Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease.

Proopiomelanocortin (POMC) is a key mediator of satiety. Epigenetic marks such as DNA methylation may modulate POMC expression and provide a biological link between early life exposures and later phenotype. Animal studies suggest epigenetic marks at POMC are influenced by maternal energy excess and restriction, prenatal stress and Triclosan exposure. Postnatal factors including energy excess, folate, vitamin A, conjugated linoleic acid and leptin may also affect POMC methylation. Recent human studies suggest POMC DNA methylation is influenced by maternal nutrition in early pregnancy and associated with childhood and adult obesity. Studies in children propose a link between POMC DNA methylation and elevated lipids and insulin, independent of body habitus. This review brings together evidence from animal and human studies and suggests that POMC is sensitive to nutritional programming and is associated with a wide range of weight-related and metabolic outcomes.

Using fNIRS to Study Working Memory of Infants in Rural Africa.

A pilot study was conducted to assess the feasibility of using fNIRS as an alternative to behavioral assessments of cognitive development with infants in rural Africa. We report preliminary results of a study looking at working memory in 12-16-month-olds and discuss the benefits and shortcomings for the potential future use of fNIRS to investigate the effects of nutritional insults and interventions in global health studies.

Optical imaging of brain activation in Gambian infants.

We used optical topography (OT) to investigate cognitive function in infants in rural Gambia. Images of changes in oxyhaemoglobin and deoxyhaemoglobin concentrations were reconstructed using a multispectral algorithm which uses the finite element method (FEM) to model the propagation of light through scattering tissue using the diffusion equation. High quality OT data enabled us to reconstruct images with robust representation of haemodynamic changes. OT is a feasible neuroimage technology for this resource-poor setting.

Early-life nutritional and environmental determinants of thymic size in infants born in rural Bangladesh.

AIM: The aim was to assess the impact of nutritional status and environmental exposures on infant thymic development in the rural Matlab region of Bangladesh. METHODS: In a cohort of N(max) 2094 infants born during a randomized study of combined interventions to improve maternal and infant health, thymic volume (thymic index, TI) was assessed by ultrasonography at birth and at 8, 24 and 52 weeks of age. Data on birth weight, infant anthropometry and feeding status were also collected. RESULTS: At all ages, TI was positively associated with infant weight and strongly associated with the month of measurement. Longer duration of exclusive breastfeeding resulted in a larger TI at 52 weeks. TI at birth and at 8 weeks correlated positively with birth weight, but by 24 and 52 weeks and when adjusted for infant weight this effect was no longer present. Thymic size was not affected by pre-natal maternal supplementation or by socioeconomic status but was correlated to arsenic exposure during pregnancy. CONCLUSION: In this population of rural Bangladeshi infants, thymic development is influenced by both nutritional and environmental exposures early in life. The long-term functional implications of these findings warrant further investigation.

Evolutionary origins of the obesity epidemic: natural selection of thrifty genes or genetic drift following predation release?

This article challenges Speakman's hypothesis that the modern genetic predisposition to obesity has arisen through random genetic drift in the two million years following predation release. We present evidence in support of the hypothesis that a mixture of famines and seasonal food shortages in the post-agricultural era have exerted natural selection in favour of fat storage; an effect most likely mediated through fertility, rather than viability, selection. We conclude that, far from being time to call off the search, recently developed genetic and bioinformatic methods will soon provide a definitive resolution to this long-standing 'thrifty gene' controversy.

Use of bioelectrical impedance analysis to assess body composition in rural Gambian children.

OBJECTIVE: To validate the Tanita BC-418MA Segmental Body Composition Analyser and four-site skinfold measurements for the prediction of total body water (TBW), percentage fat-free mass (%FFM) and percentage body fat (%BF) in a population of rural Gambian children. SUBJECTS/METHODS: One hundred and thirty-three healthy Gambian children (65 males and 68 females). FFM estimated by the inbuilt equations supplied with the Tanita system was assessed by comparison with deuterium oxide dilution and novel prediction equations were produced. Deuterium oxide dilution was also used to develop equations for %BF based on four-site skinfolds (biceps, triceps, subscapular and suprailiac). RESULTS: The inbuilt equations underestimated FFM compared to deuterium oxide dilution in all the sex and age categories (P<0.003), with greater accuracy in younger children and in males. The best prediction of %FFM was obtained from the variables height, weight, sex, impedance, age and four skinfold thickness measurements (adjusted R(2)=0.84, root mean square error (MSE)=2.07%). CONCLUSIONS: These data suggest that the Tanita instrument may be a reliable field assessment technique in African children, when using population and gender-specific equations to convert impedance measurements into estimates of FFM.

Ethnic differences in the association between body mass index and impedance index (Ht2/Z) in adult women and men using a leg-to-leg bioimpedance method.

BACKGROUND: Ethnic differences in the association between body mass index (BMI) and body fat suggest that body composition varies across ethnic groups. OBJECTIVE: To investigate the association between impedance index - a measure of tissue resistivity - and BMI in adults of different ethnic groups (Asian Indians, West Africans and White Caucasians) living in their native countries. METHODS: Male (n=329) and female (n=277) adult subjects (18-50 years) living in urban areas in the UK, The Gambia and Pakistan were studied. Body weight and height were measured and BMI calculated. The same leg-to-leg bioimpedance instrument was used in each study and impedance index (height(2) (cm)/impedance (Omega)) used as measure of tissue resistivity. RESULTS: In women, Asian Indians and West Africans had a significantly greater increase in impedance index per unit increase in BMI compared with white Caucasians (P<0.001). In men, Asian Indians had a significantly lower impedance index compared with West Africans and white Caucasians (P<0.001). CONCLUSION: Different ethnic groups may have different tissue resistivity for the same BMI indicative of systematic differences in body composition.

Cortical specialisation to social stimuli from the first days to the second year of life: A rural Gambian cohort.

Brain and nervous system development in human infants during the first 1000days (conception to two years of age) is critical, and compromised development during this time (such as from under nutrition or poverty) can have life-long effects on physical growth and cognitive function. Cortical mapping of cognitive function during infancy is poorly understood in resource-poor settings due to the lack of transportable and low-cost neuroimaging methods. Having established a signature cortical response to social versus non-social visual and auditory stimuli in infants from 4 to 6 months of age in the UK, here we apply this functional Near Infrared Spectroscopy (fNIRS) paradigm to investigate social responses in infants from the first postnatal days to the second year of life in two contrasting environments: rural Gambian and urban UK. Results reveal robust, localized, socially selective brain responses from 9 to 24 months of life to both the visual and auditory stimuli. In contrast at 0-2 months of age infants exhibit non-social auditory selectivity, an effect that persists until 4-8 months when we observe a transition to greater social stimulus selectivity. These findings reveal a robust developmental curve of cortical specialisation over the first two years of life.

Urbanization and obesity in The Gambia: a country in the early stages of the demographic transition.

OBJECTIVE: To investigate the distribution of overweight and obesity and its relationship with socio-economic and behavioural factors in a developing-country population undergoing rapid nutritional transition. DESIGN: Cross-sectional house-to-house survey in urban Gambia. SUBJECTS: Four groups of 50 subjects were sampled as follows: young men (YM, 14-25 years), young women (YW, 14-25 years), older men (OM, 35-50 years) and older women (OW, 35-50 years). MEASUREMENTS: Several socio-economic and behavioural factors were investigated. Composite indices for socio-economic status, education, healthy lifestyle and western influences were created. Body weight, height, waist and hip circumferences were measured and body mass index (BMI) was calculated. Body composition was assessed by leg-to-leg bioimpedance. Overweight was defined as BMI=25.0-29.9 kg/m(2) and obesity as BMI>or=30.0 kg/m(2). RESULTS: There were highly significant gender and age differences in overweight (YM=0%, YW=10%, OM=6% and OW=34%) and obesity (YM=0%, YW=4%, OM=6% and OW=50%). Only 16% of OW were neither overweight nor obese compared to 88% of OM. OW had a higher fat mass percent (38.4%) than other groups, while fat-free mass (kg) was significantly higher in males than females with YW having the lowest value. Young generations were more educated and more influenced by western ideals than OM and OW. Weight gain was not always associated with weight concern and many overweight/obese subjects did not perceive themselves as overweight. CONCLUSION: Social and behavioural changes are already creating a perceptible 'generational gap' among this population undergoing rapid transition. The improved education and current lean status of the younger adults offers opportunities for preventative interventions. These need to be specially targeted at women.

A pilot study on body image, attractiveness and body size in Gambians living in an urban community.

OBJECTIVE: We investigated the attitudinal and perceptual components of body image and its link with body mass index (BMI) in a sample of urban Gambians. We also looked at cross-cultural differences in body image and views on attractiveness between Gambians and Americans. METHODS: Four groups of 50 subjects were assessed: men 14- 25y (YM); women 14-25y (YW); men 35-50y (OM); women 35-50y (OW). Socio-economic status, education, healthy lifestyle and western influences were investigated. Height and weight were measured. Body dissatisfaction was assessed with the body dissatisfaction scale of the Eating Disorder Inventory. Perceptions of body image and attractiveness were assessed using the Body Image Assessment for Obesity (BIA-O) and Figure Rating Scale (FRS). RESULTS: Different generations of Gambians had very different perceptions and attitudes towards obesity. Current body size was realistically perceived and largely well tolerated. Older women had a higher body discrepancy (current minus ideal body size) than other groups (p<0.001). Regression analysis showed they were not worried about their body size until they were overweight (BMI=27.8 kg/m2), whilst OM, YM and YW started to be concerned at a BMI respectively of 22.9, 19.8 and 21.5 kg/m2. A cross-cultural comparison using published data on FRS showed that Gambians were more obesity tolerant than black and white Americans. DISCUSSION: The Gambia is a country in the early stage of demographic transitions but in urban areas there is an increase in obesity prevalence. Inherent tensions between the preservation of cultural values and traditional habits, and raising awareness of the risks of obesity, may limit health interventions to prevent weight gain.

The effects of maternal iron deficiency on infant fibroblast growth factor-23 and mineral metabolism.

Fibroblast growth factor-23 (FGF23), a phosphate(Phos)-regulating hormone, is abnormally elevated in hypophosphataemic syndromes and an elevated FGF23 is a predictor of mortality in kidney disease. Recent findings suggest iron deficiency as a potential mediator of FGF23 expression and murine studies have shown in utero effects of maternal iron deficiency on offspring FGF23 and phosphate metabolism. Our aim was to investigate the impact of maternal iron status on infant FGF23 and mineral metabolites over the first 2years of life. Infants born to mothers with normal (NIn=25,) and low (LIn=25) iron status during pregnancy, from a mother-infant trial (ISRCTN49285450) in rural Gambia, West Africa, had blood and plasma samples analysed at 12, 24, 52, 78 and 104weeks (wk) of age. Circulating intact-FGF23 (I-FGF23), Phos, total alkaline phosphatase (TALP) and haemoglobin (Hb) decreased and estimated glomerular filtration rate increased over time [all P≤0.0001)]. C-terminal-FGF23 (C-FGF23) and TALP were significantly higher in LI compared with NI, from 52wk for C-FGF23 [Beta coefficient (SE) 18.1 (0.04) %, P=0.04] and from 24wk for TALP [44.7 (29.6) U/L, P=0.04]. Infant Hb was the strongest negative predictor of C-FGF23 concentration [-21% (4%) RU/mL, P≤0.0001], Phos was the strongest positive predictor of I-FGF23 [32.0(3.9) pg/mL, P≤0.0001] and I-FGF23 did not predict C-FGF23 over time [-0.5% (0.5%), P=0.3]. In conclusion, this study suggests that poor maternal iron status is associated with a higher infant C-FGF23 and TALP but similar I-FGF23 concentrations in infants and young children. These findings further highlight the likely public health importance of preventing iron deficiency during pregnancy. Whether or not children who are born to iron deficient mothers have persistently high concentrations of these metabolites and are more likely to be at risk of impaired bone development and pre-disposed to rickets requires further research.

Anemia Offers Stronger Protection Than Sickle Cell Trait Against the Erythrocytic Stage of Falciparum Malaria and This Protection Is Reversed by Iron Supplementation.

BACKGROUND: Iron deficiency causes long-term adverse consequences for children and is the most common nutritional deficiency worldwide. Observational studies suggest that iron deficiency anemia protects against Plasmodium falciparum malaria and several intervention trials have indicated that iron supplementation increases malaria risk through unknown mechanism(s). This poses a major challenge for health policy. We investigated how anemia inhibits blood stage malaria infection and how iron supplementation abrogates this protection. METHODS: This observational cohort study occurred in a malaria-endemic region where sickle-cell trait is also common. We studied fresh RBCs from anemic children (135 children; age 6-24months; hemoglobin <11g/dl) participating in an iron supplementation trial (ISRCTN registry, number ISRCTN07210906) in which they received iron (12mg/day) as part of a micronutrient powder for 84days. Children donated RBCs at baseline, Day 49, and Day 84 for use in flow cytometry-based in vitro growth and invasion assays with P. falciparum laboratory and field strains. In vitro parasite growth in subject RBCs was the primary endpoint. FINDINGS: Anemia substantially reduced the invasion and growth of both laboratory and field strains of P. falciparum in vitro (~10% growth reduction per standard deviation shift in hemoglobin). The population level impact against erythrocytic stage malaria was 15.9% from anemia compared to 3.5% for sickle-cell trait. Parasite growth was 2.4 fold higher after 49days of iron supplementation relative to baseline (p<0.001), paralleling increases in erythropoiesis. INTERPRETATION: These results confirm and quantify a plausible mechanism by which anemia protects African children against falciparum malaria, an effect that is substantially greater than the protection offered by sickle-cell trait. Iron supplementation completely reversed the observed protection and hence should be accompanied by malaria prophylaxis. Lower hemoglobin levels typically seen in populations of African descent may reflect past genetic selection by malaria. FUNDING: National Institute of Child Health and Development, Bill and Melinda Gates Foundation, UK Medical Research Council (MRC) and Department for International Development (DFID) under the MRC/DFID Concordat.

Childhood pneumonia and crowding, bed-sharing and nutrition: a case-control study from The Gambia.

SETTING: Greater Banjul and Upper River Regions, The Gambia. OBJECTIVE: To investigate tractable social, environmental and nutritional risk factors for childhood pneumonia. DESIGN: A case-control study examining the association of crowding, household air pollution (HAP) and nutritional factors with pneumonia was undertaken in children aged 2-59 months: 458 children with severe pneumonia, defined according to the modified WHO criteria, were compared with 322 children with non-severe pneumonia, and these groups were compared to 801 neighbourhood controls. Controls were matched by age, sex, area and season. RESULTS: Strong evidence was found of an association between bed-sharing with someone with a cough and severe pneumonia (adjusted OR [aOR] 5.1, 95%CI 3.2-8.2, P < 0.001) and non-severe pneumonia (aOR 7.3, 95%CI 4.1-13.1, P < 0.001), with 18% of severe cases estimated to be attributable to this risk factor. Malnutrition and pneumonia had clear evidence of association, which was strongest between severe malnutrition and severe pneumonia (aOR 8.7, 95%CI 4.2-17.8, P < 0.001). No association was found between pneumonia and individual carbon monoxide exposure as a measure of HAP. CONCLUSION: Bed-sharing with someone with a cough is an important risk factor for severe pneumonia, and potentially tractable to intervention, while malnutrition remains an important tractable determinant.

Beyond body mass index.

Body mass index (BMI) is the cornerstone of the current classification system for obesity and its advantages are widely exploited across disciplines ranging from international surveillance to individual patient assessment. However, like all anthropometric measurements, it is only a surrogate measure of body fatness. Obesity is defined as an excess accumulation of body fat, and it is the amount of this excess fat that correlates with ill-health. We propose therefore that much greater attention should be paid to the development of databases and standards based on the direct measurement of body fat in populations, rather than on surrogate measures. In support of this argument we illustrate a wide range of conditions in which surrogate anthropometric measures (especially BMI) provide misleading information about body fat content. These include: infancy and childhood; ageing; racial differences; athletes; military and civil forces personnel; weight loss with and without exercise; physical training; and special clinical circumstances. We argue that BMI continues to serve well for many purposes, but that the time is now right to initiate a gradual evolution beyond BMI towards standards based on actual measurements of body fat mass.

Fast foods, energy density and obesity: a possible mechanistic link.

Fast foods are frequently linked to the epidemic of obesity, but there has been very little scientific appraisal of a possible causal role. Here we review a series of studies demonstrating that the energy density of foods is a key determinant of energy intake. These studies show that humans have a weak innate ability to recognise foods with a high energy density and to appropriately down-regulate the bulk of food eaten in order to maintain energy balance. This induces so called 'passive over-consumption'. Composition data from leading fast food company websites are then used to illustrate that most fast foods have an extremely high energy density. At some typical outlets the average energy density of the entire menus is approximately 1100 kJ 100 g(-1). This is 65% higher than the average British diet (approximately 670 kJ 100 g(-1)) and more than twice the energy density of recommended healthy diets (approximately 525 kJ 100 g(-1)). It is 145% higher than traditional African diets (approximately 450 kJ 100 g(-1)) that probably represent the levels against which human weight regulatory mechanisms have evolved. We conclude that the high energy densities of many fast foods challenge human appetite control systems with conditions for which they were never designed. Among regular consumers they are likely to result in the accidental consumption of excess energy and hence to promote weight gain and obesity.

Manipulation of dietary fat and energy density and subsequent effects on substrate flux and food intake.

Dietary fat has traditionally been viewed as being particularly lipogenic because of its high energy density, metabolic efficiency, and palatability. If these attributes of dietary fat were counteracted by a high satiating power, or if the body made autoregulatory adjustments in fat utilization in response to high fat intakes, energy balance would not necessarily be displaced. However, recent experiments have shown that neither of these hold true: human and animal trials consistently show that covert manipulation of dietary fat can induce hyperphagia, which can readily lead to spontaneous fat storage of 50-100 g/d in humans. Experiments with isoenergy-dense diets show that this high-fat hyperphagia (with diets of similar palatability) is caused by the high energy density of fatty foods rather than by their other attributes. Hyperphagia has therefore been termed passive overconsumption because it occurs unintentionally and without the consumption of excess bulk. When palatability is allowed to vary normally, high-fat foods may additionally induce active overconsumption in response to the enhanced organoleptic qualities of fats. In terms of substrate flux, fat is at the bottom of an oxidative hierarchy that determines fuel selection. Whereas alcohol, carbohydrates, and protein elicit powerful autoregulatory adjustments in their oxidation in response to changes in intake, fat fails to elicit such a response and fat balance is therefore easily displaced. These physiologic observations provide mechanistic support for secular-trend, cross-cultural, and cross-sectional epidemiologic studies investigating the role of energy-dense diets in the etiology of obesity.

Sugar and body weight regulation.

The need to understand reasons for the high prevalence of obesity in developed countries has led to examination of dietary habits that may contribute to obesity. We consider whether consumption of high amounts of sugars presents a public health problem by contributing to the development of obesity. Metabolic studies show that diets high in fat are more likely to result in body fat accumulation than are diets high in carbohydrate. There is no indication that simple sugars differ from complex sugars in this regard. Epidemiologic data show a clear inverse relation between intake of sugar and fat. Further, although high intake of dietary fat is positively associated with indexes of obesity, high intake of sugar is negatively associated with indexes of obesity. There is ample reason to associate high-fat diets with obesity but, at present, no reason to associate high-sugar diets with obesity.

Energy adaptations in human pregnancy: limits and long-term consequences.

The very slow rate of human fetal growth generates a lower incremental energy stress than in any other mammalian species. This creates a situation in which adaptive changes in metabolic rate and in the amount of additional maternal fat stored during gestation can make a profound difference to the overall energy needs of pregnancy. Comparisons of women in affluent and poor countries have recorded mean population energy needs ranging from as high as 520 MJ to as low as -30 MJ per pregnancy. These energy costs are closely correlated with maternal energy status when analyzed both between and within populations, suggesting that they represent functional adaptations that have been selected for their role in protecting fetal growth. Although this metabolic plasticity represents a powerful mechanism for sustaining pregnancy under very marginal nutritional conditions, it must not be construed as a perfect mechanism that obviates the need for optimal nutritional care of pregnant women. The fact that fetal weight represents up to 60% of total pregnancy weight gain in many pregnancies in poor societies (compared with a well-nourished norm of 25%) indicates that the fetus is developing under suboptimal nutritional and physiologic conditions. It has long been recognized that this has immediate consequences for the offspring in terms of increased perinatal mortality. The more recent appreciation that impaired fetal growth may also precipitate longer-term defects in terms of adult susceptibility to noncommunicable and infectious diseases reinforces the view that pregnancy may be the most sensitive period of the life cycle in which nutritional intervention may reap the greatest benefits.

Fat and energy needs of children in developing countries.

The fat requirements of children can be judged according to 4 criteria: 1) the possible obligate needs of fat as a metabolic fuel, 2) the provision of a sufficiently energy-dense diet to meet energy needs, 3) the adequate supply of essential fatty acids, and 4) the supply of sufficient fat to allow adequate absorption of fat-soluble vitamins. In these respects the fat requirements of children in developing countries are probably similar to those of children in affluent nations except for the additional needs imposed by environmental stresses, particularly recurrent infections. In many developing countries, the low energy density of weaning foods appears to be a major contributor to growth faltering and ultimate malnutrition. Evidence from doubly labeled water studies suggests that these diets are adequate when children are healthy but fail to support rapid catch-up growth after diarrhea and other infections. The issues in determining and meeting the fat needs of children in developing countries are illustrated with use of detailed comparative dietary data from a rural community in The Gambia and from Cambridge, United Kingdom. The outstanding feature of the Gambian data is the great importance of breast milk as a source of fat and essential fatty acids up until the end of the second year of life. Weaning foods and adult foods contain low amounts of fat, which causes a sharp transition from adequate fat intakes to probable inadequate fat intakes when children are weaned from the breast. The effects of such low fat intakes, particularly in terms of immune function, require investigation.

Covert manipulation of the ratio of dietary fat to carbohydrate and energy density: effect on food intake and energy balance in free-living men eating ad libitum.

We previously increased the energy density and fat content across three diets (factorial design), which led to a marked increase in energy intake in six men over 7 d while continuously resident in a whole-body indirect calorimeter. In the present study we fed the same diets to seven men who were resident in, but not confined to, a metabolic suite for 2 wk/diet. This added a component of increased physical activity. The fat, carbohydrate, and protein contents, respectively, of each diet (as a percent of energy) were as follows: low-fat (LF), 20:67:13; medium-fat (MF), 40:47:13; and high-fat (HF), 60:27:13. Energy density increased as the percent of fat in the diet increased. Energy intakes from the LF, MF, and HF diets (9.11, 10.32, and 12.78 MJ/d, respectively) were almost identical to those in our calorimeter study (9.02, 10.2, and 12.35 MJ/d, respectively) whereas energy expenditures (estimated by the doubly labeled water method) were 12.45, 12.10, and 11.97 MJ/d on the LF, MF and HF diets, respectively, compared with 9.48, 9.53, and 9.78 MJ/d, respectively, in our calorimeter study. This finding suggests that diet composition and energy expenditure combined influence energy balance in humans.