Maternal and paternal body mass index and offspring obesity: a systematic review.

BACKGROUND/AIMS: It has been hypothesized that the intrauterine environment is an independent factor in obesity development. If so, the maternal effect is likely to be a stronger influencing factor ('fetal overnutrition hypothesis'). We aimed to systematically evaluate the associations of offspring body mass index (BMI, or adiposity) with pre-pregnancy BMI (or adiposity) of the mother and the father. METHODS: The Medline, Embase and Cochrane Library databases were searched in March 2012. RESULTS: Seven cohort studies were eligible for the analysis. Among these, 2 groups of trials presented different data from the same parent-offspring cohorts (the Avon Longitudinal Study of Parents and Children, ALSPAC, and the Mater-University Study of Pregnancy, MUSP). In total, 3 large birth cohorts and 1 additional small study were identified. Three studies provided a direct comparison of parent-offspring associations, with a statistically stronger maternal influence found only in the MUSP cohort. Equivocal results were obtained from all studies describing the ALSPAC cohort. The parental effect (indirectly estimated based on the presented odds ratio) was similar in the Finnish cohort. In 1 additional small study, maternal BMI was found to be a strong predictor of childhood obesity. CONCLUSIONS: There is only limited evidence to support the 'fetal overnutrition hypothesis'.

Maternal overnutrition suppresses the phosphorylation of 5'-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep.

Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or approximately 55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139-141 days gestation (n = 14) and lambs at 30 days of postnatal age (n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPKalpha1 and AMPKalpha2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKalpha and phospho-AMPKalpha (P-AMPKalpha) was determined by Western blot analysis, and the proportion of the total AMPKalpha pool that was phosphorylated in each sample (%P-AMPKalpha) was determined. The ratio of AMPKalpha2 to AMPKalpha1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKalpha was lower in both fetuses and lambs in the Overfed group and %P-AMPKalpha in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth (r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPKalpha or P-AMPKalpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKalpha responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.

Maternal and postnatal overnutrition differentially impact appetite regulators and fuel metabolism.

Maternal obesity is increasing, and it is known that the intrauterine experience programs fetal and newborn metabolism. However, the relative contributions of pre- or postnatal factors are unknown. We hypothesized that maternal overnutrition caused by long-term maternal obesity would exert a stronger detrimental impact than postnatal overnutrition on offspring metabolic homeostasis, with additional postnatal overnutrition exaggerating these alterations. Female Sprague Dawley rats were exposed to chow or high-fat cafeteria diet for 5 wk before mating and throughout gestation and lactation. On postnatal d 1, litters were adjusted to three per litter to induce postnatal overnutrition (vs. 12 in control). Hypothalamic appetite regulators neuropeptide Y and proopiomelanocortin, glucose transporter 4, and lipid metabolic markers were measured. At postnatal d 20, male pups born of obese dams, or those overnourished postnatally, were 42% heavier than controls; combining both interventions led to 80% greater body weight. Maternal obesity increased pup adiposity and led to glucose intolerance in offspring; these were exaggerated by additional postnatal overnutrition during lactation. Maternal obesity was also linked to hyperlipidemia in offspring and reduced hypothalamic neuropeptide Y and increased proopiomelanocortin mRNA expression. Postnatal overnutrition of offspring from obese dams amplified these hypothalamic changes. Both maternal and postnatal overnutrition reduced muscle glucose transporter 4. Adipose carnitine palmitoyl-transferase-1 and adipose triglyceride lipase mRNA was up-regulated only by postnatal overnutrition. Maternal overnutrition appears to alter central appetite circuits and promotes early-onset obesity; postnatal overnutrition interacted to cause peripheral lipid and glucose metabolic disorders, supporting the critical message to reduce early-life adverse nutritional impact.

Fetal and neonatal pathways to obesity.

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

Substantial intergenerational increases in body mass index are not explained by the fetal overnutrition hypothesis: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: According to the fetal overnutrition hypothesis, intrauterine influences of maternal obesity increased lifelong obesity risk in the offspring. If the hypothesis is true, then the association between maternal body mass index (BMI; in kg/m(2)) and offspring BMI should be stronger than the association between paternal BMI and offspring BMI, because only the mother directly influences the fetal environment. OBJECTIVES: We prospectively examined intergenerational change in BMI and tested the fetal overnutrition hypothesis. DESIGN: Data on offspring weight were obtained from mothers. BMI was assessed from 2980 complete parent-offspring trios when the offspring were 3 to 18 y of age. The assessment of offspring BMI was repeated 21 y later at age 24-39 y. RESULTS: Adult BMI of the offspring was 1.21 units higher than the BMI of their parents at the same age, which indicates an increase in obesity levels across generations (P < 0.0001). Maternal BMI was more strongly associated with offspring birth weight than was paternal BMI (P = 0.0009). However, there were no such differences in parent-offspring associations for BMI at later developmental stages when offspring were aged 3-39 y (P > 0.35). The results did not materially change in a sensitivity analysis for 1% to 15% nonpaternity. CONCLUSIONS: Because offspring share all genes with their parents, the observed substantially higher adult BMI for offspring than for parents is likely explained by environmental influences. No support was found for any specific influence from fetal environment on this intergenerational increase in adult obesity. The findings were consistent with the fetal overnutrition hypothesis only in relation to birth weight.

Epidemiologic evidence for the fetal overnutrition hypothesis: findings from the mater-university study of pregnancy and its outcomes.

The fetal overnutrition hypothesis proposes that greater maternal adiposity results in increased obesity throughout life in the offspring. The authors examined the associations between parental prepregnancy body mass index (BMI; weight (kg)/height (m)(2)), based on height and weight reported by the mother at her first antenatal clinic visit, and offspring BMI (height and weight measured at age 14 years) in 3,340 parent-offspring trios from a birth cohort based in Brisbane, Australia (mothers were recruited in 1981-1984). The maternal-offspring BMI association was stronger than the paternal-offspring BMI association. In the fully adjusted model, the increase in standardized offspring BMI at age 14 for a one-standard-deviation (SD) increase in maternal BMI was 0.362 SD (95% confidence interval: 0.323, 0.402), and the corresponding result for a one-SD increase in paternal BMI was 0.239 SD (95% confidence interval: 0.197, 0.282). There was statistical support for a difference in the magnitude of the association between maternal-offspring BMI and paternal-offspring BMI in all confounder-adjusted models tested (all p's < 0.0001). In sensitivity analyses taking account of different plausible levels of nonpaternity (up to 15%), the greater maternal effect remained. These findings provide some support for the fetal overnutrition hypothesis.

Programming of the appetite-regulating neural network: a link between maternal overnutrition and the programming of obesity?

The concept of a functional foetal "appetite regulatory neural network" is a new and potentially critical one. There is a growing body of evidence showing that the nutritional environment to which the foetus is exposed during prenatal and perinatal development has long-term consequences for the function of the appetite-regulating neural network and therefore the way in which an individual regulates energy balance throughout later life. This is of particular importance in the context of evidence obtained from a wide range of epidemiological studies, which have shown that individuals exposed to an elevated nutrient supply before birth have an increased risk of becoming obese as children and adults. This review summarises the key pieces of experimental evidence, by our group and others, that have contributed to our current understanding of the programming of appetite, and highlights the important questions that are yet to be answered. It is clear that this area of research has the potential to generate, within the next few years, interventions that could begin to alleviate the adverse long-term consequences of being exposed to an elevated nutrient supply before birth.