ang II (hypertension only) differed from that of adult chickens, in which initial hypotension is followed by hypertension. The constant level of gene expression for the Ang II receptor, in conjunction with an increasing pressure response to the peptide, suggests that two Ang II receptor subtypes are present during chicken development. Collectively, the data indicate that Ang II plays an important role in the cardiovascular development of chickens; however, its role in maintaining basal function requires further study.

Developmental programming of chronic adverse cardiovascular health outcomes has been studied both using numerous human populations and an array of animal models. However, the mechanisms that produce transgenerational effects have been difficult to study due to a lack of developmentally relevant models. As such, how increased disease risk is carried to the second generation has been poorly studied. We hypothesized that the endothelium which mediates many acute and chronic vascular inflammatory responses is a key player in these effects, and epidemiological studies implicate transgenerational nutritional effects on endothelial health. To study the mutigenerational effects of maternal undernutrition on offspring endothelial health, we developed a model of transgenerational nutritional stress in guinea pigs, a translationally relevant precocial species with a relatively short lifespan. First- and second-generation offspring were subjected to a high fat diet in adolescence to exacerbate negative cardiovascular health. To assess transcriptional changes, we performed bulk RNA-sequencing in carotid artery endothelial cells, with groups stratified as prenatal control or food restricted, and postnatal control or high fat diet. We detected statistically significant gene alterations for each dietary permutation, some of which were unique to treatments and other transcriptional signatures shared by multiple or all conditions. These findings highlight a core group of genes altered by high fat diet that is shared by all cohorts and a divergence of transgenerational effects between the prenatal ad libitum and dietary restriction groups. This study establishes the groundwork for this model to be used to better understand the interplay of prenatal stress and genetic reprogramming. [ABSTRACT FROM AUTHOR]

In utero fetal development and early-life conditions are believed to have an effect on adult health and the development of chronic disease. Environmental factors also determine the development certain lifestyle disease.

While the fetal heart grows by myocyte enlargement and proliferation, myocytes lose their capacity for proliferation in the perinatal period after terminal differentiation. The relationship between myocyte enlargement, proliferation, and terminal differentiation has not been studied under conditions of combined arterial and venous hypertension, as occurs in some clinical conditions. We hypothesize that fetal arterial and venous hypertension initially leads to cardiomyocyte proliferation, followed by myocyte enlargement. Two groups of fetal sheep received intravascular plasma infusions for 4 or 8 days (from 130 days gestation) to increase vascular pressures. Fetal hearts were arrested in diastole and dissociated. Myocyte size, terminal differentiation (%binucleation), and cell cycle activity (Ki-67[+] cells as a % of mononucleated myocytes) were measured. We found that chronic plasma infusion greatly increased venous and arterial pressures. Heart (but not body) weights were ~30% greater in hypertensive fetuses than controls. The incidence of cell cycle activity doubled in hypertensive fetuses compared with controls. After 4 days of hypertension, myocytes were (~11%) longer, but only after 8 days were they wider (~12%). After 8 days, %binucleation was ~50% greater in hypertensive fetuses. We observed two phases of cardiomyocyte growth and maturation in response to fetal arterial and venous hypertension. In the early phase, the incidence of cell cycle activity increased and myocytes elongated. In the later phase, the incidence of cell cycle activity remained elevated, %binucleation increased, and cross sections were greater. This study highlights unique fetal adaptations of the myocardium and the importance of experimental duration when interpreting fetal cardiac growth data. hypertrophy; hyperplasia; terminal differentiation; cardiomyocyte

Growth of the fetal heart involves cardiomyocyte enlargement, division, and maturation. Insulin-like growth factor-1 (IGF-1) is implicated in many aspects of growth and is likely to be important in developmental heart growth. IGF-1 stimulates the IGF-1 receptor (IGF1R) and downstream signaling pathways, including extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K). We hypothesized that IGF-1 stimulates cardiomyocyte proliferation and enlargement through stimulation of the ERK cascade and stimulates cardiomyocyte differentiation through the PI3K cascade. In vivo administration of Long R3 IGF-1 (LR3 IGF-1) did not stimulate cardiomyocyte hypertrophy but led to a decreased percentage of cells that were binucleated in vivo. In culture, LR3 IGF-1 increased myocyte bromodeoxyuridine (BrdU) uptake by three- to five-fold. The blockade of either ERK or PI3K signaling (by UO-126 or LY-294002, respectively) completely abolished BrdU uptake stimulated by LR3 IGF-1. LR3 IGF-1 did not increase footprint area, but as expected, phenylephrine stimulated an increase in binucleated cardiomyocyte size. We conclude that 1) IGF-1 through IGF1R stimulates cardiomyocyte division in vivo; hyperplastic growth is the most likely explanation of IGF-1 stimulated heart growth in vivo; 2) IGF-1 through IGF1R does not stimulate binucleation in vitro or in vivo; 3) IGF-1 through IGF1R does not stimulate hypertrophy either in vivo or in vitro; and 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near-term fetal sheep cardiomyocytes in vitro. hyperplasia; hypertrophy; UO-126; LY-294002

In response to chronic fetal anemia, coronary blood flow, maximal coronary conductance, and coronary reserve increase. We sought to determine whether chronic fetal anemia alters left ventricular (LV) function in adulthood. We studied adult sheep that had been made anemic for 20 days in utero by phlebotomy. They were transfused just before birth. At 7 mo of age, LV function was measured by pressure-volume loops at rest and during hypoxic stress. The in utero anemia group (n = 8) did not differ from controls (n = 5) with respect to hematocrit, heart and body weight, or baseline hemodynamic parameters. However, the effect of hypoxia (relative to baseline) on multiple indexes of systolic function was different between the two groups. End-systolic elastance increased in the in utero anemia group (baseline to hypoxia) by 4.15 [+ or -] 3.47 mmHg/ml (mean [+ or -] SD) but changed little in controls (0.24 [+ or -] 0.45), which shows that the response to hypoxia was significantly different (P < 0.01) between groups. Similarly, the maximum derivative of LV pressure with respect to time increased in the in utero anemia group (486 [+ or -] 340 mmHg/s,) but on average fell in the controls (-503 [+ or -] 211 mmHg/s) with the response again being significantly different (P < 0.03). We conclude that in sheep, perinatal anemia can alter cardiac responses to hypoxic stress in the adult long after restoration of normocythemia. phlebotomy; end-systolic elastance