Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology.

Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly been considered so far. Our recent findings within the prospective 'EaCH' cohort study of women with GDM or normal glucose tolerance (NGT), showed the role, critical factors of insulin resistance (i.e., adiponectin, insulin receptor) may have for GDM pathophysiology with epigenetically modified expression in subcutaneous (SAT) and visceral (VAT) adipose tissues. Here we investigated the expression and promoter methylation of key inflammatory candidates, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) in maternal adipose tissues collected during caesarian section (GDM, n = 19; NGT, n = 22). The mRNA expression of TNF-α and SOCS3 was significantly increased in VAT, but not in SAT, of GDM patients vs. NGT, accompanied by specific alterations of respective promoter methylation patterns. In conclusion, we propose a critical role of VAT and visceral obesity for the pathogenesis of GDM, with epigenetic alterations of the expression of inflammatory factors as a potential factor.

Maternal overweight is not an independent risk factor for increased birth weight, leptin and insulin in newborns of gestational diabetic women: observations from the prospective 'EaCH' cohort study.

BACKGROUND: Both gestational diabetes mellitus (GDM) as well as overweight/obesity during pregnancy are risk factors for detrimental anthropometric and hormonal neonatal outcomes, identified to 'program' adverse health predispositions later on. While overweight/obesity are major determinants of GDM, independent effects on critical birth outcomes remain unclear. Thus, the aim of the present study was to evaluate, in women with GDM, the relative/independent impact of overweight/obesity vs. altered glucose metabolism on newborn parameters. METHODS: The prospective observational 'Early CHARITÉ (EaCH)' cohort study primarily focuses on early developmental origins of unfavorable health outcomes through pre- and/or early postnatal exposure to a 'diabetogenic/adipogenic' environment. It includes 205 mother-child dyads, recruited between 2007 and 2010, from women with treated GDM and delivery at the Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Germany. Recruitment, therapy, metabolite/hormone analyses, and data evaluation were performed according to standardized guidelines and protocols. This report specifically aimed to identify maternal anthropometric and metabolic determinants of anthropometric and critical hormonal birth outcomes in 'EaCH'. RESULTS: Group comparisons, Spearman's correlations and unadjusted linear regression analyses initially confirmed that increased maternal prepregnancy body-mass-index (BMI) is a significant factor for elevated birth weight, cord-blood insulin and leptin (all P < 0.05). However, consideration of and adjustment for maternal glucose during late pregnancy showed that no maternal anthropometric parameter (weight, BMI, gestational weight gain) remained significant (all n.s.). In contrast, even after adjustment for maternal anthropometrics, third trimester glucose values (fasting and postprandial glucose at 32nd and 36th weeks' gestation, HbA1c in 3rd trimester and at delivery), were clearly positively associated with critical birth outcomes (all P < 0.05). CONCLUSIONS: Neither overweight/obesity nor gestational weight gain appear to be independent determinants of increased birth weight, insulin and leptin. Rather, 3rd trimester glycemia seems to be crucial for respective neonatal outcomes. Thus, gestational care and future research studies should greatly consider late pregnancy glucose in overweight/obese women with or without GDM, for evaluation of critical causes and interventional strategies against 'perinatal programming of diabesity' in the offspring.

Altered SOCS3 DNA methylation within exon 2 is associated with increased mRNA expression in visceral adipose tissue in gestational diabetes.

Overweight/obesity is the main risk factor for gestational diabetes mellitus (GDM). In our cohort of pregnant women with GDM, n = 19, and without, n = 22, we previously reported a significant increase in SOCS3 mRNA expression (+62%) in visceral adipose tissue (VAT) according to GDM, without altered promoter DNA-methylation. Here, we examined methylation status of additional SOCS3 exon 2 regions in VAT and maternal blood. We found significantly altered methylation at specific CpG sites corresponding to aberrant mRNA expression levels of SOCS3 in VAT. We propose a potential regulatory element/region within exon 2; however, this region does not appear to be a good blood-marker representing VAT.

Epigenetic malprogramming of the insulin receptor promoter due to developmental overfeeding.

AIM: Prenatal and neonatal overfeeding programs a permanent obesity and diabetes disposition, e.g., due to induction of hypothalamic insulin resistance. We investigated acquired alterations of the DNA methylation pattern of the hypothalamic insulin receptor promoter (IRP) which might be an underlying molecular mechanism. METHODS: Neonatal overfeeding was induced by rearing Wistar rats in small litters (SL). Methylation of CpG-dinucleotides of the hypothalamic IRP was mapped using bisulfite sequencing. RESULTS: Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperglycemia, hyperinsulinemia, and increased insulin/glucose-ratio. The proportion of animals carrying any methylated CpG residue in the 322 bp CpG island of the IRP was increased in neonatally overfed SL rats (n=8), as compared to controls (n=8; P=0.04). Moreover, the mean percentage of methylated CpG positions was also higher in SL rats (P=0.01). Over both groups, neonatal blood glucose levels were positively correlated to the extent of promoter methylation (r=0.52; P=0.04). CONCLUSIONS: This study characterizes for the first time the IRP epigenomically in any species and tissue. Our data reveal that the IRP is vulnerable to hypermethylation due to overnutrition, probably especially glucose-dependent in a dose-response manner. This paradigmatically indicates the impact of nutrient-dependent epigenetic malprogramming, leading to a "diabesity" disposition which may become pathogenic throughout life.

Maternal but Not Paternal High-Fat Diet (HFD) Exposure at Conception Predisposes for 'Diabesity' in Offspring Generations.

While environmental epigenetics mainly focuses on xenobiotic endocrine disruptors, dietary composition might be one of the most important environmental exposures for epigenetic modifications, perhaps even for offspring generations. We performed a large-scale rat study on key phenotypic consequences from parental (F0) high-caloric, high-fat diet (HFD) food intake, precisely and specifically at mating/conception, focusing on 'diabesity' risk in first- (F1) and second- (F2) generation offspring of both sexes. F0 rats (maternal or paternal, respectively) received HFD overfeeding, starting six weeks prior to mating with normally fed control rats. The maternal side F1 offspring of both sexes developed a 'diabesity' predisposition throughout life (obesity, hyperleptinemia, hyperglycemia, insulin resistance), while no respective alterations occurred in the paternal side F1 offspring, neither in males nor in females. Mating the maternal side F1 females with control males under standard feeding conditions led, again, to a 'diabesity' predisposition in the F2 generation, which, however, was less pronounced than in the F1 generation. Our observations speak in favor of the critical impact of maternal but not paternal metabolism around the time frame of reproduction for offspring metabolic health over generations. Such fundamental phenotypic observations should be carefully considered in front of detailed molecular epigenetic approaches on eventual mechanisms.

Sex-specific epigenetic alterations of the hypothalamic Agrp-Pomc system do not explain 'diabesity' in the offspring of high-fat diet (HFD) overfed maternal rats.

Maternal high-fat diet (HFD) overfeeding pre- and during pregnancy and lactation may 'program' a 'diabesity' predisposition in the offspring, for inconclusive reasons. Acquired alterations of the hypothalamic promoter methylation and mRNA expression of the satiety neurohormone Pomc are possibly of critical importance here. We investigated within one developmental approach, including male and female rats, the sex-specific DNA methylation pattern and corresponding mRNA expression of both Pomc and its endogenous functional antagonist Agrp in the hypothalamus of adult HFD offspring. Obesity and diabetic disturbances occurred in both male and female HFD offspring, accompanied by altered Pomc promoter methylation pattern. However, this was not related to significant Pomc mRNA expression alterations. In contrast, male-specific alterations of Agrp promoter methylation were found, even associated with reduced mRNA expression of this orexigenic/anabolic Pomc antagonist. In conclusion, acquired epigenetic alterations of the hypothalamic Agrp-Pomc system hardly explain the 'diabesity' phenotype in HFD offspring, while distinct vulnerability and functionality of Agrp promoter and related genomic regions methylation should be further investigated.

Effectiveness of real-time continuous glucose monitoring to improve glycaemic control and pregnancy outcome in patients with gestational diabetes mellitus: a study protocol for a randomised controlled trial.

INTRODUCTION: Real-time continuous glucose monitoring (rt-CGM) informs users about current interstitial glucose levels and allows early detection of glycaemic excursions and timely adaptation by behavioural change or pharmacological intervention. Randomised controlled studies adequately powered to evaluate the impact of long-term application of rt-CGM systems on the reduction of adverse obstetric outcomes in women with gestational diabetes (GDM) are missing. We aim to assess differences in the proportion of large for gestational age newborns in women using rt-CGM as compared with women with self-monitored blood glucose (primary outcome). Rates of neonatal hypoglycaemia, caesarean section and shoulder dystocia are secondary outcomes. A comparison of glucose metabolism and quality of life during and after pregnancy completes the scope of this study. METHODS AND ANALYSIS: Open-label multicentre randomised controlled trial with two parallel groups including 372 female patients with a recent diagnosis of GDM (between 24+0 until 31+6 weeks of gestation): 186 with rt-CGM (Dexcom G6) and 186 with self-monitored blood glucose (SMBG). Women with GDM will be consecutively recruited and randomised to rt-CGM or control (SMBG) group after a run-in period of 6-8 days. The third visit will be scheduled 8-10 days later and then every 2 weeks. At every visit, glucose measurements will be evaluated and all patients will be treated according to the standard care. The control group will receive a blinded CGM for 10 days between the second and third visit and between week 36+0 and 38+6. Cord blood will be sampled immediately after delivery. 48 hours after delivery neonatal biometry and maternal glycosylated haemoglobin A1c (HbA1c) will be assessed, and between weeks 8 and 16 after delivery all patients receive a re-examination of glucose metabolism including blinded CGM for 8-10 days. ETHICS AND DISSEMINATION: This study received ethical approval from the main ethic committee in Vienna. Data will be presented at international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03981328; Pre-results.

Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome.

Pre- and neonatal overfeeding programmes a permanent obesity disposition and accompanying diabetic and cardiovascular disorders, by unknown mechanisms. We proposed that early overfeeding may alter DNA methylation patterns of hypothalamic promoter regions of genes critically involved in the lifelong regulation of food intake and body weight. We induced neonatal overfeeding by rearing Wistar rats in small litters (SL) and thereafter mapped the DNA methylation status of CpG dinucleotides of gene promoters from hypothalamic tissue, using bisulfite sequencing. Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e. obesity, hyperleptinaemia, hyperglycaemia, hyperinsulinaemia, and an increased insulin/glucose ratio. Accompanying, without group difference to controls, the promoter of the main orexigenic neurohormone, neuropeptide Y, was methylated at low levels (i.e. < 5%). In contrast, in SL rats the hypothalamic gene promoter of the main anorexigenic neurohormone, proopiomelanocortin (POMC), showed hypermethylation (P < 0.05) of CpG dinucleotides within the two Sp1-related binding sequences (Sp1, NF-kappaB) which are essential for the mediation of leptin and insulin effects on POMC expression. Consequently, POMC expression lacked upregulation, despite hyperleptinaemia and hyperinsulinaemia. Accordingly, the extent of DNA methylation within Sp1-related binding sequences was inversely correlated to the quotients of POMC expression/leptin (P = 0.02) and POMC expression/insulin (P < 0.001), indicating functionality of acquired epigenomic alterations. These data for the first time demonstrate a nutritionally acquired alteration of the methylation pattern and, consequently, the regulatory 'set point' of a gene promoter that is critical for body weight regulation. Our findings reveal overfeeding as an epigenetic risk factor of obesity programming and consecutive diabetic and cardiovascular disorders and diseases, in terms of the metabolic syndrome.

Visceral adipose tissue alteration of PI3KR1 expression is associated with gestational diabetes but not promoter DNA methylation.

Obesity and diabetes are at an epidemic rate, as well as growing incidences of gestational diabetes mellitus (GDM) which causes pregnancy risks, and harm in both maternal and child health. It remains unclear which molecular mechanisms are driving the functional differences between visceral and subcutaneous fat and how these types directly affect an individual's health outcome. Paired abdominal subcutaneous and omental visceral adipose tissue were collected from women with GDM (n = 20) and with normal glucose tolerance (NGT, n = 22) during planned caesarian section. Both groups had similar maternal age (average 32.5 years) and BMI at delivery (average 33.3 kg/m2). Adipose tissue mRNA expression analyses of insulin signalling genes: PI3KCA, PI3KR1, IRS1 and IRS2 showed significantly decreased PI3KR1 expression (-23%) in visceral fat in GDM with no association to promoter DNA methylation. Reduced visceral fat PI3KR1 expression appears to be a pathogenic factor in GDM but not through altered promoter methylation.

Hypothalamic insulin receptor expression and DNA promoter methylation are sex-specifically altered in adult offspring of high-fat diet (HFD)-overfed mother rats.

Maternal overnutrition around reproduction has been shown to increase the offspring's risk for "diabesity," mediated by altered hypothalamic neuropeptide expression. In this report, a possible contribution of altered hypothalamic sensing capacity for the peripheral satiety signals glucose, insulin and leptin will be addressed, taking into account potential sex differences. Specifically, we evaluated the effects a maternal high-fat diet (HFD) overfeeding has in rats pre- and during pregnancy and lactation on the hypothalamic gene expression patterns of insulin and leptin receptors (InsR, ObRb) and glucose transporter 3 (Glut3) as well as DNA methylation in the offspring at adult age (day 200 of life). Maternal HFD consumption resulted in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperinsulinemia, impaired glucose tolerance and increased homeostatic model assessment of insulin resistance. Interestingly, in turn, insulin resistance was more pronounced in male offspring, accompanied by decreased hypothalamic InsR-mRNA. This was linked with hypermethylation of an activating transcription factor binding site within the hypothalamic InsR promoter. The degree of methylation correlated inversely with respective InsR expression, while InsR expression itself was inversely related to phenotypic "diabesity." Expression of ObRb and Glut3 mRNA was not significantly changed. In conclusion, sex-specific alterations of hypothalamic InsR expression and DNA promoter methylation in adult offspring of HFD-overfed dams may lead to hypothalamic insulin resistance and "diabesity," with males predisposed to this epigenetic malprogramming.

Reduced Insulin Receptor Expression and Altered DNA Methylation in Fat Tissues and Blood of Women With GDM and Offspring.

Context: Altered expression of the insulin receptor (IR) in adipose tissue (AT) could contribute to gestational diabetes mellitus (GDM) etiopathogenesis. Transcriptional regulation via epigenetic mechanisms (e.g., DNA methylation) may play a critical role. However, the human IR promoter DNA methylation patterns and involvement in gene expression are unknown. Objective: We evaluated IR mRNA and protein expression accompanied by targeted DNA methylation analyses in AT and blood cells of women with GDM and their offspring. Design: Prospective observational study. Setting: Academic clinic and research unit. Participants: GDM-affected (n = 25) and matched control (n = 30) mother-child dyads. Main Outcome Measures: Maternal IR gene and protein expression in paired subcutaneous (SAT) and visceral adipose tissue samples (VAT). DNA methylation levels in IR promoter and intronic regions in maternal AT and blood cells of mother-offspring pairs. Results: In SAT and VAT, IR mRNA/protein expressions were significantly reduced in women with GDMs (P < 0.05). The decrease in VAT was more pronounced and independent of maternal body mass index. VAT IR protein levels were inversely associated with key maternal and neonatal anthropometric and metabolic parameters (P < 0.05). DNA methylation patterns were similar across tissues, with significant yet small size alterations between groups in mothers and offspring (P < 0.05). Conclusion: Decreased IR levels in AT may be a relevant pathogenic factor in GDM, affecting materno-fetal metabolism. Further investigation of causal factors for IR dysregulation is necessary, especially in VAT. Potential functional and/or clinical roles of altered DNA methylation also should be evaluated.

DNA methylation and expression of proopiomelanocortin (POMC) gene in the hypothalamus of three-week-old chickens show sex-specific differences.

Increased availability and improved sequence annotation of the chicken (Gallus gallus f. domestica) genome have sparked interest in the bird as a model system to investigate translational embryonic development and health/disease outcomes. However, the epigenetics of this bird genome remain unclear. The aim of this study was to determine the levels of gene expression and DNA methylation at the proopiomelanocortin (POMC) gene in the hypothalamus of 3-week-old chickens. POMC is a key player in the control of the stress response, food intake, and metabolism. DNA methylation of the promoter, CpG island, and gene body regions of POMC were measured. Our data illustrate the pattern, variability, and functionality of DNA methylation for POMC expression in the chicken. Our findings show correlation of methylation pattern and gene expression along with sex-specific differences in POMC. Overall, these novel data highlight the promising potential of the chicken as a model and also the need for breeders and researchers to consider sex ratios in their studies.

Alterations of adiponectin gene expression and DNA methylation in adipose tissues and blood cells are associated with gestational diabetes and neonatal outcome.

BACKGROUND: Adiponectin critically contributes to metabolic homeostasis, especially by insulin-sensitizing action. Gestational diabetes mellitus (GDM) is characterized by insulin resistance leading to materno-fetal hyperglycemia and detrimental birth outcomes. By investigating paired subcutaneous (SAT) and visceral adipose tissue (VAT) as well as blood (cell) samples of GDM-affected (n = 25) vs. matched control (n = 30) mother-child dyads of the prospective "EaCH" cohort study, we addressed whether alterations of adiponectin plasma, mRNA, and DNA methylation levels are associated with GDM and offspring characteristics. RESULTS: Hypoadiponectinemia was present in women with GDM, even after adjustment for body mass index (BMI). This was accompanied by significantly decreased mRNA levels in both SAT and VAT (P < 0.05), independent of BMI. Maternal plasma adiponectin showed inverse relations with glucose and homeostatic model assessment of insulin resistance (both P < 0.01). In parallel to reduced mRNA expression in GDM, significant (P < 0.05) yet small alterations in locus-specific DNA methylation were observed in maternal fat (~ 2%) and blood cells (~ 1%). While newborn adiponectin levels were similar between groups, DNA methylation in GDM offspring was variously altered (~ 1-4%; P < 0.05). CONCLUSIONS: Reduced adiponectin seems to be a pathogenic co-factor in GDM, even independent of BMI, affecting materno-fetal metabolism. While altered maternal DNA methylation patterns appear rather marginally involved, functional, diagnostic, and/or predictive implications of cord blood DNA methylation should be further evaluated.

Temporary prenatal hyperglycemia leads to postnatal neuronal 'glucose-resistance' in the chicken hypothalamus.

Prenatal exposures may have a distinct impact for long-term health. Exposure to maternal 'diabesity' during pregnancy increases offspring 'diabesity' risk, e.g. by malprogramming the central nervous regulation of body weight, food intake and metabolism. Critical mechanisms and concrete disrupting factors still remain unclear. Due to the independent development, from the mother, the chicken embryo could provide a valuable model to distinctively establish causal factors. Aim of this study was to determine effects of temporary prenatal hyperglycemia on postnatal hypothalamic neuronal glucose sensitivity in the chicken. To induce hyperglycemia in chicken embryos, 0.5 ml glucose solution (concentration 30 mmol/l) were daily administered via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. On day 21 of postnatal age, body weight, body fat content, blood glucose, neuroelectrophysiological glucose sensitivity as well as glucose transporter expression were determined in hypothalamic brain slices. No significant changes in morphometric and metabolic parameters were observed. However, strongly decreased neuronal glucose sensitivity and glucose transporter expression occurred, indicating prenatally acquired hypothalamic 'glucose-resistance'. In conclusion, temporary late prenatal hyperglycemia induces lasting changes in central glucose sensing. The prenatally glucose-treated chicken provides a valuable new model for investigating early central nervous origins of 'diabesity' and related disorders.

Acquired alterations of hypothalamic gene expression of insulin and leptin receptors and glucose transporters in prenatally high-glucose exposed three-week old chickens do not coincide with aberrant promoter DNA methylation.

BACKGROUND: Prenatal exposures may have a distinct impact for long-term health, one example being exposure to maternal 'diabesity' during pregnancy increasing offspring 'diabesity' risk. Malprogramming of the central nervous regulation of body weight, food intake and metabolism has been identified as a critical mechanism. While concrete disrupting factors still remain unclear, growing focus on acquired epigenomic alterations have been proposed. Due to the independent development from the mother, the chicken embryo provides a valuable model to distinctively establish causal factors and mechanisms. AIM: The aim of this study was to determine the effects of prenatal hyperglycemia on postnatal hypothalamic gene expression and promoter DNA methylation in the chicken. METHODS AND FINDINGS: To temporarily induce high-glucose exposure in chicken embryos, 0.5 ml glucose solution (30 mmol/l) were administered daily via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. At three weeks of postnatal age, body weight, total body fat, blood glucose, mRNA expression (INSR, LEPR, GLUT1, GLUT3) as well as corresponding promoter DNA methylation were determined in mediobasal hypothalamic brain slices (Nucleus infundibuli hypothalami). Although no significant changes in morphometric and metabolic parameters were detected, strongly decreased mRNA expression occurred in all candidate genes. Surprisingly, however, no relevant alterations were observed in respective promoter methylation. CONCLUSION: Prenatal hyperglycemia induces strong changes in later hypothalamic expression of INSR, LEPR, GLUT1, and GLUT3 mRNA. While the chicken provides an interesting approach for developmental malprogramming, the classical expression regulation via promoter methylation was not observed here. This may be due to alternative/interacting brain mechanisms or the thus far under-explored bird epigenome.

Increase of long-term 'diabesity' risk, hyperphagia, and altered hypothalamic neuropeptide expression in neonatally overnourished 'small-for-gestational-age' (SGA) rats.

BACKGROUND: Epidemiological data have shown long-term health adversity in low birth weight subjects, especially concerning the metabolic syndrome and 'diabesity' risk. Alterations in adult food intake have been suggested to be causally involved. Responsible mechanisms remain unclear. METHODS AND FINDINGS: By rearing in normal (NL) vs. small litters (SL), small-for-gestational-age (SGA) rats were neonatally exposed to either normal (SGA-in-NL) or over-feeding (SGA-in-SL), and followed up into late adult age as compared to normally reared appropriate-for-gestational-age control rats (AGA-in-NL). SGA-in-SL rats displayed rapid neonatal weight gain within one week after birth, while SGA-in-NL growth caught up only at juvenile age (day 60), as compared to AGA-in-NL controls. In adulthood, an increase in lipids, leptin, insulin, insulin/glucose-ratio (all p<0.05), and hyperphagia under normal chow as well as high-energy/high-fat diet, modelling modern 'westernized' lifestyle, were observed only in SGA-in-SL as compared to both SGA-in-NL and AGA-in-NL rats (p<0.05). Lasercapture microdissection (LMD)-based neuropeptide expression analyses in single neuron pools of the arcuate hypothalamic nucleus (ARC) revealed a significant shift towards down-regulation of the anorexigenic melanocortinergic system (proopiomelanocortin, Pomc) in SGA-in-SL rats (p<0.05). Neuropeptide expression within the orexigenic system (neuropeptide Y (Npy), agouti-related-peptide (Agrp) and galanin (Gal)) was not significantly altered. In essence, the 'orexigenic index', proposed here as a neuroendocrine 'net-indicator', was increased in SGA-in-SL regarding Npy/Pomc expression (p<0.01), correlated to food intake (p<0.05). CONCLUSION: Adult SGA rats developed increased 'diabesity' risk only if exposed to neonatal overfeeding. Hypothalamic malprogramming towards decreased anorexigenic activity was involved into the pathophysiology of this neonatally acquired adverse phenotype. Neonatal overfeeding appears to be a critical long-term risk factor in 'small-for-gestational-age babies'.

Birth weight and long-term overweight risk: systematic review and a meta-analysis including 643,902 persons from 66 studies and 26 countries globally.

BACKGROUND: Overweight is among the major challenging health risk factors. It has been claimed that birth weight, being a critical indicator of prenatal developmental conditions, is related to long-term overweight risk. In order to check this important assumption of developmental and preventive medicine, we performed a systematic review and comprehensive meta-analysis. METHODS AND FINDINGS: Relevant studies published up to January 2011 that investigated the relation between birth weight and later risk of overweight were identified through literature searches using MEDLINE and EMBASE. For meta-analysis, 66 studies from 26 countries and five continents were identified to be eligible, including 643,902 persons aged 1 to 75 years. We constructed random-effects and fixed-effects models, performed subgroup-analyses, influence-analyses, assessed heterogeneity and publication bias, performed meta-regression analysis as well as analysis of confounder adjusted data. Meta-regression revealed a linear positive relationship between birth weight and later overweight risk (p<0.001). Low birth weight (<2,500 g) was found to be followed by a decreased risk of overweight (odds ratio (OR) =0.67; 95% confidence interval (CI) 0.59-0.76). High birth weight (>4,000 g) was associated with increased risk of overweight (OR=1.66; 95% CI 1.55-1.77). Results did not change significantly by using normal birth weight (2,500-4,000 g) as reference category (OR=0.73, 95% CI 0.63-0.84, and OR=1.60, 95% CI 1.45-1.77, respectively). Subgroup- and influence-analyses revealed no indication for bias/confounding. Adjusted estimates indicate a doubling of long-term overweight risk in high as compared to normal birth weight subjects (OR=1.96, 95% CI 1.43-2.67). CONCLUSIONS: Findings demonstrate that low birth weight is followed by a decreased long-term risk of overweight, while high birth weight predisposes for later overweight. Preventing in-utero overnutrition, e.g., by avoiding maternal overnutrition, overweight and/or diabetes during pregnancy, might therefore be a promising strategy of genuine overweight prevention, globally.

Early postnatal life as a critical time window for determination of long-term metabolic health.

Epidemiological studies demonstrated a clear phenomenological association between low birth weight and increased cardiometabolic risk later in life, very similar to that in high birth weight subjects. Pre- and/or neonatal overfeeding appears to be an etiological clue. In animal studies, irrespective of birth weight neonatal over-nutrition leads to later overweight, impaired glucose tolerance and cardiometabolic alterations. Probably, perinatally acquired alterations of DNA methylation patterns of gene promoters of central nervous regulators of body weight and metabolism play a key role in mediating these relationships. In humans, the long-term impact of neonatal nutrition is conclusively demonstrated by studies on the consequences of breastfeeding vs. formula-feeding. Taken together, the quantity and quality of nutrition during neonatal life plays a critical role, beyond prenatal development, in the long-term programming of health and disease. This opens a variety of opportunities and challenges to primarily prevent chronic diseases, e.g. the metabolic syndrome.