Different response of embryos originating from control and obese mice to insulin in vitro.

The aim of the present work was to investigate the impact of maternal obesity on DNA methylation in ovulated oocytes, and to compare the response of in vitro-developing preimplantation embryos originating from control and obese mice to insulin. An intergenerational, diet-induced obesity model was used to produce outbred mice with an increased body weight and body fat. Two-cell and eight-cell embryos recovered from obese and control mice were cultured in a medium supplemented with 1 or 10 ng/ml insulin until blastocyst formation. In the derived blastocysts, cell proliferation, differentiation, and death rates were determined. The results of immunochemical visualization of 5-methylcytosine indicated a slightly higher DNA methylation in ovulated metaphase II oocytes recovered from obese females; however, the difference between groups did not reach statistical significance. Expanded blastocysts developed from embryos provided by control dams showed increased mean cell numbers (two and eight-cell embryos exposed to 10 ng/ml), an increased inner-cell-mass/trophectoderm ratio (two-cell embryos exposed to 1 ng/ml and eight-cell embryos exposed to 10 ng/ml), and a reduced level of apoptosis (two and eight-cell embryos exposed to 10 ng/ml). In contrast, embryos originating from obese mice were significantly less sensitive to insulin; indeed, no difference was recorded in any tested variable between the embryos exposed to insulin and those cultured in insulin-free medium. Real-time RT-PCR analysis showed a significant increase in the amount of insulin receptor transcripts in blastocysts recovered from obese dams. These results suggest that maternal obesity might modulate the mitogenic and antiapoptotic responses of preimplantation embryos to insulin.

Gene expression and epigenetic aberrations in F1-placentas fathered by obese males.

Gene expression and/or epigenetic deregulation may have consequences for sperm and blastocysts, as well as for the placenta, together potentially contributing to problems observed in offspring. We previously demonstrated specific perturbations of fertilization, blastocyst formation, implantation, as well as aberrant glucose metabolism and adiposity in offspring using a mouse model of paternal obesity. The current investigation analyzed gene expression and methylation of specific CpG residues in F1 placentas of pregnancies fathered by obese and normal-weight male mice, using real-time PCR and bisulfite pyrosequencing. Our aim was to determine if paternal obesity deregulated placental gene expression and DNA methylation when compared to normal-weight males. Gene methylation of sperm DNA was analyzed and compared to placentas to address epigenetic transmission. Of the 10 paternally expressed genes (Pegs), 11 genes important for development and transport of nutrients, and the long-terminal repeat Intracisternal A particle (IAP) elements, derived from a member of the class II endogenous retroviral gene family, we observed a significant effect of paternal diet-induced obesity on deregulated expression of Peg3, Peg9, Peg10, and the nutrient transporter gene Slc38a2, and aberrant DNA methylation of the Peg9 promoter in F1 placental tissue. Epigenetic changes in Peg9 were also found in sperm from obese fathers. We therefore propose that paternal obesity renders changes in gene expression and/or methylation throughout the placental genome, which could contribute to the reproductive problems related to fertility and to the metabolic, long-term health impact on offspring.

Maternal Body Mass Index and Regional Anaesthesia Use at Term: Prevalence and Complications.

BACKGROUND: There is an evidence gap regarding the use of regional anaesthesia (epidural, spinal, or combined epidural/spinal anaesthesia) and associated complications by maternal body mass index (BMI). We examine associations between regional anaesthesia, mode of delivery, and regional anaesthesia complications by pre-pregnancy BMI categories among term deliveries. METHODS: Retrospective cohort study of births in California, 2007-2010, utilizing linked birth certificate data and patient discharge data. Outcomes were mode of delivery (among laboured deliveries) and select regional anaesthesia complications. Multivariable Poisson regression was used to adjust for maternal characteristics. RESULTS: In women undergoing labour (i.e. laboured delivery), women with higher BMI categories were more likely to receive regional analgesia in a dose-response fashion (adjusted risk ratio [RR] 1.10, 95% confidence interval [CI] 1.10, 1.11 for primiparous women with category I obesity), and in those receiving regional anaesthesia, were less likely to deliver vaginally (e.g. RR 0.85, 95% CI 0.84, 0.85 for the same category of women). Regional anaesthesia complications displayed a complex relationship with maternal BMI, with women in intermediate obesity categories having decreased odds as compared to normal-weight women, and women in the highest BMI category having a twofold increased risk of complications (RR 2.34, 95% CI 1.37, 4.02 for primiparous women). CONCLUSION: Labouring women in higher BMI categories were more likely to receive regional anaesthesia and more likely to deliver via caesarean compared to normal weight women and women without regional anaesthesia. Rates of anaesthesia complications were highest among women in the highest BMI category.

Impact of maternal obesity on fetal programming of cardiovascular disease.

The in utero environment is a key determinant of long-term health outcomes; poor maternal metabolic state and placental insufficiency are strongly associated with these long-term health risks. Human epidemiological studies link maternal obesity and offspring cardiovascular disease in later life, but mechanistic studies in animal models are limited. Here, we review the literature pertaining to maternal consequences of obesity during pregnancy and the subsequent impact on fetal cardiovascular development.

Ethnic Disparities in CKD in the Netherlands: The Healthy Life in an Urban Setting (HELIUS) Study.

BACKGROUND: Evidence suggesting important ethnic differences in chronic kidney disease (CKD) prevalence comes mainly from the United States, and data among various ethnic groups in Europe are lacking. We therefore assessed differences in CKD in 6 ethnic groups living in the Netherlands and explored to what extent the observed differences could be accounted for by differences in conventional cardiovascular risk factors (smoking, physical activity, obesity, hypertension, diabetes, and hypercholesterolemia). STUDY DESIGN: Cross-sectional analysis of baseline data from the Healthy Life in an Urban Setting (HELIUS) cohort study. SETTING & PARTICIPANTS: A random sample of 12,888 adults (2,129 Dutch, 2,273 South Asian Surinamese, 2,159 African Surinamese, 1,853 Ghanaians, 2,255 Turks, and 2,219 Moroccans) aged 18 to 70 years living in Amsterdam, the Netherlands. PREDICTORS: Ethnicity. OUTCOMES & MEASUREMENTS: CKD status was defined using the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) severity of CKD classification. CKD was defined as albumin-creatinine ratio ≥ 3mg/mmol (category ≥ A2) or glomerular filtration rate < 60mL/min/1.73m(2) (category ≥ G3). Comparisons among groups were made using prevalence ratios (PRs). RESULTS: The age-standardized prevalence of CKD was higher in all ethnic minority groups, ranging from 4.6% (95% CI, 3.8%-5.5%) in African Surinamese to 8.0% (95% CI, 6.7%-9.4%) in Turks, compared with 3.0% (95% CI, 2.3%-3.7%) in Dutch. Adjustment for conventional risk factors reduced the PR substantially, but ethnic differences remained for all ethnic minority groups except African Surinamese, with the PR ranging from 1.48 (95% CI, 1.12-1.97) in Ghanaians to 1.75 (95% CI, 1.33-2.30) in Turks compared with Dutch. Similar findings were found when CKD was stratified into a moderately increased and a combined high/very high risk group. Among the combined high/very high CKD risk group, conventional risk factors accounted for most of the ethnic differences in CKD except for South Asian Surinamese (PR, 2.60; 95% CI, 1.26-5.34) and Moroccans (PR, 2.33; 95% CI, 1.05-5.18). LIMITATIONS: Cross-sectional design. CONCLUSIONS: These findings suggest ethnic inequalities in CKD for most groups even after adjustment for conventional risk factors. These findings highlight the need for further research to identify other potential factors contributing to the ethnic inequalities in CKD.

Proteomic analysis of fetal programming-related obesity markers.

The objectives of this study were to analyze fetal programming in rat brain using proteomic analysis and to identify fetal programming-related obesity markers. Sprague-Dawley rats were divided into four feeding groups: (i) the Ad Libitum (AdLib)/AdLib group was given a normal diet during pregnancy and the lactation period; (ii) the AdLib/maternal food restriction group (FR) was subjected to 50% FR during the lactation period; (iii) the FR/AdLib group was subjected to 50% FR during pregnancy; and (iv) the FR/FR group was subjected to 50% FR during pregnancy and the lactation period. Offspring from each group were sacrificed at 3 weeks of age and whole brains were dissected. To obtain a maximum number of protein markers related to obesity, 2DE and Pathway Studio bioinformatics analysis were performed. The identities of the markers among the selected and candidate proteins were confirmed by Western blotting and immunohistochemistry. Proteomic and bioinformatics analyses revealed that expression of ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and Secernin 1 (SCRN1) were significantly different in the FR/AdLib group compared with the AdLib/AdLib group for both male and female offspring. These findings suggest that UCHL1 and SCRN1 may be used as fetal programming-related obesity markers.

[Developmental programming of metabolic diseases--a review of studies on experimental animal models]. / Programowanie rozwojowe chorób metabolicznych--przeglad wyników badan na zwierzecych modelach doswiadczalnych.

Growth and development in utero is a complex and dynamic process that requires interaction between the mother organism and the fetus. The delivery of macro--and micronutrients, oxygen and endocrine signals has crucial importance for providing a high level of proliferation, growth and differentiation of cells, and a disruption in food intake not only has an influence on the growth of the fetus, but also has negative consequences for the offspring's health in the future. Diseases that traditionally are linked to inappropriate life style of adults, such as type 2 diabetes, obesity, and arterial hypertension, can be "programmed" in the early stage of life and the disturbed growth of the fetus leads to the symptoms of the metabolic syndrome. The structural changes of some organs, such as the brain, pancreas and kidney, modifications of the signaling and metabolic pathways in skeletal muscles and in fatty tissue, epigenetic mechanisms and mitochondrial dysfunction are the basis of the metabolic disruptions. The programming of the metabolic disturbances is connected with the disruption in the intrauterine environment experienced in the early and late gestation period. It causes the changes in deposition of triglycerides, activation of the hormonal "stress axis" and disturbances in the offspring's glucose tolerance. The present review summarizes experimental results that led to the identification of the above-mentioned links and it underlines the role of animal models in the studies of this important concept.

Developmental programming of offspring obesity, adipogenesis, and appetite.

A newly recognized primary cause of the obesity epidemic is the developmental programming effects of infants born to mothers with obesity or gestational diabetes, intrauterine growth-restricted newborns, and offspring exposed to environmental toxins including bisphenol A. The mechanisms which result in offspring obesity include the programming of the hypothalamic appetite pathway and adipogenic signals regulating lipogenesis. Processes include nutrient sensors, epigenetic modifications, and alterations in stem cell precursors of both appetite/satiety neurons and adipocytes which are modulated to potentiate offspring obesity. Future strategies for the prevention and therapy of obesity must address programming effects of the early life environment.

Parental diet-induced obesity leads to retarded early mouse embryo development and altered carbohydrate utilisation by the blastocyst.

Maternal obesity results in reproductive complications, whereas the impact of paternal obesity is unclear. In the present study, the effects of parental obesity on preimplantation embryo cell cycle length and carbohydrate utilisation were investigated. Maternal and paternal obesity were assessed independently by deriving zygotes from normal or obese C57BL/6 female mice mated with normal Swiss male mice (maternal obesity), or from normal Swiss female mice mated with normal or obese C57BL/6 male mice (paternal obesity). Zygotes were cultured in vitro and development was then assessed by time-lapse microscopy and metabolism determined using ultramicrofluorescence. Maternal obesity was associated with a significant delay in precompaction cell cycle kinetics from the 1-cell stage. A significant increase in glucose consumption by embryos from obese compared with normal females occurred after compaction, although glycolysis remained unchanged. Similarly, paternal obesity led to significant delays in cell cycle progression during preimplantation embryo development. However, this developmental delay was observed from the second cleavage stage onwards, following embryonic genome activation. Blastocysts from obese males showed disproportionate changes in carbohydrate metabolism, with significantly increased glycolysis. Overall, metabolic changes were not inhibitory to blastocyst formation; however, blastocyst cell numbers were significantly lower when either parent was obese. These data suggest that both maternal and paternal obesity significantly impacts preimplantation embryo physiology.

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

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

Altered adipose tissue metabolism in offspring of dietary obese rat dams.

To investigate further the mechanisms of developmental programming, we analysed the effects of maternal overnutrition and of postnatal high-fat feeding on adipose tissue metabolism in the offspring. Postnatal changes in serum adiponectin, leptin and TAG [triacylglycerol (triglyceride)] levels, adipose tissue TAGs, fatty acids and enzyme activities were determined in offspring of cafeteria-diet-fed dams during gestation and lactation, weaned on to standard chow or on to cafeteria diet. Obese rats showed higher adiposity (+35% to 85%) as well as a significant increase in serum glucose, insulin, leptin, adiponectin and TAG levels (P<0.01) and adipose tissue LPL (lipoprotein lipase) and GPDH (glycerol-3-phosphate dehydrogenase) activities (P<0.01), compared with control pups at weaning (day 21) and at adulthood (day 90). Adipose HSL (hormone-sensitive lipase) activity was increased only at day 90 (P<0.05), and FAS (fatty acid synthase) activity remained unchanged. The proportions of SFAs (saturated fatty acids) and MUFAs (mono-unsaturated fatty acids) and the Δ(9)-desaturation index were significantly increased (P<0.05), whereas PUFAs (polyunsaturated fatty acids) were decreased (P<0.01) in serum and adipose TAGs of obese pups compared with controls. The cafeteria diet at weaning induced more severe abnormalities in obese rats. In conclusion, maternal overnutrition induced permanent changes in adipose tissue metabolism of the offspring. These pre-existing alterations in offspring were worsened under a high-fat diet from weaning to adulthood. Consequently, adipose adipokines and enzymes could provide a potential therapeutic target, and new investigations in this field could constitute strategies to improve the impact of early-life overnutrition.

Evidence for the intra-uterine programming of adiposity in later life.

AIM: Research in animals has shown that altering foetal nutrition by under-nourishing or over-nourishing the mother or rendering her diabetic or foetal exposure to glucocorticoids and toxins can programme obesity in later life. The increased adiposity is mediated by permanent changes in appetite, food choices, physical activity and energy metabolism. In humans, increased adiposity has been shown in people who experienced foetal under-nutrition due to maternal famine or over-nutrition due to maternal diabetes. Lower birth weight (a proxy for foetal under-nutrition) is associated with a reduced adult lean mass and increased intra-abdominal fat. Higher birth-weight caused by maternal diabetes is associated with increased total fat mass and obesity in later life. There is growing evidence that maternal obesity, without diabetes, is also a risk factor for obesity in the child, due to foetal over-nutrition effects. Maternal smoking is associated with an increased risk of obesity in the children, although a causal link has not been proven. Other foetal exposures associated with increased adiposity in animals include glucocorticoids and endocrine disruptors. CONCLUSIONS: Reversing the current obesity epidemic will require greater attention to, and better understanding of, these inter-generational (mother-offspring) factors that programme body composition during early development.

Impact of maternal obesity on offspring obesity and cardiometabolic disease risk.

The prevalence of obesity among pregnant women is increasing. In addition to the short-term complications of obesity during pregnancy in both mother and child, it is now recognised that maternal obesity has long-term adverse outcomes for the health of her offspring in later life. Evidence from both animal and human studies indicates that maternal obesity increases the risk for the offspring in developing obesity and altering body composition in child- and adulthood and, additionally, it also has an impact on the offspring's cardiometabolic health with dysregulation of metabolism including glucose/insulin homoeostasis, and development of hypertension and vascular dysfunction. Potential mechanisms include effects on the development and function of adipose tissue, pancreas, muscle, liver, the vasculature and the brain. Further studies are required to elucidate the mechanisms underpinning the programming of disease risk in the offspring as a consequence of maternal obesity. The ultimate aim is to identify potential targets, which may be amenable to prevention or early intervention in order to improve the health of this and future generations.

Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth study.

OBJECTIVE: Obesity's association with type 2 diabetes (T2DM) is well established, but is less clear with type 1 diabetes (T1DM). We calculated the prevalence of overweight and obesity among diabetic youth in the USA from a six-center, population-based study of racially and ethnically diverse youth with diabetes, and we compared these rates with estimates among nondiabetic youth. DESIGN/SETTING: Diabetic participants were examined in 2001-2004 for the SEARCH for Diabetes in Youth study (SEARCH) and nondiabetic participants were examined during the same years of the National Health and Nutrition Examination Survey (NHANES). PARTICIPANTS: 3953 diabetic youth and 7666 nondiabetic youth aged 3-19 yr. MAIN OUTCOME MEASURES: Overweight was defined as body mass index (BMI) from the 85th to <95th percentile for age and sex and obesity defined as > or = 95th percentile. Diabetes type was categorized as T1DM or T2DM based on physician diagnosis. RESULTS: Among youth with T2DM, the prevalence of overweight was 10.4% and obesity was 79.4%. Among youth with T1DM, 22.1% were overweight. The prevalence of overweight among youth with T1DM was higher than among those without diabetes overall (22.1% vs. 16.1%) (P <.05). The obesity rate for T1DM was 12.6% overall (range Non-Hispanic White 10.7%-African-American 20.1%). CONCLUSIONS: As expected, most of the youth with T2DM were obese. Youth with T1DM had a higher prevalence of overweight, but not of obesity, than nondiabetic youth. Future studies of obesity among youth with diabetes of all types will further our understanding of the impact of obesity on diabetes both as a risk factor and a comorbidity.

[Obesity and chronic kidney disease]. / L'obesità come causa di insufficienza renale.

In the last century, life expectancy in the economically developed countries has significantly increased. In parallel there has been an increase in the prevalence of obesity and of chronic kidney disease. Abdominal obesity is a relevant risk factor for death and cardiovascular complications in chronic kidney disease and in dialysis patients as well.

Moderate daily exercise activates metabolic flexibility to prevent prenatally induced obesity.

Obesity and its associated comorbidities are of major worldwide concern. It is now recognized that there are a number of metabolically distinct pathways of obesity development. The present paper investigates the effect of moderate daily exercise on the underlying mechanisms of one such pathway to obesity, through interrogation of metabolic flexibility. Pregnant Wistar rats were either fed chow ad libitum or undernourished throughout pregnancy, generating control or intrauterine growth restricted (IUGR) offspring, respectively. At 250 d of age, dual-emission x-ray absorptiometry scans and plasma analyses showed that moderate daily exercise, in the form of a measured amount of wheel running (56 m/d), prevented the development of obesity consistently observed in nonexercised IUGR offspring. Increased plasma C-peptide and hepatic atypical protein kinase Czeta levels explained increased glucose uptake and increased hepatic glycogen storage in IUGR offspring. Importantly, whereas circulating levels of retinol binding protein 4 were elevated in obese, nonexercised IUGR offspring, indicative of glucose sparing without exercise, retinol binding protein 4 levels were normalized in the exercised IUGR group. These data suggest that IUGR offspring have increased flexibility of energy storage and use and that moderate daily exercise prevents obesity development through activation of distinct pathways of energy use. Thus, despite a predisposition to develop obesity under sedentary conditions, obesity development was prevented in IUGR offspring when exercise was available. These results emphasize the importance of tailored lifestyle changes that activate distinct pathways of metabolic flexibility for obesity prevention.

Impairment of the serotonergic control of feeding in adult female rats exposed to intra-uterine malnutrition.

We have previously shown that adult female rats exposed to intra-uterine malnutrition were normophagic, although obese and resistant to insulin-induced hypophagia. The present study aimed at examining aspects of another important catabolic component of energy homeostasis control, the hypothalamic serotonergic function, which inhibits feeding and stimulates energy expenditure. Pregnant dams were fed ad libitum or were restricted to 50 % of ad libitum intake during the first 2 weeks of pregnancy. Control and restricted 4-month-old progeny were studied. The restricted rats had increased body adiposity with normal daily food intake but failed to respond with hypophagia to an intracerebroventricular injection of serotonin (5-hydroxytryptamine; 5-HT). Stimulation, by food ingestion, of extracellular levels of serotonin in medial hypothalamus microdialysates was more pronounced and lasted longer in the restricted than in the control rats. In the restricted group, hypothalamic levels of 5-HT 2C receptor protein tended to be reduced (P = 0.07) while the levels of 5-HT1B receptor and serotonin transporter proteins were significantly elevated (36 and 79 %, respectively). In conclusion, female rats undernourished in utero had normophagic obesity as adults but had an absence of serotonin-induced hypophagia and low hypothalamic levels of the 5-HT 2C receptor. Compensatory adaptations for the functional serotonergic impairment were evidenced, such as an enhanced release of serotonin in response to a meal allied to up-regulated hypothalamic 5-HT1B and transporter expression. Whether these compensations will persist in later life warrants further investigation. Moreover, it cannot be ruled out that the serotonergic component of energy expenditure was already impaired, thus contributing to the observed body-fat phenotype.

The developmental origins of adult disease.

PURPOSE OF REVIEW: Intrauterine growth restriction (IUGR) is associated with an increased propensity to develop adult-onset disease and is described by the developmental origins of adult disease hypothesis. Sequelae of fetal growth restriction include metabolic disease as well as nonmetabolic disorders. Although it has become clear that the morbidities associated with IUGR are complex and result from disruptions to multiple pathways and multiple organs, the mechanisms driving the long-term effects are only just beginning to be understood. RECENT FINDINGS: IUGR affects most organ systems by either interrupting developmental processes such as apoptosis or producing lasting changes to levels of key regulatory factors. Both of these are associated with an often persistent change in gene expression. Epigenetic modulation of transcription is a mechanism that is at least partially responsible for this. IUGR is accompanied by changes in the quantity and activity of enzymes responsible for making modifications to chromatin as well as global and gene-specific modifications of chromatin. SUMMARY: The subtle adjustments needed to ensure developmental plasticity in IUGR are provided by epigenetic modulation of critical genes. Translating the messages of the epigenetic profile and identifying the players that mediate the effects remains one of the major challenges in the field. An understanding of the mechanisms driving the epigenetic changes will facilitate identification of dietary and pharmaceutical approaches that can be applied in the postnatal period.

AMP-activated protein kinase signalling pathways are down regulated and skeletal muscle development impaired in fetuses of obese, over-nourished sheep.

Maternal obesity and over-nutrition give rise to both obstetric problems and neonatal morbidity. The objective of this study was to evaluate effects of maternal obesity and over-nutrition on signalling of the AMP-activated protein kinase (AMPK) pathway in fetal skeletal muscle in an obese pregnant sheep model. Non-pregnant ewes were assigned to a control group (Con, fed 100% of NRC nutrient recommendations, n = 7) or obesogenic group (OB, fed 150% of National Research Council (NRC) recommendations, n = 7) diet from 60 days before to 75 days after conception (term 150 days) when fetal semitendinosus skeletal muscle (St) was sampled. OB mothers developed severe obesity accompanied by higher maternal and fetal plasma glucose and insulin levels. In fetal St, activity of phosphoinositide-3 kinase (PI3K) associated with insulin receptor substrate-1 (IRS-1) was attenuated (P < 0.05), in agreement with the increased phophorylation of IRS-1 at serine 1011. Phosphorylation of AMP-activated protein kinase (AMPK) at Thr 172, acetyl-CoA carboxylase at Ser 79, tuberous sclerosis 2 at Thr 1462 and eukaryotic translation initiation factor 4E-binding protein 1 at Thr 37/46 were reduced in OB compared to Con fetal St. No difference in energy status (AMP/ATP ratio) was observed. The expression of protein phosphatase 2C was increased in OB compared to Con fetal St. Plasma tumour necrosis factor alpha (TNFalpha) was increased in OB fetuses indicating an increased inflammatory state. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) was higher in OB St, indicating enhanced adipogenesis. The glutathione: glutathione disulphide ratio was also lower, showing increased oxidative stress in OB fetal St. In summary, we have demonstrated decreased signalling of the AMPK system in skeletal muscle of fetuses of OB mothers, which may play a role in altered muscle development and development of insulin resistance in the offspring.

Adipocytes and adipose tissue.

An epidemic of obesity is taking place in most societies around the world. Overall obesity substantially increases the risk of subsequent morbidity. In children and adolescents the degree of body fat mass depends upon ethnic background, gender, developmental stage and age. Obesity is characterized by increases in the number or size of fat cells, or a combination of both. It is generally believed that the number of fat cells depends on age of onset and degree of obesity. This chapter provides information on intrauterine growth of fetal adipose tissue, the earliest period of onset of proliferation, and some of the factors that interact to enhance or suppress development. Fetal adipose tissue development is regulated by the complex interaction of transcription factors, nutrients and adipocytokines. Maternal, endocrine, and paracrine factors also influence specific changes in angiogenesis, adipogenesis, and metabolism. During embryogenesis and in fetal life, leptin and adiponectin, two important adipocytokines, are present at high concentrations in the circulation and in tissues. Developmental stages and metabolic processes influenced by specific hormones and paracrine factors have been identified through examination of the offspring of obese and diabetic pregnancies, hormonal manipulation during late pregnancy in animal models, and the use of cell cultures. Collectively, the results of the studies cited herein delineate the basis for imprinting or conditioning of fetal pre-adipocytes at the paracrine/autocrine level, and of fetal adipose tissue development and metabolism.