Birthweight and adult disease and the controversies

A large number of studies show that low birth weight is associated with cardiovascular disease and its risk factors including raised blood pressure, glucose intolerance and the metabolic syndrome. These findings have formed the basis for the ‘fetal origins hypothesis’. This suggests that the operation of adverse influences during intrauterine life leads to permanent alterations in fetal structure and physiology which predispose to adult disease. The process is known as developmental plasticity or programming and is strongly supported by studies in experimental animals. Ongoing research is providing important insights in to the underlying mechanisms. It is likely that adverse environmental factors during pregnancy are important, and that these include suboptimal nutrition of the mother. The long-term programming effects may be transduced by alterations in the set-point of key hormonal axes, especially the hypothalamic-pituitary-adrenal axis, and recent evidence suggests that epigenetic modification of gene expression may be a key factor. Importantly, this has the potential to produce transgenerational effects.The hypothesis has not remained unchallenged and a wide variety of criticisms have been put forward. These include accusations that the associations are weak and overestimated due to publication bias, that there are many inconsistencies between studies, that the associations are confounded by lifestyle factors, and that there has been inappropriate adjustment for adult size. Finally many studies report that the findings in singletons do not seem to be replicated in twins. While many of these issues have been resolved, some continue to form the basis of a lively dialogue and ongoing research. Nevertheless the research findings have important implications for clinical obstetric practice and maternal-fetal medicine

Fetal programming of the neuroendocrine response to stress: links between low birth weight and the metabolic syndrome

There is now substantial agreement that small size at birth is associated with increased rates of the metabolic syndrome (glucose intolerance, high blood pressure, and dyslipidaemia) and related pathologies including cardiovascular disease in adult life. Evidence is also emerging that suggests programming of hormonal systems in response to an adverse fetal environment may be one of the mechanisms underlying these long-term consequences of early life events. In particular, alterations in the neuroendocrine response to stress may play an important part. Recent research suggests that increased adrenocortical and sympathoadrenal responses are associated with small size at birth. Evidence from epidemiological studies shows that subtle alterations in these neuroendocrine systems appear to exert a powerful influence on the levels of cardiovascular risk factors including plasma glucose and lipid concentrations and blood pressure

Regulation of glucocorticoid receptor ? and ß isoforms and type I 11ß-hydroxysteroid dehydrogenase expression in human skeletal muscle cells: a key role in the pathogenesis of insulin resistance?

Glucocorticoid excess frequently results in obesity, insulin resistance, glucose intolerance, and hypertension and may be the product of altered glucocorticoid hormone action. Tissue sensitivity to glucocorticoid is regulated by the expression of glucocorticoid receptor isoforms (GR? and GRß) and 11ß-hydroxysteroid dehydrogenase type I (11ßHSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed the expression of GR?, GRß, and 11ßHSD1 and their hormonal regulation in skeletal myoblasts from men (n = 14) with contrasting levels of adiposity and insulin resistance. Immunohistochemical, Northern blot, and Western blot analysis indicated abundant expression of GR? and 11ßHSD1 under basal conditions. The apparent Km and maximum velocity for the conversion of cortisone to cortisol were 440 ± 14 nmol/L and 75 ± 7 pmol/mg protein·h and 437 ± 16 nmol/L and 33 ± 6 pmol/mg protein·h (mean ± SEM; n = 4) in the presence and absence of 20% serum. Incubation of myoblasts with increasing concentrations of glucocorticoid (50–1000 nmol/L) resulted in a dose-dependent decline in GR? expression and a dose-dependent increase in GRß expression. 11ßHSD1 activity was sensitively up-regulated by increasing concentrations of glucocorticoid (50–1000 nmol/L: P < 0.05). Abolition of these effects by the GR antagonist, RU38486, indicates that regulation of GR?, GRß, and 11ßHSD1 expression is mediated exclusively by the GR? ligand-binding variant. In contrast, 11ßHSD1 was down-regulated by insulin (20–100 mU/mL: P < 0.01) in the presence of 20% serum, whereas incubation with insulin under serum-free conditions resulted in a dose-dependent increase in 11ßHSD1 activity (P < 0.05). Incubation with insulin-like growth factor I resulted in a similar pattern of 11ßHSD1 activity. Although neither testosterone nor androstenedione (5–200 nmol/L) affected 11ßHSD1 activity, incubation of myoblasts with dehydroepiandrosterone (500 nmol/L) resulted in a decline in 11ßHSD1 activity (P < 0.05). These data suggest that glucocorticoid hormone action in skeletal muscle is determined principally by autoregulation of GR?, GRß, and 11ßHSD1 expression by the ligand-binding GR? isoform. Additionally, insulin and insulin-like growth factor I regulation of 11ßHSD1 may represent a novel mechanism that maintains insulin sensitivity in skeletal muscle tissue by diminishing glucocorticoid antagonism of insulin action

Maternal BMI, parity, and pregnancy weight gain influences on offspring adiposity in young adulthood

Context: The prevalence of obesity among women of childbearing age is increasing. Emerging evidence suggests that this has long-term adverse influences on offspring health. Objective: The aim was to examine whether maternal body composition and gestational weight gain have persisting effects on offspring adiposity in early adulthood. Design and Setting: The Motherwell birth cohort study was conducted in a general community in Scotland, United Kingdom. Participants: We studied 276 men and women whose mothers’ nutritional status had been characterized in pregnancy. Four-site skinfold thicknesses, waist circumference, and body mass index (BMI), were measured at age 30 yr; sex-adjusted percentage body fat and fat mass index were calculated. Main Outcome Measure: Indices of offspring adiposity at age 30 yr were measured. Results: Percentage body fat was greater in offspring of mothers with a higher BMI at the first antenatal visit (rising by 0.35%/kg/m2; P &lt; 0.001) and in offspring whose mothers were primiparous (difference, 1.5% in primiparous vs. multiparous; P = 0.03). Higher offspring percentage body fat was also independently associated with higher pregnancy weight gain (7.4%/kg/wk; P = 0.002). There were similar significant associations of increased maternal BMI, greater pregnancy weight gain, and parity with greater offspring waist circumference, BMI, and fat mass index. Conclusions: Adiposity in early adulthood is influenced by prenatal influences independently of current lifestyle factors. Maternal adiposity, greater gestational weight, and parity all impact on offspring adiposity. Strategies to reduce the impact of maternal obesity and greater pregnancy weight gain on offspring future health are required.<br/

Human skeletal muscle PPAR? expression correlates with fat metabolism gene expression but not BMI or insulin sensitivity

Peroxisome proliferator-activated receptor-? (PPAR?) is a key regulator of fatty acid oxidation in skeletal muscle, but few data exist from humans in vivo. To investigate whether insulin sensitivity in skeletal muscle and body mass index (BMI) were associated with skeletal muscle expression of PPAR? and with important genes regulating lipid metabolism in humans in vivo, we undertook hyperinsulinemic-euglycemic clamps and measured PPAR? mRNA levels and mRNA levels of lipid regulating PPAR? response genes in skeletal muscle biopsies. mRNA levels were measured in 16 men, using a novel highly sensitive and specific medium throughput quantitative competitive PCR that allows reproducible measurement of multiple candidate mRNAs simultaneously. mRNA levels of PPAR? were positively correlated with mRNA levels of CD36 (r = 0.77, P = 0.001), lipoprotein lipase (r = 0.54, P = 0.024), muscle-type carnitine palmitoyltransferase-I (r = 0.54, P = 0.024), uncoupling protein-2 (r = 0.63, P = 0.008), and uncoupling protein-3 (r = 0.53, P = 0.026), but not with measures of insulin sensitivity, BMI, or GLUT4, which plays an important role in insulin-mediated glucose uptake. Thus our data suggest that in humans skeletal muscle PPAR? expression and genes regulating lipid metabolism are tightly linked, but there was no association between both insulin sensitivity and BMI with PPAR? expression in skeletal muscle

The ratio of second to fourth digit lengths: a marker of impaired fetal growth?

Background: epidemiological studies showing that impaired fetal growth has long-term adverse health consequences have depended on crude measures of fetal growth such as overall weight or length. For future studies, there is a need to develop improved morphological markers of fetal growth which persist into adult life. Recent studies have suggested that the ratio of the length of the second finger relative to the length of the fourth finger (2D:4D ratio) is determined during fetal life and may be such a marker. Aims: to determine whether the 2D:4D ratio is associated with size at birth. Design: Cohort study. Subjects: 139 men and women born in Preston, Lancashire between 1935 and 1943. Outcome measures: Measurements of the 2D:4D ratio in palm prints. Results: men who had an above average placental weight and a shorter neonatal crown-heel length had higher 2D:4D ratios in adult life. Conclusions: these preliminary findings lend support to the hypothesis that the 2D:4D ratio is determined during fetal life

A common mitchondrial DNA variant is associated with thinness in mothers and their 20-yr-old offspring

A common mitochondrial (mt)DNA variant that is maternally inherited, the 16189 variant, is associated with type 2 diabetes and thinness at birth. To elucidate the association of the variant with thinness, we studied the 16189 variant in a well-characterized Australian cohort (n = 161) who were followed up from birth to age 20 yr. PCR analysis and mtDNA haplotyping was carried out on DNA from 161 offspring from consecutive, normal, singleton pregnancies followed from birth to age 20 yr. The 16189 mtDNA variant was present in 14 of the 161 20 yr olds (8.7%). Both the mothers with the 16189 variant and their 20-yr-old offspring were thinner than those without. Median (interquartile range) BMI was 21.9 kg/m2 (20.4 to 22.9) in mothers with the variant compared with 23.5 (21.4 to 26.6) in those without (P = 0.013) and 22.2 (21.1 to 23.8) in 20 yr olds with the variant compared with 22.7 (20.8 to 25.6) in those without (P = 0.019). The 16189 variant was also associated with a high placental weight and high placental-to-birth weight ratio (P = 0.051 and P = 0.0024, respectively). Insulin sensitivity was normal in 20 yr olds with the 16189 variant. This contrasts with 20 yr olds who did not have the variant but who had been thin or small at birth and who had normal BMI and normal placental-to-birth weight ratio, but were insulin resistant. This study suggests that the 16189 mtDNA variant is associated with maternally inherited thinness in young adults. This may be mediated by effects on mtDNA replication and, thence, placental function. Further research is required to confirm these hypotheses. <br/