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1.  Placental Transport in Response to Altered Maternal Nutrition 
The mechanisms linking maternal nutrition to fetal growth and programming of adult disease remain to be fully established. We review data on changes in placental transport in response to altered maternal nutrition, including compromised utero-placental blood flow. In human intrauterine growth restriction and in most animal models involving maternal under-nutrition or restricted placental blood flow the activity of placental transporters, in particular for amino acids, is decreased in late pregnancy. The effect of maternal over-nutrition on placental transport remains largely unexplored. However some, but not all, studies in women with diabetes giving birth to large babies indicate an up-regulation of placental transporters for amino acids, glucose and fatty acids. These data support the concept that the placenta responds to maternal nutritional cues by altering placental function to match fetal growth to the ability of the maternal supply line to allocate resources to the fetus. On the other hand, some findings in humans and mice suggest that placental transporters are regulated in response to fetal demand signals. These observations are consistent with the idea that fetal signals regulate placental function to compensate for changes in nutrient availability. We propose that the placenta integrates maternal and fetal nutritional cues with information from intrinsic nutrient sensors. Together these signals regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.
doi:10.1017/S2040174412000529
PMCID: PMC4237017  PMID: 25054676
Maternal-fetal exchange; trophoblast; pregnancy; obesity; fetal programming
2.  Strategies for Feeding the Preterm Infant 
Neonatology  2008;94(4):245-254.
According to many experts in neonatal nutrition, the goal for nutrition of the preterm infant should be to achieve a postnatal growth rate approximating that of the normal fetus of the same gestational age. Unfortunately, most preterm infants, especially those born very preterm with extremely low birth weight, are not fed sufficient amounts of nutrients to produce normal fetal rates of growth and, as a result, end up growth-restricted during their hospital period after birth. Growth restriction is a significant problem, as numerous studies have shown definitively that under nutrition, especially of protein, at critical stages of development produces long-term short stature, organ growth failure, and both neuronal deficits of number and dendritic connections as well as later behavioral and cognitive outcomes. Furthermore, clinical follow-up studies have shown that among infants fed formulas, the nutrient content of the formula is directly and positively related to mental and motor outcomes later in life. Nutritional requirements do not stop at birth. Thus, delaying nutrition after birth ‘until the infant is stable’ ignores the fundamental point that without nutrition starting immediately after birth, the infant enters a catabolic condition, and catabolism does not contribute to normal development and growth. Oxygen is necessary for all metabolic processes. Recent trends to limit oxygen supply to prevent oxygen toxicity have the potential, particularly when the blood hemoglobin concentration falls to less than 8 g/dl, to develop growth failure. Glucose should be provided at 6–8 mg/min/kg as soon after birth as possible and adjusted according to frequent measurements of plasma glucose to achieve and maintain concentrations > 45 mg/dl but < 120 mg/dl to avoid the frequent problems of hyperglycemia and hypoglycemia. Similarly, lipid is required to provide at least 0.5 g/kg/day to prevent essential fatty acid deficiency. However, the high rate of carbohydrate and lipid supply that preterm infants often get, based on the incomplete assumption that this is necessary to promote protein growth, tends to produce increased fat in organs like the liver and heart as well as adipose tissue. More and better essential fatty acid nutrition is valuable, but more organ and adipose fat has no known benefit and many problems. Amino acids and protein are essential not only for body growth but for metabolic signaling, protein synthesis, and protein accretion. 3.5–4.0 g/kg/day are necessary to produce normal protein balance and growth in very preterm infants. Attempts to promote protein growth with insulin has many problems – it is ineffective while contributing to even further organ and adipose tissue fat deposition. Enteral feeding always is indicated and to date nearly all studies have shown that minimal enteral feeding approaches (e.g., ‘trophic feeds’) promote the capacity to feed enterally. Milk has distinct advantages over formulas in avoiding necrotizing enterocolitis (NEC), and while feeding is associated with NEC, minimal enteral feeding regimens produce less NEC than those geared towards more aggressive introduction of enteral feeding. Finally, overfeeding has the definite potential to produce adipose tissue, or obesity, which then leads to insulin resistance, glucose intolerance, and diabetes. This scenario occurs more commonly as infants are fed more and gain weight more rapidly after birth, regardless of their birth weight. Infants with IUGR and postnatal growth failure may be uniquely ‘set up’ for this outcome, while infants with in utero obesity, such as infants of diabetic mothers, already are well along this adverse outcome pathway
doi:10.1159/000151643
PMCID: PMC2912291  PMID: 18836284
Nutrition; Feeding; Preterm infant; Oxygen; Glucose; Amino acids; Lipids; Insulin; Minimal enteral nutrition; Intravenous feeding; Intrauterine growth restriction
3.  Placental Insufficiency and Fetal Growth Restriction 
Objectives
Fetal growth restriction is defined as a pathologic decrease in the rate of fetal growth. The most frequent etiology for late onset fetal growth restriction is uteroplacental dysfunction which is due to inadequate supply of nutrients and oxygen to support normal aerobic growth of the fetus. However, for symmetrical IUGR, fetal chromosomal anomalies, structural anomalies and fetal infections should be carefully excluded. Consequent to the uteroplacental vascular maladaptation of endovascular trophoblastic invasion, there is increased vascular resistance and decreased blood flow to the placenta in the choriodecidual compartment.
Conclusions
This under perfusion of the placenta causes villous damage; that is, total tertiary villous capillary bed is reduced leading to increased placental resistance. These changes can be diagnosed by Doppler and characteristic changes are seen in the uterine, umbilical, middle cerebral arteries and ductus venosus vessels. In severe cases, delivery of the fetus with optimum intrapartum surveillance, or caesarean section, is essential.
doi:10.1007/s13224-011-0092-x
PMCID: PMC3257343  PMID: 23024517
IUGR; Placental insufficiency; Colour doppler; Low birth weight
4.  Transgenic Increase in N-3/N-6 Fatty Acid Ratio Reduces Maternal Obesity-Associated Inflammation and Limits Adverse Developmental Programming in Mice 
PLoS ONE  2013;8(6):e67791.
Maternal and pediatric obesity has risen dramatically over recent years, and is a known predictor of adverse long-term metabolic outcomes in offspring. However, which particular aspects of obese pregnancy promote such outcomes is less clear. While maternal obesity increases both maternal and placental inflammation, it is still unknown whether this is a dominant mechanism in fetal metabolic programming. In this study, we utilized the Fat-1 transgenic mouse to test whether increasing the maternal n-3/n-6 tissue fatty acid ratio could reduce the consequences of maternal obesity-associated inflammation and thereby mitigate downstream developmental programming. Eight-week-old WT or hemizygous Fat-1 C57BL/6J female mice were placed on a high-fat diet (HFD) or control diet (CD) for 8 weeks prior to mating with WT chow-fed males. Only WT offspring from Fat-1 mothers were analyzed. WT-HFD mothers demonstrated increased markers of infiltrating adipose tissue macrophages (P<0.02), and a striking increase in 12 serum pro-inflammatory cytokines (P<0.05), while Fat1-HFD mothers remained similar to WT-CD mothers, despite equal weight gain. E18.5 Fetuses from WT-HFD mothers had larger placentas (P<0.02), as well as increased placenta and fetal liver TG deposition (P<0.01 and P<0.02, respectively) and increased placental LPL TG-hydrolase activity (P<0.02), which correlated with degree of maternal insulin resistance (r = 0.59, P<0.02). The placentas and fetal livers from Fat1-HFD mothers were protected from this excess placental growth and fetal-placental lipid deposition. Importantly, maternal protection from excess inflammation corresponded with improved metabolic outcomes in adult WT offspring. While the offspring from WT-HFD mothers weaned onto CD demonstrated increased weight gain (P<0.05), body and liver fat (P<0.05 and P<0.001, respectively), and whole body insulin resistance (P<0.05), these were prevented in WT offspring from Fat1-HFD mothers. Our results suggest that reducing excess maternal inflammation may be a promising target for preventing adverse fetal metabolic outcomes in pregnancies complicated by maternal obesity.
doi:10.1371/journal.pone.0067791
PMCID: PMC3692451  PMID: 23825686
5.  Effects on Coronary Heart Disease of Increasing Polyunsaturated Fat in Place of Saturated Fat: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
PLoS Medicine  2010;7(3):e1000252.
Dariush Mozaffarian and colleagues conduct a systematic review and meta-analysis to investigate the effect of consuming polyunsaturated fats in place of saturated fats for lowering the risk of coronary heart disease.
Background
Reduced saturated fat (SFA) consumption is recommended to reduce coronary heart disease (CHD), but there is an absence of strong supporting evidence from randomized controlled trials (RCTs) of clinical CHD events and few guidelines focus on any specific replacement nutrient. Additionally, some public health groups recommend lowering or limiting polyunsaturated fat (PUFA) consumption, a major potential replacement for SFA.
Methods and Findings
We systematically investigated and quantified the effects of increased PUFA consumption, as a replacement for SFA, on CHD endpoints in RCTs. RCTs were identified by systematic searches of multiple online databases through June 2009, grey literature sources, hand-searching related articles and citations, and direct contacts with experts to identify potentially unpublished trials. Studies were included if they randomized participants to increased PUFA for at least 1 year without major concomitant interventions, had an appropriate control group, and reported incidence of CHD (myocardial infarction and/or cardiac death). Inclusions/exclusions were adjudicated and data were extracted independently and in duplicate by two investigators and included population characteristics, control and intervention diets, follow-up duration, types of events, risk ratios, and SEs. Pooled effects were calculated using inverse-variance-weighted random effects meta-analysis. From 346 identified abstracts, eight trials met inclusion criteria, totaling 13,614 participants with 1,042 CHD events. Average weighted PUFA consumption was 14.9% energy (range 8.0%–20.7%) in intervention groups versus 5.0% energy (range 4.0%–6.4%) in controls. The overall pooled risk reduction was 19% (RR = 0.81, 95% confidence interval [CI] 0.70–0.95, p = 0.008), corresponding to 10% reduced CHD risk (RR = 0.90, 95% CI = 0.83–0.97) for each 5% energy of increased PUFA, without evidence for statistical heterogeneity (Q-statistic p = 0.13; I2 = 37%). Meta-regression identified study duration as an independent determinant of risk reduction (p = 0.017), with studies of longer duration showing greater benefits.
Conclusions
These findings provide evidence that consuming PUFA in place of SFA reduces CHD events in RCTs. This suggests that rather than trying to lower PUFA consumption, a shift toward greater population PUFA consumption in place of SFA would significantly reduce rates of CHD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is the leading cause of death among adults in developed countries. It is caused by disease of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, inflammatory deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, causing angina (chest pains that are usually relieved by rest), shortness of breath, and, if these plaques rupture or break, heart attacks (myocardial infarctions), which can reduce the heart's function or even be fatal. The key risk factors for CHD are smoking, physical inactivity, and poor diet. Blood cholesterol levels are altered by consuming dietary fats. There are three main types of dietary fats—“saturated” fatty acids (SFA) and unsaturated fatty acids; the latter can be “mono” unsaturated (MUFA) or “poly” unsaturated (PUFA). Eating SFA-rich foods (for example, meat, butter, and cheese) increases the amount of LDL-C in the blood but also increases HDL-C (the “good” cholesterol) and decreases triglycerides. Eating foods that are rich in unsaturated fatty acids (for example, vegetable oils and fatty fish) decreases the amount of LDL-C and triglycerides in the blood and also raises HDL-C.
Why Was This Study Done?
Because of the connection between eating SFA and high blood LDL-C levels, reduced SFA consumption is recommended as a way to avoid CHD. However, the evidence from individual randomized controlled trials that have studied CHD events (such as heart attacks and CHD-related deaths) have been mixed and could not support this recommendation. Furthermore, dietary recommendations to reduce SFA have generally not specified any replacement, i.e., whether SFA should be replaced with carbohydrate, protein, or unsaturated fats. Because of their beneficial effects on blood LDL-C and HDL-C levels, PUFA could be one important replacement for SFA, but, surprisingly, some experts argue that eating PUFA could actually increase CHD risk. Consequently, some guidelines recommend that PUFA consumption should be limited or even reduced. In this systematic review (a study that uses predefined criteria to identify all the research on a specific topic) and meta-analysis (a statistical method for combining the results of several studies) of randomized controlled trials, the researchers assess the impact of increased PUFA consumption as replacement for SFA on CHD events.
What Did the Researchers Do and Find?
The researchers' search of the published literature, “grey” literature (doctoral dissertations, technical reports, and other documents not printed in books and journals), and contacts with relevant experts identified eight trials in which participants were randomized to increase their PUFA intake for at least a year and in which CHD events were reported. 1,042 CHD events were recorded among the 13,614 participants enrolled in these trials. In their meta-analysis, the researchers found that on average the consumption of PUFA accounted for 14.9% of total energy intake in the intervention groups compared with only 5% of total energy intake in the control groups. Participants in the intervention groups had a 19% reduced risk of CHD events compared to participants in the control groups. Put another way, each 5% increase in the proportion of energy obtained from PUFA reduced the risk of CHD events by 10%. Finally, the researchers found that the benefits associated with PUFA consumption increased with longer duration of the trials.
What Do These Findings Mean?
These findings suggest that the replacement of some dietary SFA with PUFA reduces CHD events. Because the trials included in this study looked only at replacing SFA with PUFA, it is not possible from this evidence alone to distinguish between the benefits of reducing SFA and the benefits of increasing PUFA. Furthermore, the small number of trials identified in this study all had design faults, so the risk reductions reported here may be inaccurate. However, other lines of evidence (for example, observational studies that have examined associations between the fat intake of populations and their risk of CHD) also suggest that consumption of PUFA in place of SFA reduces CHD risk. Thus, in the light of these findings, future recommendations to reduce SFA in the diet should stress the importance of replacing SFA with PUFA rather than with other forms of energy, and the current advice to limit PUFA intake should be revised.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000252.
The American Heart Association provides information about all aspects of coronary heart disease for patients, caregivers, and professionals, including advice on dietary fats (in several languages)
The UK National Health Service Choices Web site provides information about coronary heart disease
Eatwell, a resource provided by the UK Food Standards Agency, gives advice on all aspects of healthy eating, including fat consumption
MedlinePlus provides links to further resources on coronary heart disease and on cholesterol (in English and Spanish)
doi:10.1371/journal.pmed.1000252
PMCID: PMC2843598  PMID: 20351774
6.  Adiponectin Enhances Mouse Fetal Fat Deposition 
Diabetes  2012;61(12):3199-3207.
Maternal obesity increases offspring birth weight and susceptibility to obesity. Adiponectin is an adipocyte-secreted hormone with a prominent function in maintaining energy homeostasis. In contrast to adults, neonatal blood adiponectin levels are positively correlated with anthropometric parameters of adiposity. This study was designed to investigate the role of adiponectin in maternal obesityenhanced fetal fat deposition. By using high-fat diet–induced obese mouse models, our study showed that maternal obesity increased fetal fat tissue mass, with a significant elevation in fetal blood adiponectin. However, adiponectin gene knockout (Adipoq−/−) attenuated maternal obesity-induced high fetal fat tissue mass. We further studied the effects of fetal adiponectin on fetal fat deposition by using a cross breeding approach to create Adipoq−/+ and Adipoq−/− offspring, whereas maternal adiponectin was null. Adipoq−/+ offspring had more fat tissue mass at both birth and adulthood. Significantly high levels of lipogenic genes, such as sterol regulatory element–binding protein 1c and fatty acid synthase, were detected in the livers of Adipoq−/+ fetuses. In addition, expression of genes for placental fatty acid transport was significantly increased in Adipoq−/+ fetuses. Together, our study indicates that adiponectin enhances fetal fat deposition and plays an important role in maternal obesity-induced high birth weight.
doi:10.2337/db12-0055
PMCID: PMC3501876  PMID: 22872236
7.  Adipocyte ALK7 links nutrient overload to catecholamine resistance in obesity 
eLife  2014;3:e03245.
Obesity is associated with blunted β-adrenoreceptor (β-AR)-mediated lipolysis and lipid oxidation in adipose tissue, but the mechanisms linking nutrient overload to catecholamine resistance are poorly understood. We report that targeted disruption of TGF-β superfamily receptor ALK7 alleviates diet-induced catecholamine resistance in adipose tissue, thereby reducing obesity in mice. Global and fat-specific Alk7 knock-out enhanced adipose β-AR expression, β-adrenergic signaling, mitochondrial biogenesis, lipid oxidation, and lipolysis under a high fat diet, leading to elevated energy expenditure, decreased fat mass, and resistance to diet-induced obesity. Conversely, activation of ALK7 reduced β-AR-mediated signaling and lipolysis cell-autonomously in both mouse and human adipocytes. Acute inhibition of ALK7 in adult mice by a chemical-genetic approach reduced diet-induced weight gain, fat accumulation, and adipocyte size, and enhanced adipocyte lipolysis and β-adrenergic signaling. We propose that ALK7 signaling contributes to diet-induced catecholamine resistance in adipose tissue, and suggest that ALK7 inhibitors may have therapeutic value in human obesity.
DOI: http://dx.doi.org/10.7554/eLife.03245.001
eLife digest
Adrenaline and noradrenaline are two hormones that trigger the burst of energy and increase in heart rate and blood pressure that are needed for the ‘fight-or-flight’ response. Both belong to a group of chemicals called catecholamines. These chemicals bind to cells carrying proteins called adrenoceptors on their surface and stimulate the breakdown of fat, which releases energy. However, when nutrients are plentiful, fat cells become resistant to catecholamines and instead store fat so it can be used for energy if food becomes scarce. In the industrialized world where food is easily and constantly accessible, this resistance can cause an unhealthy increase in body fat and result in obesity.
Increasing fat metabolism by making fat cells more able to respond to catecholamines is an attractive strategy for combating obesity. Indeed, drugs that mimic the effect of catecholamines on an adrenoceptor found in mice reduce obesity caused by over-eating. However, these drugs are ineffective in humans and can cause harmful side effects to the cardiovascular system, including high blood pressure and an increased heart rate. Devising a strategy that specifically targets catecholamine resistance in fat cells is therefore desirable.
A protein called ALK7 is a cell surface receptor that is predominantly found in fat cells and tissues involved in controlling the metabolism. Mice with a mutation in ALK7 that stops this protein from working properly accumulate less fat than mice with a functional version of the protein, but it is not known why. To understand ALK7's involvement in fat metabolism, Guo et al. created mice whose fat cells lack ALK7, but whose other cells all produce ALK7 as normal. When fed a diet rich in fat, these mice are leaner than regular mice and they burn more energy.
The metabolic responses seen in ALK7 mutant mice are very similar to those seen in mice treated with drugs targeting adrenoceptors, suggesting that there may be a link between ALK7 and catecholamine resistance. Indeed, Guo et al. demonstrate that fat cells lacking ALK7 have an increased sensitivity to catecholamines when the mice are on a high fat diet, which decreases the amount of fat the mice accumulate. Conversely, increasing the activity of ALK7 reduces the ability of the cells to respond to catecholamines, and they accumulate more fat.
Guo et al. also generated a second line of mice carrying a mutation in ALK7 that does not affect its function, but renders it sensitive to inhibition by a custom-made chemical. When these animals were on a high-fat diet, administering the chemical made the mice leaner, suggesting that inhibiting the ALK7 receptor can prevent obesity in adult animals.
Guo et al. also performed experiments in human fat cells, which showed that the ALK7 receptor works in a similar way in human cells as it does in mice. As ALK7 is largely specific for fat cells and is not known to affect the cardiovascular system, drugs that inhibit ALK7 could potentially safely suppress catecholamine resistance and reduce human obesity.
DOI: http://dx.doi.org/10.7554/eLife.03245.002
doi:10.7554/eLife.03245
PMCID: PMC4139062  PMID: 25161195
adipose tissue; obesity; TGF-beta; beta-adrenergic; chemical-genetic; lipolysis; human; mouse
8.  Doppler and birth weight Z score: predictors for adverse neonatal outcome in severe fetal compromise 
Background
An adequate placental perfusion is crucial for the normal growth and well being of the fetus and newborn. The blood flow through the placenta can be compromised in a variety of clinical situations, always causing important damage to the gestation. Our objective is to identify significant predictors for adverse neonatal outcome in severe fetal compromise.
Methods
Consecutive premature fetuses at between 25 and 32 weeks with severe placental insufficiency were examined prospectively. Inclusion criteria were: (i) singletons (ii) normal anatomy; (iii) abnormal umbilical artery Doppler pulsatility index (PI); (iv) abnormal cerebroplacental ratio; (v) middle cerebral artery (MCA) PI < - 2SD ("brain sparing"); (vi) last Doppler examination performed within 24 hours prior to delivery. All 46 patients that met criteria and started the study were followed to the end. We considered as independent potential predicting variables: absent or reversed end diastolic flow in umbilical artery, abnormal ductus venosus S/A ratio, absent or reversed flow during atrial contraction in the ductus venosus and birth weight Z score. Outcome parameters were: neonatal mortality and severe neonatal morbidity.
Results
Backward stepwise logistic regression analysis was used to determine the optimal model for the prediction of neonatal mortality and severe neonatal morbidity. In this analysis birth weight Z score index showed the strongest association OR = 1,87 [1,17-2,99] with all neonatal outcome, all other independent variables were excluded for the optimal model. There was no mortality for the group with normal birth weight Z score.
Conclusion
Our study suggests that birth weight Z score is the strongest predictor of adverse neonatal outcome in severe placental insufficiencies. Such use of Z scores, allowing to get rid of gestational age or sex covariates could be extended to estimated fetal weight and might help in making important decisions in the management of compromised pregnancies.
doi:10.1186/1476-7120-5-15
PMCID: PMC1838895  PMID: 17374167
9.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655
10.  A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction 
PLoS Computational Biology  2014;10(6):e1003667.
Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.
Author Summary
Intrauterine growth restriction (IUGR) is one of the leading causes of perinatal mortality and can be defined as a low birth weight together with signs of chronic hypoxia or malnutrition. It is mostly due to placental insufficiency resulting in a chronic restriction of oxygen and nutrients to the fetus. IUGR leads to cardiac dysfunction in utero which can persist postnatally. Under these altered conditions, IUGR fetuses redistribute their blood in order to maintain delivery of oxygenated blood to the brain, known as brain sparing. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. However, which remodeling or redistribution processes in the cardiovascular systems induce the observed changes in AoI flow in IUGR fetuses is not fully understood. We developed a computational model of the fetal circulation, including the key elements related to fetal blood redistribution. Using measured cardiac outflow profiles to allow personalization, we can recreate and better understand the blood flow changes in individual IUGR fetuses.
doi:10.1371/journal.pcbi.1003667
PMCID: PMC4055406  PMID: 24921933
11.  Evaluation of utero-placental and fetal hemodynamic parameters throughout gestation in pregnant mice using high-frequency ultrasound 
Ultrasound in medicine & biology  2013;40(2):351-360.
Changes throughout gestation of maternal and fetal Doppler parameters in pregnant mice, similar to those obtained in human fetuses, using a high frequency ultrasound with a 55 MHz linear probe are described. The uterine arteries (UtA), fetal umbilical (UA) and fetal ductus venosus (DV) showed: increased peak systolic velocity (UtA, p=0.04; UA, p=0.0004; DV, p=0.02), reduced end diastolic velocity (UtA, p<0.001; UA, p<.0001; DV, p=0.01), and reduced resistance index (UtA, p=0.0004; UA, p=0.0001; DV, p=0.04) toward the end of pregnancy. The middle cerebral (MCA) and carotid arteries (CAR) showed reduced end diastolic velocity (MCA, p=0.02; CAR, p<0.0001), and resistance index (both vessels, p<0.0001). The umbilical vein showed a reduction in the pulsatile pattern (p<0.05). Increased velocities and reduced resistance index suggest a progressive increment in blood flow to the fetal mouse towards the end of pregnancy. Evaluation of fetal and utero-placental vascular parameters in CD-1 mice can be reliably performed using high frequency ultrasound.
doi:10.1016/j.ultrasmedbio.2013.09.026
PMCID: PMC4179107  PMID: 24342911
Doppler; experimental mouse model; pregnancy; high frequency ultrasound
12.  Human fetal cardiac function during the first trimester of pregnancy 
Heart  2005;91(3):334-338.
Objective: To investigate first trimester human fetal cardiac function in relation to cardiac volume blood flow, and peripheral arterial and venous blood flow patterns.
Methods: Transvaginal Doppler ultrasonography was performed in 16 uncomplicated pregnancies at 6+, 7+, 8+, 9+, and 10+ gestational weeks. The shape of the inflow waveform and the presence of atrioventricular valve regurgitation (AVVR) were noted. The outflow mean velocity (Vmean) was calculated. The proportions of the isovolumetric relaxation (IRT%) and contraction times (ICT%) of the cardiac cycle were defined. Ductus venosus and umbilical artery pulsatility indices (PI) were obtained.
Results: Every inflow waveform was monophasic before 9+ weeks. At 9+ weeks 11 of 16 and at 10+ weeks all waveforms were biphasic. At 7+ and 8+ weeks AVVR was documented in one case. At 9+ and 10+ weeks AVVR was present in four and seven fetuses, respectively. Mean (SD) outflow Vmean increased between 6+ and 8+ weeks from 3.6 (1.5) to 8.4 (3.0) cm/s (p < 0.05). IRT% decreased significantly from 6+ to 7+ weeks (39.8 (2.6) to 19.2 (6.2), p < 0.001). ICT% decreased between 8+ and 9+ weeks from 13.2 (4.0) to 8.5 (2.5) (p < 0.05). Ductus venosus PIs were unchanged. Umbilical artery Vmean increased between 7+ and 10+ weeks from 1.59 (0.51) to 5.06 (1.06) cm/s (p < 0.001) and PIs remained unchanged.
Conclusions: The first trimester of pregnancy is characterised by significant improvements in cardiac diastolic and systolic function with a concomitant increase in cardiac volume blood flow. At 10+ weeks AVVR is a common finding. Placental volume blood flow increases significantly with no change in the placental vascular impedance.
doi:10.1136/hrt.2003.029736
PMCID: PMC1768783  PMID: 15710713
fetus; early pregnancy; Doppler; ventricular function; physiology
13.  Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction—a phase I pilot clinical trial: study protocol 
BMJ Open  2013;3(12):e004141.
Background
Fetal growth restriction complicates about 5% of pregnancies and is commonly caused by placental dysfunction. It is associated with increased risks of perinatal mortality and short-term and long-term morbidity, such as cerebral palsy. Chronic in utero hypoxaemia, inflammation and oxidative stress are likely culprits contributing to the long-term neurological sequelae of fetal growth restriction. In this regard, we propose that melatonin, a powerful antioxidant, might mitigate morbidity and/or mortality associated with fetal growth restriction. Melatonin has an excellent biosafety profile and crosses the placenta and blood–brain barrier. We present the protocol for a phase I clinical trial to investigate the efficacy of maternal oral melatonin administration in women with a pregnancy complicated by fetal growth restriction.
Methods and analysis
The proposed trial is a single-arm, open-label clinical trial involving 12 women. Severe, early onset fetal growth restriction will be diagnosed by an estimated fetal weight ≤10th centile in combination with abnormal fetoplacental Doppler studies, occurring before 34 weeks of pregnancy. Baseline measurements of maternal and fetal well-being, levels of oxidative stress and ultrasound and Doppler measurements will be obtained at the time of diagnosis of fetal growth restriction. Women will then start melatonin treatment (4 mg) twice daily until birth. The primary outcomes are the levels of oxidative stress in the maternal and fetal circulation and placenta. Secondary outcomes are fetoplacental Doppler studies (uterine artery, umbilical artery middle cerebral artery and ductus venosus), fetal biometry, fetal biophysical profile and a composite determination of neonatal outcome. A historical cohort of gestational-matched fetal growth restriction and a healthy pregnancy cohort will be used as comparators.
Ethics and dissemination
Ethical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC12133B). Data will be presented at international conferences and published in peer-reviewed journals.
Trial registration number
Clinical Trials, protocol registration system: NCT01695070.
doi:10.1136/bmjopen-2013-004141
PMCID: PMC3884842  PMID: 24366583
OBSTETRICS
14.  High fat and/or high salt intake during pregnancy alters maternal meta‐inflammation and offspring growth and metabolic profiles 
Physiological Reports  2014;2(8):e12110.
Abstract
A high intake of fat or salt during pregnancy perturbs placental function, alters fetal development, and predisposes offspring to metabolic disease in adult life. Despite its relevance to modern dietary habits, the developmental programming effects of excessive maternal fat and salt, fed in combination, have not been examined. We investigated the effects of moderately high maternal fat and/or salt intake on maternal metainflammation and its consequences on fetal and weanling growth and metabolic profile. Female Sprague–Dawley rats were fed a standard control diet (CD), 4% salt diet (SD), 45% fat diet (HF) or 4% salt/45% fat combined diet (HFSD) 3 weeks prior to and throughout pregnancy and lactation. Plasma and tissue samples were collected at day 18 of pregnancy from mother and fetus, and at postnatal day 24 in weanlings. Markers of adipose tissue inflammation, macrophage infiltration, lipogenesis, nutrient transport, and storage were altered in pregnant dams receiving high‐fat and/or ‐salt diets. This was accompanied by increased fat mass in high‐fat groups and differential hepatic lipid and glucose homeostasis. Offspring of high fat‐fed mothers had reduced fetal weight, displayed catch‐up growth, increased fat mass, and altered metabolic profiles at weaning. Maternal diets high in fat and/or salt affect maternal metabolic parameters, fetal growth and development, metabolic status, and adipoinsular axis in the weanling. Results presented here highlight the importance of diet in expectant mothers or women considering pregnancy. Furthermore, the potential for maternal nutritional intervention strategies may be employed to modify the metabolic disease risk in adult offspring during later life.
We investigated the effects of moderately high maternal fat and/or salt intake on maternal metainflammation and its consequences on fetal and weanling growth and metabolic profile. Maternal diets high in fat and/or salt affect maternal metabolic parameters, fetal growth and development, metabolic status, and adipoinsular axis in the weanling. Results presented here highlight the importance of diet in expectant mothers or women considering pregnancy.
doi:10.14814/phy2.12110
PMCID: PMC4246600  PMID: 25096554
Developmental programming; high fat; high salt; inflammation; maternal metabolism
15.  Ultrasonographic study of ductus venosus in healthy neonates 
AIM—To assess ultrasonographically the flow pattern and the time of postnatal closure of ductus venosus related to the other fetal shunts.
METHODS—Fifty healthy, term neonates were studied from day 1 up to day 18 using a VingMed CFM 800A ultrasound scanner.
RESULTS—Ductus arteriosus was closed in 94% of the infants before day 3. Ductus venosus, however, was closed in only 12% at the same time, in 76% before day 7, and in all infants before day 18. A closed ductus venosus or ductus arteriosus did not show signs of reopening. Pulsed and colour Doppler flow could be detected across the foramen ovale in all infants during the sequential investigation. At day 1, when the pulmonary vascular resistance was still high, a reversed Doppler flow velocity signal was seen in ductus venosus in 10 infants (20%) and a bidirectional flow in ductus arteriosus in 26 (52%). Closure of the ductus venosus was not significantly correlated with closure of the ductus arteriosus nor related to sex nor weight loss.
CONCLUSIONS—The time of closure of the ductus venosus evaluated by ultrasonography is much later than that of the ductus arteriosus. The flow pattern in ductus venosus reflects the portocaval pressure gradient and the pressure on the right side of the heart and in the pulmonary arteries. Both the flow pattern in the ductus venosus as well as that in the ductus arteriosus may be an indication of compromised neonatal haemodynamics.

 Keywords: ductus venosus; ductus arteriosus; foramen ovale; Doppler echocardiography
PMCID: PMC1720700  PMID: 9377136
16.  Role of placental nutrient sensing in developmental programming 
Altered maternal nutrition and metabolism, restricted utero-placental blood flow and other perturbations in the maternal compartment may disturb critical periods of fetal development resulting in increased susceptibility to develop disease in childhood and adult life. In response to these perturbations, placental structure and function changes, which influence the supply of nutrients, oxygen and methyl donors and alter the secretion of hormones and other signaling molecules into the fetal circulation. Thus, the placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring.
doi:10.1097/GRF.0b013e3182993a2e
PMCID: PMC3732521  PMID: 23703224
Maternal-fetal exchange; nutrient transport; trophoblast; pregnancy; fetal programming
17.  Eating Time Modulations of Physiology and Health: Life Lessons from Human and Ruminant Models 
Tissue nutrient supply may be synchronized with endogenous physiological rhythms to optimize animal and human health. Glucose tolerance and insulin sensitivity have endogenous rhythms that are not essentially dependent on food type and eating. Human glucose tolerance declines as day comes into night. Based on such evolutionary findings, large evening meals must be avoided to reduce risks of visceral adiposity, diabetes, hypertension and related cardiovascular complexities. Ruminants as extremely important food-producing livestock have evolved to ruminate mostly overnight when little grazing occurs, and when rumen reaches a larger volume and fermentation capacity. As such, eating time (e.g., evening vs. morning) will alter postprandial and diurnal patterns of food intake, rumen and peripheral metabolites production and supply, and milk and meat production efficiency. Most recent discoveries suggest that eating time modulates postprandial intake and metabolism patterns in non-grazing lactating cows. Eating rate and absolute intake can increase by evening vs. morning feeding in dairy cows. Evening feeding increased postprandial rumen volatile fatty acids (VFA) peak, and surges of blood insulin, lactate and beta-hydroxybutyrate, and induced a peripartal decline in blood glucose. As a result, milk fat and energy production were increased. While being unfavorable to human health, evening and night feeding have proved beneficial to ruminants. These findings establish a differential chronological basis for food intake and nutrient metabolism in man and food-producing animals. Eating time is a major external cue and a feasible life strategy that affects production and health physiology.
PMCID: PMC3586911  PMID: 23492863
Eating time; Health; Human; Physiology; Ruminant
18.  Significant correlations between the flow volume of patent ductus venosus and early neonatal liver function: possible involvement of patent ductus venosus in postnatal liver function 
Background
The biochemical features of portosystemic venous shunt with high flow volume are hypergalactosaemia, hyperammonaemia, prolonged blood coagulation time, and raised serum bile acid concentration. The ductus venosus remains open with shunt flow in most neonates for a certain period after birth. However, the effects of blood flow through the ductus venosus on neonatal liver function remain unclear.
Objective
To elucidate the effect of patency of the ductus venosus on liver function in early neonates.
Methods
Subjects were divided into three groups by gestational age (group I, 29–32 weeks; group II, 33–36 weeks; group III, 37–41 weeks). The shunt flow volume through the ductus venosus was examined serially using ultrasonography, and correlations between flow volume and liver function in the respective groups were calculated during the first week after birth.
Results
Group I had a higher flow volume and later functional closure than the other two groups. Plasma ammonia and serum total bile acid concentrations correlated with flow volume in groups I and II, and blood galactose and galactose 1‐phosphate concentrations correlated significantly with flow volume in group III. Percentage hepaplastin also correlated significantly with flow volume in all groups, but plasma vitamin K concentration did not in any group.
Conclusions
Patent ductus venosus has a considerable effect on crucial liver functions such as ammonia detoxification, blood coagulation, and regulation of serum total bile acid concentration in early neonates.
doi:10.1136/adc.2005.079822
PMCID: PMC2672699  PMID: 16449256
gestational age; liver function; patent ductus venosus; portosystemic venous shunt
19.  Appetite control and energy balance regulation in the modern world: Reward-driven brain overrides repletion signals 
International journal of obesity (2005)  2009;33(Suppl 2):S8-13.
Powerful biological mechanisms evolved to defend adequate nutrient supply and optimal levels of body weight/adiposity. Low levels of leptin indicating food deprivation and depleted fat stores have been identified as the strongest signals to induce adaptive biological actions such as increased energy intake and reduced energy expenditure. In concert with other signals from the gut and metabolically active tissues, low leptin levels trigger powerful activation of multiple peripheral and brain systems to restore energy balance. It is not just neurons in the arcuate nucleus, but many other brain systems involved in finding potential food sources, smelling and tasting food, and learning to maximize rewarding effects of foods, that are affected by low leptin. Food restriction and fat depletion thus lead to a “hungry” brain, preoccupied with food. In contrast, because of less (adaptive thrifty fuel efficiency) or lost (lack of predators) evolutionary pressure, upper limits of body weight/adiposity are not as strongly defended by high levels of leptin and other signals. The modern environment is characterized by increased availability of large amounts of energy dense foods and increased presence of powerful food cues, together with minimal physical procurement costs and a sedentary lifestyle. Much of these environmental influences impact cortico-limbic brain areas concerned with learning and memory, reward, mood, and emotion. Common obesity results when individual predisposition to deal with a restrictive environment as engraved by genetics, epigenetics, and/or early life experience, is confronted with an environment of plenty. Therefore, increased adiposity in prone individuals should be seen as a normal physiological response to a changed environment, not in pathology of the regulatory system. The first line of defense should ideally lie in modifications to the environment and lifestyle. However, because such modifications will be slow and incomplete, it is equally important to gain better insight how the brain deals with environmental stimuli and to develop behavioral strategies to better cope with them. Clearly, alternative therapeutic strategies such as drugs and bariatric surgery should also be considered to prevent or treat this debilitating disease. It will be crucial to understand the functional crosstalk between neural systems responding to metabolic and environmental stimuli, i.e. crosstalk between hypothalamic and cortico-limbic circuitry.
doi:10.1038/ijo.2009.65
PMCID: PMC2838178  PMID: 19528982
Neural control of appetite; metabolic need; internal depletion signals; environmental food cues; cortico-limbic systems; food reward; leptin; obesity
20.  Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup 
PLoS Biology  2014;12(2):e1001799.
A mouse genetic study reveals that a single gene acting in both mother and offspring has a central role in the uniquely mammalian phenomenon of nutrient provisioning through the placenta and the mammary gland.
Developmental programming links growth in early life with health status in adulthood. Although environmental factors such as maternal diet can influence the growth and adult health status of offspring, the genetic influences on this process are poorly understood. Using the mouse as a model, we identify the imprinted gene Grb10 as a mediator of nutrient supply and demand in the postnatal period. The combined actions of Grb10 expressed in the mother, controlling supply, and Grb10 expressed in the offspring, controlling demand, jointly regulate offspring growth. Furthermore, Grb10 determines the proportions of lean and fat tissue during development, thereby influencing energy homeostasis in the adult. Most strikingly, we show that the development of normal lean/fat proportions depends on the combined effects of Grb10 expressed in the mother, which has the greater effect on offspring adiposity, and Grb10 expressed in the offspring, which influences lean mass. These distinct functions of Grb10 in mother and pup act complementarily, which is consistent with a coadaptation model of imprinting evolution, a model predicted but for which there is limited experimental evidence. In addition, our findings identify Grb10 as a key genetic component of developmental programming, and highlight the need for a better understanding of mother-offspring interactions at the genetic level in predicting adult disease risk.
Author Summary
Experiences during early life can impact on health status in adulthood; low birth weight, for example, is linked to an increased risk of diabetes and obesity in later life. Such developmental programming can be influenced by environmental factors such as diet, but the importance of genetics in this process is not well understood. Using the mouse as a model, we investigate the gene Grb10, which is imprinted, meaning that it is expressed from only one of its two copies. We show that Grb10 is a key mediator of developmental programming, controlling supply and demand of nutrients in the postnatal period and influencing growth and body composition. Specifically, we find that Grb10 determines the proportions of lean and fat tissue during development, and that this is dependent on the combined actions of Grb10 in the mother and offspring. Our findings have two main implications. First, they suggest that the functions of Grb10 in mother and offspring are coadapted, providing support for a coadaptation model for the evolution of imprinted genes. Second, they highlight the need for a better grasp of how maternal and offspring genetics interact during development if we are to understand more fully the causes of complex adult disorders such as obesity.
doi:10.1371/journal.pbio.1001799
PMCID: PMC3934836  PMID: 24586114
21.  PPAR gamma 2 Prevents Lipotoxicity by Controlling Adipose Tissue Expandability and Peripheral Lipid Metabolism 
PLoS Genetics  2007;3(4):e64.
Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2−/− Lepob/Lepob (POKO mouse), resulted in decreased fat mass, severe insulin resistance, β-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the β-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of β-cells to insulin resistance.
Author Summary
It is known that obesity is linked to type 2 diabetes, however how obesity causes insulin resistance and diabetes is not well understood. Some extremely obese people are not diabetic, while other less obese people develop severe insulin resistance and diabetes. We believe diabetes occurs when adipose tissue becomes “full,” and fat overflows into other organs such as liver, pancreas, and muscle, causing insulin resistance and diabetes. Peroxisome proliferator activated receptor gamma (PPARg) is essential for the development of adipose tissue and control of insulin sensitivity. PPARg2 is the isoform of PPARg regulated by nutrition. Here we investigate the role of PPARg2 under conditions of excess nutrients by removing the PPARg2 isoform in genetically obese mice, the POKO mouse. We report that removing PPARg2 decreases adipose tissue's capacity to expand and prevents the mouse from making as much fat as a normal obese mouse, despite eating similarly. Our studies suggest that PPARg plays an important antitoxic role when it is induced in liver, muscle, and beta cells by facilitating deposition of fat as relatively harmless lipids and thus prevents accumulation of toxic lipid species. We also show that PPARg2 may be involved in the adaptive response of beta cells to insulin resistance.
doi:10.1371/journal.pgen.0030064
PMCID: PMC1857730  PMID: 17465682
22.  Nutrition in pregnancy 
Postgraduate Medical Journal  1979;55(643):295-302.
Epidemiological evidence shows that women living in affluent circumstances have bigger babies with a lower mortality than underpriviliged women. How much of that effect is due to nutrition alone is not known but supplementary feeding in pregnancy of chronically ill nourished women does appear to increase mean birth weight, and famine conditions in a basically well nourished community reduce the birth weight; in both cases the birth weight difference is relatively small and could be accounted for by no more than fetal adipose tissue.
The fetus may be much less vulnerable to vagaries of maternal diet than has been thought because of protective physiological mechanisms associated with pregnancy. Firstly the mother's energy balance changes, so that if she has access to extra food in the first half of pregnancy she will store large amounts of depot fat as an energy buffer against possible privation later. Secondly, there are widespread changes in nutrient metabolism one of which is to lower plasma levels of most nutrients, and that may tip the balance of advantage away from maternal tissue towards the placenta. Finally, the placenta itself has developed elaborate mechanisms to acquire nutrients from the maternal circulation. A notable exception to that rule is glucose for which no active transport mechanism has evolved and which might therefore be regarded as a low priority nutrient; it may be that the generous supply of glucose for the fetus which would be provided by a well fed woman does little more than allow the fetus to build up its fat stores.
PMCID: PMC2425462  PMID: 382160
23.  Predictors of Poor Perinatal Outcome following Maternal Perception of Reduced Fetal Movements – A Prospective Cohort Study 
PLoS ONE  2012;7(7):e39784.
Background
Maternal perception of reduced fetal movement (RFM) is associated with increased risk of stillbirth and fetal growth restriction (FGR). RFM is thought to represent fetal compensation to conserve energy due to insufficient oxygen and nutrient transfer resulting from placental insufficiency.
Objective
To identify predictors of poor perinatal outcome after maternal perception of reduced fetal movements (RFM).
Design
Prospective cohort study.
Methods
305 women presenting with RFM after 28 weeks of gestation were recruited. Demographic factors and clinical history were recorded and ultrasound performed to assess fetal biometry, liquor volume and umbilical artery Doppler. A maternal serum sample was obtained for measurement of placentally-derived or modified proteins including: alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), human placental lactogen (hPL), ischaemia-modified albumin (IMA), pregnancy associated plasma protein A (PAPP-A) and progesterone. Factors related to poor perinatal outcome were determined by logistic regression.
Results
22.1% of pregnancies ended in a poor perinatal outcome after RFM. The most common complication was small-for-gestational age infants. Pregnancy outcome after maternal perception of RFM was related to amount of fetal activity while being monitored, abnormal fetal heart rate trace, diastolic blood pressure, estimated fetal weight, liquor volume, serum hCG and hPL. Following multiple logistic regression abnormal fetal heart rate trace (Odds ratio 7.08, 95% Confidence Interval 1.31–38.18), (OR) diastolic blood pressure (OR 1.04 (95% CI 1.01–1.09), estimated fetal weight centile (OR 0.95, 95% CI 0.94–0.97) and log maternal serum hPL (OR 0.13, 95% CI 0.02–0.99) were independently related to pregnancy outcome. hPL was related to placental mass.
Conclusion
Poor perinatal outcome after maternal perception of RFM is closely related to factors which are connected to placental dysfunction. Novel tests of placental function and associated fetal response may provide improved means to detect fetuses at greatest risk of poor perinatal outcome after RFM.
doi:10.1371/journal.pone.0039784
PMCID: PMC3394759  PMID: 22808059
24.  Nutrition of the Fetus and Newborn 
Western Journal of Medicine  1987;147(4):435-448.
Both the successful development of healthy, long-term animal models to study fetal nutrition and metabolism and the improved survival of low-birth-weight, preterm infants have focused interest and research on fetal and neonatal nutrition and metabolism. Such a focus is important, given the recent emphasis on promoting neonatal growth in preterm infants at “normal” in utero growth rates. Estimates of nutrient requirements for growth in a human fetus remain ill defined, however. Body composition data appear biased toward thin infants. Animal data suggest that fetal nutrition proceeds according to species-specific growth rates, with variations in fat content largely dependent on placental fat permeability and on maternal nutrient supply as regulated by the placenta.
After birth, neonatal nutrition is affected primarily by food intake and the functional integrity and capacity of the gastrointestinal tract. Additionally, muscle activity, thermoregulation and stresses of various kinds and degrees modify a neonate's nutritional requirements. Functional deficits of the gastrointestinal tract have been circumvented by a more aggressive use of intravenous nutrition. Both intravenous and enteral nutrient mixtures have been substantially improved in the quantity of all nutrients and have been modified qualitatively toward compositions that are closer to those of human milk. These nutrient mixtures now produce plasma nutrient concentrations that approximate those of a healthy, breast-fed infant.
Although such efforts to improve the nutritional balance and growth of preterm infants have been successful, much remains to be learned about the nutritional requirements of sick infants.
PMCID: PMC1025905  PMID: 3318138
25.  Delivery of circulating lipoproteins to specific neurons in the Drosophila brain regulates systemic insulin signaling 
eLife  2014;3:e02862.
The Insulin signaling pathway couples growth, development and lifespan to nutritional conditions. Here, we demonstrate a function for the Drosophila lipoprotein LTP in conveying information about dietary lipid composition to the brain to regulate Insulin signaling. When yeast lipids are present in the diet, free calcium levels rise in Blood Brain Barrier glial cells. This induces transport of LTP across the Blood Brain Barrier by two LDL receptor-related proteins: LRP1 and Megalin. LTP accumulates on specific neurons that connect to cells that produce Insulin-like peptides, and induces their release into the circulation. This increases systemic Insulin signaling and the rate of larval development on yeast-containing food compared with a plant-based food of similar nutritional content.
DOI: http://dx.doi.org/10.7554/eLife.02862.001
eLife digest
How does an animal sense if it is well nourished or not, and then regulate its metabolism appropriately? This process largely relies on the animal's body deciphering signals that that are transmitted between different organs in the form of molecules and hormones. Many animals—ranging from insects to mammals (including humans)—also use their brains to sense and decipher these nutritional signals.
A signaling pathway involving the hormone insulin controls how various different animals grow and develop—and how long they will live—based on these animals' food intake. Insulin is produced in mammals by an organ called the pancreas. But in the fruit fly Drosophila, this hormone is produced by cells within different tissues, including the insect’s brain.
The fruit fly is used to study many biological processes because it is easy to work with in a laboratory. Insulin-producing cells make and release insulin-like molecules into the insect's hemolymph (a blood-like fluid) in response to sugar and to other nutrients (which are detected via molecules generated in a fruit fly organ called the fat body). The fat body produces lipophorin, a protein which carries fat molecules in the hemolymph, and which is known to be able to move from the hemolymph to the brain and accumulate within the brain. The fat body also produces lipid transfer protein (or LTP), which transfers fats absorbed or made within the insect's gut onto lipophorin, and can also unload fat molecules to other insect cells. If LTP can also enter the brain, and what it might do there, was unclear.
Brankatschk et al.now discover that LTP can cross the ‘blood brain barrier’ in fruit fly larvae and can accumulate over time on their insulin-producing cells and the neurons in direct contact with these cells. This accumulation depends on the flies’ diet: flies fed a diet made from yeast cells accumulated LTP on these neurons, while those fed only on sugar and proteins did not.
Furthermore Brankatschk et al. found that when they switched flies from a yeast-based to a plant-based diet, the larvae grew more slowly and the flies lived longer. Both of the diets contained abundant calories and nutrients, but contained slightly different kinds of fat molecules. The fly larvae on the plant-based diet also accumulated less LTP on their insulin-pathway neurons, and insulin signaling was reduced.
Branskatschk et al. also found that fat molecules from the yeast-based diet activated the cells of the blood brain barrier, and that this encouraged LTP to be transported the brain. Blocking LTP from crossing the blood brain barrier reduced insulin signaling, slowed the growth of the fly larvae, and extended the lifespan of the flies.
These findings of Brankatschk et al. thus reveal that fat-containing molecules carry information about specific nutrients to the brain. The extent to which these mechanisms operate in other animals—such as mammals—remains to be explored.
DOI: http://dx.doi.org/10.7554/eLife.02862.002
doi:10.7554/eLife.02862
PMCID: PMC4210815  PMID: 25275323
lipoprotein; insulin; blood brain barrier; D. melanogaster

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