Observational studies suggest a longer duration of breastfeeding to be associated dose dependently with a decrease in risk of overweight in later life. The authors performed a comprehensive meta-analysis of the existing studies on duration of breastfeeding and risk of overweight. Studies were included that reported the odds ratio and 95% confidence interval (or the data to calculate them) of overweight associated with breastfeeding and that reported the duration of breastfeeding and used exclusively formula-fed subjects as the referent. Seventeen studies met the inclusion criteria. By meta-regression, the duration of breastfeeding was inversely associated with the risk of overweight (regression coefficient=0.94, 95% confidence interval (CI): 0.89, 0.98). Categorical analysis confirmed this dose-response association (<1 month of breastfeeding: odds ratio (OR)=1.0, 95% CI: 0.65, 1.55; 1-3 months: OR=0.81, 95% CI: 0.74, 0.88; 4-6 months: OR=0.76, 95% CI: 0.67, 0.86; 7-9 months: OR=0.67, 95% CI: 0.55, 0.82; >9 months: OR=0.68, 95% CI: 0.50, 0.91). One month of breastfeeding was associated with a 4% decrease in risk (OR=0.96/month of breastfeeding, 95% CI: 0.94, 0.98). The definitions of overweight and age had no influence. These findings strongly support a dose-dependent association between longer duration of breastfeeding and decrease in risk of overweight.

The "small baby syndrome hypothesis" suggests that an inverse linear relation exists between birth weight and risk of type 2 diabetes. The authors conducted a meta-analysis to examine this association. They included studies that reported odds ratios and 95% confidence intervals (or data with which to calculate them) for the association of type 2 diabetes with birth weight. Fourteen studies involving a total of 132,180 persons were identified. Low birth weight (<2,500 g), as compared with a birth weight of >/=2,500 g, was associated with increased risk of type 2 diabetes (odds ratio (OR) = 1.32, 95% confidence interval (CI): 1.06, 1.64). High birth weight (>4,000 g), as compared with a birth weight of

BackgroundOverweight 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 FindingsRelevant 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).ConclusionsFindings 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.

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-κB) 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.

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The importance of the intrauterine and neonatal metabolic environment as possible teratogenic determinants of predispositions to diabetes, obesity and cardiovascular diseases is discussed. Epidemiological, clinical and experimental results suggest that gestational diabetes or even slightly impaired glucose tolerance during pregnancy are important risk factors for the development of an increased Type II- and even Type I diabetes susceptibility in the offspring. In addition, early prenatal undernutrition might also predispose to enhanced risk of Type II diabetes, whereas perinatal overnutrition seems to enhance predominantly Type I diabetes susceptibility. In this context, fetal and/or neonatal hyperinsulinism occurring during a critical period of brain development and leading to permanent malorganization of hypothalamic regulation centres for metabolism and hence to malprogramming of the hypothalamo-pancreatic system, is discussed as a possible reason for lifelong enhanced diabetes susceptibility. In view of epidemiological and experimental findings, an epigenetic maternofetal transmission of such acquired persistent modifications can run over several generations, mediated by gestational hyperglycaemia and fetal or neonatal hyperinsulinism. In conclusion, a partial prophylaxis of diabetes mellitus, obesity and cardiovascular diseases appears to be possible by prevention of gestational diabetes--even mild forms of impaired glucose tolerance during pregnancy--as well as early prenatal undernutrition and perinatal overnutrition.

Early postnatal overnutrition is a risk factor for obesity in juvenile and adult life. Underlying pathophysiological mechanisms are still unclear. Hypothalamic neuropeptides are decisively involved in the regulation of body weight and food intake. In this study, we investigated consequences of early postnatal overnutrition, as compared to normo-and undernutrition, on NPY within the arcuate nucleus and paraventricular nucleus (PVN). The normal litter size of Wistar rats was adjusted on the third day of life from 10 pups (normal litters, NL; normonutrition) to only three newborns (small litters, SL; overnutrition) or 18 pups per mother (large litters, LL; undernutrition). SL rats developed clear overweight until the day 21 of life (P<0.0001), as well as hyperleptinaemia (P<0.001), and hyperinsulinaemia (P<0.01). LL rats were underweight and had decreased leptin and insulin concentrations. Using radioimmunoassay, NPY contents were determined in hypothalamic micropunches, and immunocytochemistry for NPY was performed in serial hypothalamic sections on day 21 of life. While in the underweight, hypoleptinaemic, and hypoinsulinaemic LL rats increased concentrations of NPY in the arcuate nucleus and PVN were observed, no decrease in NPY content was found in the overweight, hyperleptinaemic, and hyperinsulinaemic SL rats. Moreover, the percentage of NPY-immunopositive neurones per total number of neurones was increased not only in the LL rats, but also in the SL rats. Since the NPY system is functionally mature already at this age, these findings might indicate an acquired resistance of the hypothalamic NPY system to increased levels of insulin and/or leptin in early postnatally overfed SL rats.

OBJECTIVE -Offspring born to women with pregnancies complicated by diabetes are at increased childhood risk of developing obesity and impaired glucose tolerance (IGT). In population-based studies, breast-feeding has been shown to be protective against obesity and diabetes later in life. To date, the role of breast-feeding on offspring of diabetic mothers (ODM) has not been investigated in this context. RESEARCH DESIGN AND METHODS-A total of 112 ODM (type 1 diabetes, n ϭ 83; gestational diabetes, n ϭ 29) were evaluated prospectively for impact of ingestion of either diabetic breast milk (DBM) or nondiabetic banked donor breast milk (BBM) during the early neonatal period (day 1-7 of life) on relative body weight and glucose tolerance at a mean age of 2 years.RESULTS -There was a positive correlation between the volume of DBM ingested and risk of overweight at 2 years of age (odds ratio [OR] 2.47, 95% CI 1.25-4.87). In contrast, the volume of BBM ingested was inversely correlated to body weight at follow-up (P ϭ 0.001). Risk of childhood IGT decreased by increasing amounts of BBM ingested neonatally (OR 0.19, 95% CI 0.05-0.70). Stepwise regression analysis showed volume of DBM to be the only significant predictor of relative body weight at 2 years of age (P ϭ 0.001).CONCLUSIONS -Early neonatal ingestion of breast milk from diabetic mothers may increase risk of becoming overweight and, consequently, developing IGT during childhood. Additional studies are needed to assess long-term consequences that might result from the type of neonatal nutrition in ODM. Diabetes Care 25:16 -22, 2002