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ABSTRACT: 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.
Best practice & research. Clinical endocrinology & metabolism 10/2012; 26(5):641-53. · 3.89 Impact Factor
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ABSTRACT: Abstract Aim: Increased neonatal weight gain has been suggested as risk factor for later overweight. Offspring of diabetic mothers (ODM) have a long-term increased overweight risk. However, the role of early postnatal weight gain for later overweight has not been addressed so far in ODM. We investigated whether increased weight gain during the first 4 months is related to later overweight in ODM. Methods: Determinants of childhood overweight and neonatal weight gain were analyzed in 152 ODM from the Kaulsdorf Cohort Study by MANOVA and regression analyses. Results: Independent of birth weight, weight gain during the first 4 months was positively related to childhood relative body weight (P=0.001). Each 100 g-increase in weight during this period increased overweight risk by 65% (95%CI: 10-247%). ODM with rapid early weight gain had a more than six-fold increased risk of later overweight (OR: 6.77; 95%CI: 1.36-33.6). Early neonatal intake of breast milk from metabolically healthy mothers protected from rapid early weight gain (P=0.03). Conclusions: Increased weight gain during the first 4 months of life is a strong, independent risk factor for childhood overweight in ODM. Preventing nutritionally-induced rapid early weight gain in ODM might be a promising strategy to lower their long-term overweight risk.
Journal of Perinatal Medicine 09/2012; 40(5):557-63. · 1.70 Impact Factor
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ABSTRACT: It is well established that under fasting conditions the expression of the orexigenic neuropeptide agouti-related peptide (AGRP) is up-regulated in the hypothalamic arcuate nucleus (ARC), while inconsistent data exist regarding fasting regulation of the anorexigenic neurohormone proopiomelanocortin (POMC). Inconsistencies might have methodological reasons, especially concerning neuromorphological and/or experimental (nutritional) specificity. We analyzed the expression of both neuropeptides in ARC neurons, using lasercapture microdissection (LMD) and real-time PCR in 12h fasted vs. fed Wistar rats as well as after a standardized glucose load, i.e., under clinically relevant conditions in terms of diagnosing glucose intolerance in the human. Under fasting conditions, clear up-regulation of AGRP was observed, with increasing magnitude in ARC single neurons (SNP) as compared to ARC cell layers (+125% vs. +23%, resp.), closely correlated to hypoinsulinemia and hypoleptinemia. Surprisingly, in the fasting state POMC was not found to be down-regulated, neither in ARC cell layers nor in ARC single neurons (+9% vs. +6%). However, glucose-refeeding under diagnostically relevant conditions led to strong neuronal up-regulation of POMC expression in ARC SNP (+128%), and AGRP down-regulation (-50%). In conclusion, experimentally, topographically, and analytically specific and standardized conditions confirmed AGRP in ARC neurons as being neuronally up- and down-regulated, resp., depending on the general nutritional state, while POMC was found to be (up-) regulated only after peripheral glucose load. Findings suggest that POMC in ARC neurons acts glucose-mediated as an "anti-orexigenic" neurohormone, specifically responding to hyperglycemia.
Neuroscience Letters 03/2012; 515(1):87-91. · 2.11 Impact Factor
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ABSTRACT: 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.
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).
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.
PLoS ONE 01/2012; 7(10):e47776. · 4.09 Impact Factor
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ABSTRACT: Leptin is involved in the regulation of food intake and energy expenditure and is therefore important for growth and brain development. Analytical methods used for leptin measurement in human milk differ widely in the literature and yield varying results.
To compare different preparation methods for the analysis of leptin in human milk and to investigate the leptin levels in colostrum and mature human milk from mothers of preterm or term infants.
Mothers delivering a preterm (n=37) or a term infant (n=40) were recruited for a prospective study and were ask to collect breast milk on the 3rd and 28th day of lactation. Leptin, protein and fat concentrations were analysed. Clinical data of mother and child were recorded prospectively.
Skim milk was most appropriate for leptin analysis. Human milk leptin concentrations did not differ between preterm and term human milk. In term milk, leptin concentration on day 28 was lower than on day 3 (p<0.05). Milk leptin levels on the 3rd and 28th day were positively correlated with mothers' body mass index, but not with fat content in milk.
Skim milk was the most stabile preparation for leptin analysis. Preterm and term human milk contain leptin in equal concentrations. Human milk leptin depends on mothers' body mass index.
Early human development 06/2011; 87(6):415-9. · 2.12 Impact Factor
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Diabetes care 03/2011; 34(3):779-81. · 8.09 Impact Factor
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Klinische Pädiatrie 03/2011; 223 Suppl 1:S1-9. · 1.77 Impact Factor
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ABSTRACT: According to the "small baby syndrome hypothesis," low birthweight and intrauterine growth restriction (IUGR) occurring in westernized countries mainly through altered placental flow, have been linked to increased metabolic syndrome risk in later life. Independency and causal mechanisms of this phenomenological association are a matter of controversy. By means of epidemiological as well as experimental methods, using meta-analyses and different rodent models of pre- and/or neonatal malnutrition and altered placental flow (uterine artery ligation; Lig), we systematically addressed the phenomenon. Our data and systematic literature analysis revealed that neither epidemiological nor experimental evidence seems to exist linking prenatal underfeeding, low birthweight, IUGR, or decreased placental flow in rats (Lig-model) as independent risk factors to increased metabolic syndrome risk in later life. Rather, pre- and/or neonatal overfeeding, elevated birthweight, rapid neonatal weight gain, and especially increased adiposity during critical periods of perinatal life may increase long-term risks. Perinatally acquired microstructural and epigenomic alterations in regulatory systems of metabolism and body weight seem to be critical, leading to a cardiometabolic risk disposition throughout life. While experimental data in Lig-offspring seem to be considerably biased, prenatal stress and postnatal overfeeding/rapid neonatal weight gain might be causally linked to a long-term deleterious outcome in growth restricted newborns. From a clinical point of view, prevention of causes of IUGR, as well as avoidance of perinatal overnourishment, might be prophylactic approaches to avoid perinatal programming of cardiometabolic risks.
Microcirculation (New York, N.Y.: 1994) 02/2011; 18(4):304-11. · 2.37 Impact Factor
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Andreas Plagemann,
Katharina Roepke, Thomas Harder,
Matthias Brunn,
Anja Harder,
Manon Wittrock-Staar,
Thomas Ziska,
Karen Schellong,
Elke Rodekamp,
Kerstin Melchior,
Joachim W Dudenhausen
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ABSTRACT: 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.
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.
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).
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.
Journal of Perinatal Medicine 05/2010; 38(4):393-400. · 1.70 Impact Factor
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New England Journal of Medicine 05/2010; 362(19):1840-1; author reply 1841-2. · 53.30 Impact Factor
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European journal of human genetics: EJHG 04/2010; 18(4):509. · 3.56 Impact Factor
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ABSTRACT: Neuroblastoma is the most common solid tumour in infancy but its aetiology is largely unknown. Prenatal factors might play a key role in its pathogenesis. Previous studies investigated whether birth weight is associated with risk of neuroblastoma, with conflictive results. We conducted a meta-analysis to quantitatively summarize the published evidence.
Results from 10 case-control studies and one cohort study (1966 to December 2008) were included, involving a total of 3004 children with neuroblastoma. We constructed random-effects and fixed-effects models, performed 'pool-first' analyses, assessed heterogeneity and publication bias and performed sensitivity and influence analyses.
High birth weight (>4000 g) was associated with increased risk of neuroblastoma [odds ratio (OR) 1.19; 95% confidence interval (CI) 1.04-1.36]. Results for high birth weight were highly homogenous (I(2) = 0%). Low birth weight (<2500 g) was also related to increased risk of neuroblastoma (OR 1.24; 95% CI 1.0-1.55), but results were more heterogeneous (I(2 )= 30%). No evidence for particularly influential studies or for publication bias was found. However, sensitivity analysis indicated the presence of bias in studies on the association with low birth weight. Above 2500 g each 1000-g increase in birth weight was associated with a 13% (95% CI 3-25) increase in risk of neuroblastoma.
This meta-analysis shows that high birth weight is highly reproducibly associated with increased risk of neuroblastoma. The association with low birth weight was found to be less robust and deserves further studies.
International Journal of Epidemiology 03/2010; 39(3):746-56. · 6.41 Impact Factor
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Diabetes care 11/2009; 32(11):e140. · 8.09 Impact Factor
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Andreas Plagemann, Thomas Harder,
Matthias Brunn,
Anja Harder,
Katharina Roepke,
Manon Wittrock-Staar,
Thomas Ziska,
Karen Schellong,
Elke Rodekamp,
Kerstin Melchior,
Joachim W Dudenhausen
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ABSTRACT: 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.
The Journal of Physiology 09/2009; 587(Pt 20):4963-76. · 4.72 Impact Factor
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JAMA The Journal of the American Medical Association 05/2009; 301(15):1540; author reply 1540-1. · 30.03 Impact Factor
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ABSTRACT: Previous studies suggest that birth weight and weight gain during the first year of life are related to later risk of type 1 diabetes. The authors performed a systematic review and meta-analysis on these associations. Twelve studies involving 2,398,150 persons of whom 7,491 had type 1 diabetes provided odds ratios and 95% confidence intervals of type 1 diabetes associated with birth weight. Four studies provided data on weight and/or weight gain during the first year of life. High birth weight (>4,000 g) was associated with increased risk of type 1 diabetes (odds ratio = 1.17, 95% confidence interval (CI): 1.09, 1.26). According to sensitivity analysis, this result was not influenced by particular study characteristics. The pooled confounder-adjusted estimate was 1.43 (95% CI: 1.11, 1.85). No heterogeneity was found (I(2) = 0%) and no publication bias. Low birth weight (<2,500 g) was associated with a nonsignificantly decreased risk of type 1 diabetes (odds ratio = 0.82, 95% CI: 0.54, 1.23). Each 1,000-g increase in birth weight was associated with a 7% increase in type 1 diabetes risk. In all studies, patients with type 1 diabetes showed increased weight gain during the first year of life, compared with controls. This meta-analysis indicates that high birth weight and increased early weight gain are risk factors for type 1 diabetes.
American journal of epidemiology 04/2009; 169(12):1428-36. · 5.59 Impact Factor
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The British journal of nutrition 09/2008; 101(2):151-2. · 3.45 Impact Factor
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06/2008; 105(19):362. · 2.92 Impact Factor
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ABSTRACT: The etiology of primary brain tumors is largely unknown. Since a peak of incidence occurs during childhood, factors operating very early in life might play a key role. Previous studies have suggested that high birth weight is associated with an increased brain tumor risk. The authors conducted a meta-analysis on the association between birth weight and risk of specific histologic types of primary brain tumors. They included published studies (1966-2007) that reported odds ratios and 95% confidence intervals for brain tumors associated with birth weight. The authors identified eight studies involving 1,748,964 children, of whom 4,162 suffered from brain tumors of three histologic types (astrocytoma, medulloblastoma, and ependymoma). For astrocytoma, high birth weight (>4,000 g) was associated with increased risk (odds ratio = 1.38, 95% confidence interval (CI): 1.07, 1.79), with each 1,000-g increase in birth weight being associated with a 19% (95% CI: 4, 36) increase in risk. For medulloblastoma, high birth weight was also positively associated with increased risk (odds ratio = 1.27, 95% CI: 1.02, 1.60). No association was found for ependymoma. These findings indicate that birth weight is related to the development of childhood brain tumors, with high birth weight being a risk factor for the two most common types of brain tumors.
American journal of epidemiology 06/2008; 168(4):366-73. · 5.59 Impact Factor
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ABSTRACT: Currently, epidemiological and experimental data indicate that exposures during prenatal and perinatal life may have lifelong consequences for the risk of developing obesity and metabolic and cardiovascular diseases. In this context, observations of the offspring of mothers with gestational diabetes as well as studies of children with low birth weight were most influential. This paper illustrates the current knowledge about perinatal programming of obesity and associated diseases and discusses possible etiopathogenic mechanisms, focussing on epidemiological and animal studies of the consequences of exposure to maternal diabetes and pre-/neonatal undernutrition. The resultant far-reaching potential for primary prevention of chronic diseases as well as the paradigmatic character of these hypotheses and observations for the general understanding of health and disease are highlighted.
Gynäkologisch-geburtshilfliche Rundschau 02/2008; 48(4):215-24.
