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Objective: This study aimed to evaluate fetal epicardial fat thickness (EFT) together with fetal myocardial performance index (MPI) and its effects on neonatal outcomes in obese pregnant women., Materials and Methods: A total of 102 pregnant women, 51 obese and 51 of normal weight, were included in this prospective study. Fetal EFT, and MPI measurements were performed for all patients., Results: Fetal EFT and Mod-MPI showed a statistically significant difference between obese pregnant women and the control group (p=0.0001, p=0.001). The optimal fetal EFT predictive cut-off value for the 5th-minute APGAR score below 7 was 1.22 mm, with a sensitivity of 86.96% and a specificity of 54.43% (p=0.001)., Conclusion: Fetal EFT and mod-MPI were higher in obese pregnant women. It is encouraging that fetal EFT predicts low APGAR, but more important information can be obtained if postnatal follow-up of these cardiac changes caused by obesity can be performed., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

High-Mobility-Group-A1 (HMGA1) proteins are non-histone proteins that regulate chromatin structure and gene expression during embryogenesis, tumourigenesis and immune responses. In vitro studies suggest that HMGA1 proteins may be required to regulate adipogenesis. To examine the role of HMGA1 in vivo, we generated transgenic mice overexpressing HMGA1 in adipose tissues. HMGA1 transgenic mice showed a marked reduction in white and brown adipose tissue mass that was associated with downregulation of genes involved in adipogenesis and concomitant upregulation of preadipocyte markers. Reduced adipogenesis and decreased fat mass were not associated with altered glucose homeostasis since HMGA1 transgenic mice fed a regular-chow diet exhibited normal glucose tolerance and insulin sensitivity. However, when fed a high-fat diet, overexpression of HMGA1 resulted in decreased body-weight gain, reduced fat mass, but improved insulin sensitivity and glucose tolerance. Although HMGA1 transgenic mice exhibited impaired glucose uptake in adipose tissue due to impaired adipogenesis, the increased glucose uptake observed in skeletal muscle may account for the improved glucose homeostasis. Our results indicate that HMGA1 plays an important function in the regulation of white and brown adipogenesis in vivo and suggests that impaired adipocyte differentiation and decreased fat mass is not always associated with impaired whole-body glucose homeostasis.

The Developmental Origins of Health and Disease hypothesis holds that alterations to homeostasis during critical periods of development can predispose individuals to adult-onset chronic diseases such as diabetes and metabolic syndrome. It remains controversial whether preimplantation embryo manipulation, clinically used to treat patients with infertility, disturbs homeostasis and affects long-term growth and metabolism. To address this controversy, we have assessed the effects of in vitro fertilization (IVF) on postnatal physiology in mice. We demonstrate that IVF and embryo culture, even under conditions considered optimal for mouse embryo culture, alter postnatal growth trajectory, fat accumulation, and glucose metabolism in adult mice. Unbiased metabolic profiling in serum and microarray analysis of pancreatic islets and insulin sensitive tissues (liver, skeletal muscle, and adipose tissue) revealed broad changes in metabolic homeostasis, characterized by systemic oxidative stress and mitochondrial dysfunction. Adopting a candidate approach, we identify thioredoxin-interacting protein (TXNIP), a key molecule involved in integrating cellular nutritional and oxidative states with metabolic response, as a marker for preimplantation stress and demonstrate tissue-specific epigenetic and transcriptional TXNIP misregulation in selected adult tissues. Importantly, dysregulation of TXNIP expression is associated with enrichment for H4 acetylation at the Txnip promoter that persists from the blastocyst stage through adulthood in adipose tissue. Our data support the vulnerability of preimplantation embryos to environmental disturbance and demonstrate that conception by IVF can reprogram metabolic homeostasis through metabolic, transcriptional, and epigenetic mechanisms with lasting effects for adult growth and fitness. This study has wide clinical relevance and underscores the importance of continued follow-up of IVF-conceived offspring.

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

A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target-specific modalities that depend on the primary etiology., (© Thieme Medical Publishers.)

The emerging role of adipose tissue as a dynamic endocrine organ with an extent of anatomical and physiological plasticity has generated numerous studies linking early-life events with long-term alterations in adipose tissue structure and function. Coupled with increasing rates of human obesity, which cannot be explained without some genetic component, the role of early programming of adipose tissue may provide an insight into potential mechanisms. The developmental origins of health and disease hypothesis investigates the potential association between a compromised fetal and postnatal environment and later disease, such as obesity and type 2 diabetes, in the offspring. A number of animal models have been developed to examine potential mechanisms that drive these physiological changes, including rodent and large-mammal models that provide mechanistic insights into the epidemiological findings. In utero challenges such as under- or over-provision of nutrients, placental insufficiency and glucocorticoid infusion, as well as postnatal nutritional challenges, can all result in the long-term programming of adipose tissue abundance and function. A range of hormones, enzymes, transcription factors and other metabolic signalling molecules have been implicated in adverse adipose tissue development, including leptin, glucocorticoids, members of the PPAR family, fatty acid-binding proteins and adipokines. The long-term structural and physiological consequences associated with these molecular and cellular changes are less well described. The experimental models, potential mechanisms and regulators of the early programming of adipose tissue in large mammalian species will be summarised in the present review.

Objective: Offspring of obese mothers have an increased risk for obesity and diabetes. The purpose of this study was to determine whether fetuses of obese women have increased obesity, insulin resistance, and markers of inflammation, supporting the concept of fetal programming., Research Design and Methods: Fifty-three lean and 68 obese women with singleton term pregnancies were evaluated at elective cesarean delivery. Maternal and umbilical cord blood was obtained for measures of insulin resistance and cytokines. Neonatal body composition was estimated using anthropometric measurements within 24 h of delivery., Results: The fetuses of obese mothers had greater percent body fat (13.1 +/- 3.4 vs. 11.6 +/- 2.9%, P = 0.02), homeostasis model assessment of insulin resistance (1.51 +/- 0.86 vs. 1.06 +/- 0.70, P = 0.003), cord leptin (14.5 +/- 13.5 vs. 8.2 +/- 4.7 ng/ml, P = 0.001), and interleukin-6 (3.5 +/- 2.3 vs. 2.4 +/- 1.4 pg/ml, P = 0.02) than fetuses of lean women. There was a strong positive correlation between fetal adiposity and insulin resistance (r = 0.32, P = 0.0008) as well as maternal pregravid BMI and fetal insulin resistance (r = 0.31, P = 0.007) even with adjustment for potential confounders. Cord leptin had a significant correlation with fetal insulin resistance (r = 0.30, P = 0.001), but there was no significant correlation between any other umbilical cord cytokines and fetal insulin resistance., Conclusions: These data suggest that maternal obesity creates a significant risk for the next generations with metabolic compromise already apparent at birth. Therefore, if prevention of obesity is the goal rather than treatment, the perinatal period may be an important focus of future research.

Whilst previously type 2 diabetes occurred in older adults, its incidence, together with obesity, has increased rapidly in children. An improved understanding of this disease pathway from a developmental view point is critical. It is likely that subtle changes in dietary patterns over an extended period of time contribute to diabetes, although this type of rationale is largely ignored in animal studies aimed at determining the mechanisms involved. Small-animal studies in which large, and often extreme, changes in the diet are imposed at different stages of the life cycle can have substantial effects on fat mass and/or pancreatic functions. These responses are not representative of the much more gradual changes seen in the human population. An increasing number of studies indicate that it is growth rate per se, rather than the type of dietary intervention that determines pancreatic function during development. Epigenetic mechanisms that regulate insulin secretion by the pancreas can be re-set by more extreme changes in dietary supply in early life. The extent to which these changes may contribute to more subtle modulations in glucose homeostasis that can accompany excess fat growth in childhood remains to be established. For human subjects there is much less information as to whether specific dietary components determine disease onset. Indeed, it is highly likely that genotype has a major influence, although recent data relating early diet to physical activity and the FTO gene indicate the difficulty of establishing the relative contribution of diet and changes in body mass to diabetes.

Evolutionary and developmental perspectives add considerably to our understanding of the aetiology of obesity and its related disorders. One pathway to obesity represents the maladaptive consequences of an evolutionarily preserved mechanism by which the developing mammal monitors nutritional cues from its mother and adjusts its developmental trajectory accordingly. Prediction of a nutritionally sparse environment leads to a phenotype that promotes metabolic parsimony by favouring fat deposition, insulin resistance, sarcopenia and low energy expenditure. But this adaptive mechanism evolved to accommodate gradual changes in nutritional environment; rapid transition to a situation of high energy density results in a mismatch between predicted and actual environments and increased susceptibility to metabolic disease. This pathway may also explain why breast and bottle feeding confer different risks of obesity. We discuss how early environmental signals act through epigenetic mechanisms to alter metabolic partitioning, glucocorticoid action and neuroendocrine control of appetite. A second pathway involves alterations in fetal insulin levels, as seen in gestational diabetes, leading to increased prenatal fat mass which is subsequently amplified by postnatal factors. Both classes of pathway may coexist in an individual. This developmental approach to obesity suggests that potential interventions will vary according to the target population.

In developed countries, the increasing incidence of obesity is a serious health problem. Leptin exposure in the perinatal period affects long-term regulation of appetite and energy expenditure, but control of leptin production in utero is unclear. This study investigated perirenal adipose tissue (PAT) and placental leptin expression in ovine fetuses during late gestation and after manipulation of plasma glucocorticoid and thyroid hormone concentrations. Between 130 and 144 d of gestation (term at 145 +/- 2 d), plasma leptin and PAT leptin mRNA levels increased in association with increments in plasma cortisol and T(3). Fetal adrenalectomy prevented these developmental changes, and exposure of intact 130 d fetuses to glucocorticoids, by cortisol infusion or maternal dexamethasone treatment, caused premature elevations in plasma leptin and PAT leptin gene expression. Fetal thyroidectomy increased plasma leptin and PAT leptin mRNA abundance, whereas intravenous T(3) infusion to intact 130 d fetuses had no effect on circulating or PAT leptin. Leptin mRNA expression was low in the ovine placenta. Therefore, in the sheep fetus, PAT appears to be a primary source of leptin in the circulation, and leptin gene expression is regulated by both glucocorticoids and thyroid hormones. Developmental changes in circulating and PAT leptin may mediate the maturational effects of cortisol in utero and have long-term consequences for appetite regulation and the development of obesity.

The developed and developing worlds are experiencing an epidemic of obesity and associated predisposition to diabetes. This epidemic places a major drain on health care resources. It is now clear that maternal obesity and gestational diabetes have major adverse effects on the developing fetus that lead to increased neonatal morbidity and mortality, as discussed elsewhere in this issue. Obesity in pregnancy and gestational diabetes represent a special problem, not only as a result of their immediate adverse effects on maternal health and pregnancy outcome, but also because of growing evidence for their persistent and deleterious effects on the developing child.

As obesity reaches epidemic levels in the United States there is an urgent need to understand the developmental pathways leading to this condition. Obesity increases the risk of hypertension and diabetes, symptoms of which are being seen with increased incidence in children. Adipocyte development begins in the fetus and, in contrast to all other tissues whose growth ceases in late juvenile life, it has the capacity for "unlimited" growth. In normal healthy individuals, the increase in fat mass with age is accompanied by a parallel increase in cortisol sensitivity, i.e., increased glucocorticoid receptor abundance and increased activity of the enzyme 11beta hydroxysteroid dehydrogenase type 1. Enhanced adipocyte sensitivity to cortisol is promoted in offspring born to mothers that were nutrient-restricted in utero in conjunction with increased peroxisome proliferator activated receptor alpha. This adaptation only appears to be associated with greater fat mass in the offspring when maternal nutrient restriction is confined to late gestation, coincident with the period of maximal fetal growth. In these offspring, increased fat mass is accompanied by glucose intolerance and insulin resistance, in conjunction with an adipose tissue specific reduction in glucose transporter 4 abundance. In conclusion, changes in maternal and, therefore, fetal nutrient supply at specific stages of gestation have the potential to substantially increase the risk of those offspring becoming obese in later life. The extent to which changes in dietary habits, both during pregnancy and in later life, may act to contribute to the current explosion in childhood and adult obesity remains a scientific and public health challenge to us all., (Copyright (c) 2005 Wiley-Liss, Inc.)

It is apparent from epidemiological studies that the timing of maternal nutrient restriction has a major influence on outcome in terms of predisposing the resulting offspring to adult obesity. The present review will consider the extent to which maternal age, parity and nutritional restriction at defined stages of gestation can have important effects on fat deposition and endocrine sensitivity of adipose tissue in the offspring. For example, in 1-year-old sheep the offspring of juvenile mothers have substantially reduced fat deposition compared with those born to adult mothers. Offspring of primiparous adult mothers, however, show increased adiposity compared with those born to multiparous mothers. These offspring of multiparous ewes show retained abundance of the brown adipose tissue-specific uncoupling protein 1 at 1 month of age. A stimulated rate of metabolism in brown fat of these offspring may act to reduce adipose tissue deposition in later life. In terms of defined windows of development that can programme adipose tissue growth, maternal nutrient restriction targetted over the period of maximal placental growth results in increased adiposity at term in conjunction with enhanced abundance of mRNA for the insulin-like growth factor-I and -II receptors. In contrast, nutrient restriction in late gestation, coincident with the period of maximal fetal growth, has no major effect on adiposity but results in greater abundance of specific mitochondrial proteins, i.e. voltage-dependent anion channel and/or uncoupling protein 2. These adaptations may increase the predisposal of these offspring to adult obesity. Increasing maternal nutrition in late gestation, however, can result in proportionately less fetal adipose tissue deposition in conjunction with enhanced abundance of uncoupling protein 1.

The importance of dietary fat in human obesity remains a controversial issue as the prevalence of overweight and obesity has increased despite no dramatic change in the amount of ingested fats over the past few decades. However, qualitative changes (i.e. the fatty acid composition of fats) have been largely disregarded. In this review, we summarize experimental evidence which supports polyunsaturated fatty acids of the omega6 series as being potent promoters of both adipogenesis in vitro and adipose tissue development in vivo during the gestation/lactation period. This conclusion is also supported by epidemiological data from infant studies as well as by the assessment of the fatty acid composition of mature breast milk and formula milk. It is proposed that unnoticed changes in fatty acid composition of ingested fats over the last decades have been important determinants in the increasing prevalence of childhood overweight and obesity.

The metabolic development of the liver and adipose tissue was examined in 75 and 110 day fetuses from genetically obese and control sows. In the liver, glucose and palmitate utilization was influenced by both age and strain. Higher rates of glucose oxidation and palmitate oxidation and esterification were observed in the 75 day compared to the 110 day fetuses. Hepatic palmitate oxidation was greater in pre-obese than in control fetuses at both fetal ages, while hepatic palmitate esterification was greater in pre-obese than in control fetuses at 75 days of gestation only. In subcutaneous adipose tissue, de novo lipogenesis increased with age and was higher in pre-obese than in control fetuses by 110 days of gestation. At 75 days of gestation, glucose oxidation and incorporation into fatty acids was similar in adipose tissue from both strains. However, by 110 days of gestation, both basal and insulin-stimulated rates of glucose metabolism were greater in pre-obese compared to control fetuses. Palmitate esterification increased with age but was similar in pre-obese and control fetuses. Basal lipolysis was not affected by strain or age. Isoproterenol had no effect on lipolysis in the 75 day fetuses while stimulating glycerol release to a comparable degree in 110 day fetuses of both strains. This study demonstrates that metabolic differences between genetically obese and control pigs are already apparent in the pre-obese state prior to birth. Such alterations in hepatic and adipose tissue carbohydrate and lipid metabolism, which promote early lipid storage by the pre-obese fetuses, may serve as useful metabolic markers for the development of obesity.

Subcutaneous adipose tissue was obtained from fetuses removed from pregnant obese (Ossabaw) and lean (crossbred) sows at three stages of gestation (70, 90, and 110 days). Histochemical analysis for nucleo-side phosphatase (NPase), alkaline phosphatase (APase), and NADH tetrazoleum reductase (NADH-TR) was conducted on fresh-frozen cryostat sections. Age- associated changes in NPase and NADH-TR reactions in the arteriolar system were correlated with the morphological development of the medial layer of arterioles and arteries. For instance, a strong NPase reaction in small arterioles was associated temporally with the assumption of a normal smooth muscle cell morphology and arrangement in the medial layer. In the youngest fetuses, strong NADH-TR reactions were only evident in small and presumptive arterioles and venules (associated with fat cells). Little NADH-TR reactivity was evident in larger arterioles and venules in 70-day tissue. Arteries and large arterioles were distinguished from veins and venules (strong reactions vs. weak reactions) with NADH-TR and NPase reactions in the oldest fetuses. In the younger fetuses, the NPase distinction (arterioles vs. veinules) was obvious before NADH-TR distinction. Small adipocyte-associated vessels were APase positive in the youngest fetuses, but APase reactivity was limited to short segments of vessel between arterioles and capillaries in the oldest fetuses. With the following exceptions, all the above observations were independent of fetal strain. In obese fetuses (110 day) small venules and small arterioles were equally reactive for NPase activity. Capillaries in obese fetuses (110 day) were NADH-TR reactive, whereas no activity was evident in capillaries from lean fetuses (110 day).(ABSTRACT TRUNCATED AT 250 WORDS)

The differentiation of perirenal adipose tissue was ascertained in fetuses from Ossabaw (wild and obese) and cross-bred lean dams at 70, 90 and 110 days gestation and from domestic lean and obese dams (USDA) at 110 days gestation. Condensation of presumptive adipocyte clusters was more apparent in Ossabaw sections than in cross-bred (lean) sections at 90 and 110 days gestation. Enzyme and lipid histochemistry showed fat cell cluster development to be largely independent of fetal strain (Ossabaw vs crossbred). However, adipocytes in Ossabaw fetuses were larger (110 days) and more reactive for esterase activity (all three ages) than were adipocytes from crossbred fetuses. Fetuses from USDA-obese dams had larger fat cell diameters (P less than 0.01), a higher percentage of lipoprotein lipase (LPL) positive cells than did fetuses from USDA-lean dams. Perirenal fat pad weights, percent depot lipid, percentages of glucose-6-phosphate dehydrogenase (G6PDH) and succinate dehydrogenase (SDH) positive cells were independent of fetal strain (USDA, lean vs obese). Fat cell cluster development was independent of fetal strain but large cellular condensations of presumptive cells were only present in sections from lean fetuses. Immature capillary beds (devoid of adipocytes) were demonstrable in lean sections but were not observed in obese sections. Morphological and histochemical results from both studies provide no evidence for brown adipocyte-like cells in fetal perirenal tissues.

In a historical cohort study of 300,000 19-year-old men exposed to the Dutch famine of 1944-45 and examined at military induction, we tested the hypothesis that prenatal and early postnatal nutrition determines subsequent obesity. Outcomes were opposite depending on the time of exposure. During the last trimester of pregnancy and the first months of life, exposure produced significantly lower obesity rates (P less than 0.005). This result is consistent with the inference that nutritional deprivation affected a critical period of development for adipose-tissue cellularity. During the first half of pregnancy, however, exposure resulted in significantly higher obesity rates (P less than 0.0005). This observation is consistent with the inference that nutritional deprivation affected the differentiation of hypothalamic centers regulating food intake and growth, and that subsequent increased food availability produced an accumulation of excess fat in an organism growing to its predetermined maximum size.