Sarah McMullen

Childhood obesity and risk of the adult metabolic syndrome: a systematic review

Background:While many studies have demonstrated positive associations between childhood obesity and adult metabolic risk, important questions remain as to the nature of the relationship. In particular, it is unclear whether the associations reflect the tracking of body mass index (BMI) from childhood to adulthood or an independent level of risk. This systematic review aimed to investigate the relationship between childhood obesity and a range of metabolic risk factors during adult life.Objective:To perform an unbiased systematic review to investigate the association between childhood BMI and risk of developing components of metabolic disease in adulthood, and whether the associations observed are independent of adult BMI.Design:Electronic databases were searched from inception until July 2010 for studies investigating the association between childhood BMI and adult metabolic risk. Two investigators independently reviewed studies for eligibility according to the inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle–Ottawa Scale.Results:The search process identified 11 articles that fulfilled the inclusion and exclusion criteria. Although several identified weak positive associations between childhood BMI and adult total cholesterol, low-density lipo protein-cholesterol, triglyceride and insulin concentrations, these associations were ameliorated or inversed when adjusted for adult BMI or body fatness. Of the four papers that considered metabolic syndrome as an end point, none showed evidence of an independent association with childhood obesity.Conclusions:Little evidence was found to support the view that childhood obesity is an independent risk factor for adult blood lipid status, insulin levels, metabolic syndrome or type 2 diabetes. The majority of studies failed to adjust for adult BMI and therefore the associations observed may reflect the tracking of BMI across the lifespan. Interestingly, where adult BMI was adjusted for, the data showed a weak negative association between childhood BMI and metabolic variables, with those at the lower end of the BMI range in childhood, but obese during adulthood at particular risk.

Childhood obesity and adult cardiovascular disease risk: a systematic review

Background:Although the relationship between adult obesity and cardiovascular disease (CVD) has been shown, the relationship with childhood obesity remains unclear. Given the evidence of tracking of body mass index (BMI) from childhood to adulthood, this systematic review investigated the independent relationship between childhood BMI and adult CVD risk.Objective:To investigate the association between childhood BMI and adult CVD risk, and whether the associations observed are independent of adult BMI.Design:Electronic databases were searched from inception until July 2008 for studies investigating the association between childhood BMI and adult CVD risk. Two investigators independently reviewed studies for eligibility according to inclusion/exclusion criteria, extracted the data and assessed study quality using the Newcastle–Ottawa Scale.Results:Positive associations between childhood BMI and adult blood pressure or carotid intima-media thickness were generally attenuated once adjusted for adult BMI. Associations between childhood BMI and CVD morbidity/mortality had not been adjusted and do not provide evidence of an independent relationship. Negative associations between childhood BMI and blood pressure were observed in several adjusted data sets.Conclusions:Little evidence was found to suggest that childhood obesity is an independent risk factor for CVD risk. Instead, the data suggest that relationships observed are dependent on the tracking of BMI from childhood to adulthood. Importantly, evidence suggests that risk of raised blood pressure is highest in those who are at the lower end of the BMI scale in childhood and overweight in adulthood. The findings challenge the widely accepted view that the presence of childhood obesity is an independent risk factor for CVD and that this period should be a priority for public health intervention. Although interventions during childhood may be important in prevention of adult obesity, it is important to avoid the potential for negative consequences when the timing coincides with critical stages of neurological, behavioural and physical development.

Developmental Origins of Adult Disease

Variation in the quality or quantity of nutrients consumed during pregnancy can exert permanent and powerful effects upon the developing fetus. This programming of fetal development is emerging as a new risk factor for non-communicable diseases of adulthood, including coronary heart disease and the metabolic syndrome. Epidemiological studies show that indicators of nutritional deficit in pregnancy are associated with greater risk of diabetes and cardiovascular mortality. The study of programming in relation to disease processes has been advanced by the development of animal models, which have utilized both under- and overfeeding of specific nutrients in pregnancy. Studies of this nature support the nutritional programming hypothesis and provide tools with which to examine the mechanisms through which programming may occur. Studies of animals subject to undernutrition in utero generally exhibit changes in the structure of key organs, such as the kidney and pancreas. These effects are consistent with the concept that programming influences remodel the development of organs. The causal pathways which extend from tissue remodelling to disease processes are relatively well characterised. In contrast, the processes which drive disordered organ development are poorly understood. It is noteworthy that minor perturbation of maternal nutritional status can programme fetal development. It is suggested therefore that programming is a product of altered expression of key genes. This drives the tissue remodelling response and future disease risk.

Prenatal programming of angiotensin II type 2 receptor expression in the rat.

Exposure to undernutrition during fetal life has been proposed as an underlying cause of adult hypertension. Epidemiological studies demonstrating relationships between low birth weight and later CVD are supported by animal experiments indicating that manipulations of the maternal diet in pregnancy exert programming effects upon blood pressure control. Pregnant female Wistar rats were fed a control diet (n 13) or a low-protein diet (n 12) throughout pregnancy. At delivery all animals were fed the same standard laboratory chow diet. Analysis of nephron number in kidneys obtained from 4-week-old offspring showed that this was significantly (P<0.05) reduced in animals exposed to maternal protein restriction. At this age rats exposed to low-protein diets in utero had systolic blood pressures that were significantly greater than those of control animals (+23 mmHg, P<0.05). Administration of ascending doses of angiotensin II (1-40 ng/kg body weight intravenously) to 10-week-old anaesthetised female rats showed that the pressor response to the peptide was greater and more prolonged in animals exposed to low-protein diets in utero. Renal expression of mRNA for the angiotensin II type 1A receptor was similar in the two groups of rats, but low-protein-exposed animals had significantly lower renal expression of the type 2 receptor (P=0.023). These results suggest that maternal nutritional status programmes expression of the renal angiotensin II type 2 receptor. This may play a key role in the impairment of renal development and the elevation of blood pressure noted in rats exposed to intra-uterine protein restriction.

Sex-Specific Effects of Prenatal Low-Protein and Carbenoxolone Exposure on Renal Angiotensin Receptor Expression in Rats

Experimental models have shown the developing cardiovascular and renal systems to be sensitive to mild shifts in maternal nutrition, leading to altered function and risk of disease in adult life. The offspring of Wistar rats fed a low-protein diet during pregnancy exhibit a reduced nephron number and hypertension in postnatal life, providing a useful tool to examine the mechanistic basis of programming. Evidence indicates that upregulation of the renin-angiotensin system plays an important role, in particular through receptor-mediated changes in angiotensin II activity. However, although programmed hypertension has proven dependent on maternal glucocorticoids, there appear to be conflicting effects of prenatal low-protein and glucocorticoid exposure on postnatal angiotensin receptor expression. This study aimed to resolve this issue by comparing the effects of low-protein and glucocorticoid exposures on postnatal nephron number and angiotensin receptor expression. In addition, this study examined the modulation of prenatal treatment effects by postnatal inhibition of type 1 angiotensin receptor. The data demonstrates that whereas prenatal low-protein and glucocorticoid exposure have a similar effect in reducing nephron number, there are age- and gender-related differences in their effects on postnatal angiotensin receptor expression. In addition, this study provides novel evidence of a substantial upregulation of type 2 angiotensin receptor expression in low-protein- and glucocorticoid-exposed female offspring at 20 weeks of age, with implications for subsequent renal remodeling and function. Despite being targeted to the postnephrogenic period, inhibition of type 1 angiotensin receptor had an inhibitory effect on renal and somatic growth, additionally indicating its unsuitability during early life.

Animal models for the study of the developmental origins of health and disease.

Human epidemiological studies have indicated that the risk of developing non-communicable diseases in later life may be related to exposures during the developmental period. Developmental life is a vulnerable period of the lifespan during which adverse environmental factors have the potential to disturb the processes of cell proliferation and differentiation or to alter patterns of epigenetic remodelling. Animal models have been instrumental in demonstrating the biological plausibility of the associations observed in human populations, providing proof of principle to the theory of the developmental origins of health and disease (DOHaD). A variety of large- and small-animal models have made important contributions to the field, providing strong evidence of a causal relationship between early-life exposures and metabolic risk factors in later life. Studies of animal models are continuing to contribute to improving the understanding of the mechanisms of the developmental origins of disease. All models have their advantages and disadvantages, and the model that is most appropriate for any particular study is hypotheses dependent. The present review aims to briefly summarise the contributions that animal models have made to the DOHaD field, before reviewing the strengths and weaknesses of these animal models. It is proposed that the integration of evidence from a variety of different models is required for the advancement of understanding within the field.

Obesity induced by cafeteria feeding and pregnancy outcome in the rat

Obesity during pregnancy has major consequences for maternal and neonatal health, but the long-term effects on the offspring are less clear. It is not known whether the effects observed in animal models are a result of maternal obesity per se or of the high-fat diets used to induce obesity. This investigation aimed to develop a model for the evaluation of the independent effects of cafeteria feeding and maternal obesity, considering their impact on plasma volume expansion, circulating metabolites, and fetal and placental growth. Wistar rats were fed a control or cafeteria diet from weaning. After 8 weeks, all animals were mated and half of the animals within each group were crossed-over to the alternative diet. This generated four treatment groups, differing in their pre-gestational and gestational diets. Half of the animals were culled at day 5 of gestation and the remainder at day 20. Maternal body composition, blood volume and circulating glucose, TAG and cholesterol were determined. Cafeteria feeding was effective in inducing obesity, as demonstrated by increased fat depot weights and total body fat, without impacting upon reproductive success or circulating lipid concentrations. The study successfully demonstrated that there were differential effects of maternal body fatness and diet upon fetal and placental growth, with pre-gestational obesity leading to lower fetal weight at day 20 of gestation (P < 0.001). The model will provide a useful vehicle for the investigation of the complex interactions between dietary- and obesity-related factors during pregnancy in their effects on fetal development and postnatal metabolic function.

A common cause for a common phenotype: the gatekeeper hypothesis in fetal programming

Sub-optimal nutrition during pregnancy has been shown to have long-term effects on the health of offspring in both humans and animals. The most common outcomes of such programming are hypertension, obesity, dyslipidaemia and insulin resistance. This spectrum of disorders, collectively known as metabolic syndrome, appears to be the consequence of nutritional insult during early development, irrespective of the nutritional stress experienced. For example, diets low in protein diet, high in fat, or deficient in iron are all associated with programming of cardiovascular and metabolic disorders when fed during rat pregnancy. In this paper, we hypothesise that the nutritional stresses act on genes or gene pathways common to all of the insults. We have termed these genes and/or gene pathways the “gatekeepers” and hence developed the “gatekeeper hypothesis”. In this paper, we examine the background to the hypothesis and postulate some possible mechanisms or pathways that may constitute programming gatekeepers.

Cell cycle regulation and cytoskeletal remodelling are critical processes in the nutritional programming of embryonic development.

Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming. Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency. The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.

Glucose intolerance associated with early-life exposure to maternal cafeteria feeding is dependent upon post-weaning diet

In addition to being a risk factor for adverse outcomes of pregnancy, maternal obesity may play a role in determining the long-term disease patterns observed in the resulting offspring, with metabolic and dietary factors directly programming fetal development. The present study evaluated the potential for feeding rats an obesogenic cafeteria diet (O) pre-pregnancy, during pregnancy, during lactation and for the offspring post-weaning, to programme glucose tolerance. Early-life exposure to an O diet had no significant effect on offspring food intake. Early-life programming associated with O feeding to induce maternal obesity was associated with reduced adiposity in offspring weaned onto low-fat chow. Adult offspring exposed to an O diet in early life and weaned on a chow diet had low fasting glucose and insulin concentrations and appeared to be more sensitive to insulin during an intraperitoneal glucose tolerance test. When weaned on an O diet, male offspring were more prone to glucose intolerance than females. On the basis of the area under the glucose curve, maternal O feeding at any point from pre-mating to lactation was associated with impaired glucose tolerance. The mechanism for this was not identified, although increased hepatic expression of Akt2 may have indicated disturbance of insulin signalling pathways. The observations in the present study confirm that maternal overnutrition and obesity during pregnancy are risk factors for metabolic disturbance in the resulting offspring. Although the effects on glucose homeostasis were independent of offspring adiposity, the programming of a glucose-intolerant phenotype was only observed when offspring were weaned on a diet that induced greater fat deposition.