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.

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.

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.

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.

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.

Elevated hepcidin at HIV diagnosis is associated with incident tuberculosis in a retrospective cohort study.

Hepcidin inhibits ferroportin-mediated iron efflux, leading to intracellular macrophage iron retention, possibly favoring Mycobacterium tuberculosis iron acquisition and tuberculosis (TB) pathogenesis. Plasma hepcidin was measured at human immunodeficiency virus (HIV) diagnosis in a retrospective HIV-prevalent, antiretroviral-naïve African cohort to investigate the association with incident pulmonary and/or extra-pulmonary TB. One hundred ninety-six participants were followed between 5 August 1992 and 1 June 2002, with 32 incident TB cases identified. Greater hepcidin was associated with significantly increased likelihood of TB after a median time to TB of 6 months. Elucidation of iron-related causal mechanisms and time-sensitive biomarkers that identify individual changes in TB risk are needed.

Functional near infrared spectroscopy (fNIRS) to assess cognitive function in infants in rural Africa.

Cortical mapping of cognitive function during infancy is poorly understood in low-income countries due to the lack of transportable neuroimaging methods. We have successfully piloted functional near infrared spectroscopy (fNIRS) as a neuroimaging tool in rural Gambia. Four-to-eight month old infants watched videos of Gambian adults perform social movements, while haemodynamic responses were recorded using fNIRS. We found distinct regions of the posterior superior temporal and inferior frontal cortex that evidenced either visual-social activation or vocally selective activation (vocal > non-vocal). The patterns of selective cortical activation in Gambian infants replicated those observed within similar aged infants in the UK. These are the first reported data on the measurement of localized functional brain activity in young infants in Africa and demonstrate the potential that fNIRS offers for field-based neuroimaging research of cognitive function in resource-poor rural communities.

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.

Skeletal muscle mass reference curves for children and adolescents.

BACKGROUND: Skeletal muscle is key to motor development and represents a major metabolic end organ that aids glycaemic regulation. OBJECTIVES: To create gender-specific reference curves for fat-free mass (FFM) and appendicular (limb) skeletal muscle mass (SMMa) in children and adolescents. To examine the muscle-to-fat ratio in relation to body mass index (BMI) for age and gender. METHODS: Body composition was measured by segmental bioelectrical impedance (BIA, Tanita BC418) in 1985 Caucasian children aged 5-18.8 years. Skeletal muscle mass data from the four limbs were used to derive smoothed centile curves and the muscle-to-fat ratio. RESULTS: The centile curves illustrate the developmental patterns of %FFM and SMMa. While the %FFM curves differ markedly between boys and girls, the SMMa (kg), %SMMa and %SMMa/FFM show some similarities in shape and variance, together with some gender-specific characteristics. Existing BMI curves do not reveal these gender differences. Muscle-to-fat ratio showed a very wide range with means differing between boys and girls and across fifths of BMI z-score. CONCLUSIONS: BIA assessment of %FFM and SMMa represents a significant advance in nutritional assessment since these body composition components are associated with metabolic health. Muscle-to-fat ratio has the potential to provide a better index of future metabolic health.

Evidence for metabolic endotoxemia in obese and diabetic Gambian women.

OBJECTIVE: Emerging evidence from animal models suggests that translocation of bacterial debris across a leaky gut may trigger low-grade inflammation, which in turn drives insulin resistance. The current study set out to investigate this phenomenon, termed 'metabolic endotoxemia', in Gambian women. METHODS: In a cross-sectional study, we recruited 93 age-matched middle-aged urban Gambian women into three groups: lean (body mass index (BMI): 18.5-22.9 kg m(-2)), obese non-diabetic (BMI: 30.0 kg m(-2)) and obese diabetic (BMI: 30.0 kg m(-2) and attending a diabetic clinic). We measured serum bacterial lipopolysaccharide (LPS) and endotoxin-core IgM and IgG antibodies (EndoCAb) as measures of endotoxin exposure and interleukin-6 (IL-6) as a marker of inflammation. RESULTS: Inflammation (IL-6) was independently and positively associated with both obesity and diabetes (F=12.7, P<0.001). LPS levels were highest in the obese-diabetic group compared with the other two groups (F=4.4, P<0.02). IgM EndoCAb (but not total IgM) was highly significantly reduced in the obese (55% of lean value) and obese diabetic women (30% of lean; F=21.7, P<0.0001 for trend) compared with lean women. CONCLUSION: These data support the hypothesis that gut-derived inflammatory products are associated with obesity and diabetes. Confirmation of these findings and elucidation of the role of the microbiota, gut damage and the pathways for translocation of bacterial debris, could open new avenues for prevention and treatment of type 2 diabetes.

Disproportionate early fetal growth predicts postnatal thymic size in humans.

Prenatal events can affect neonatal thymus size and adult immune function. The causal insults are unknown, although fetal nutrient restriction is suspected. We used ultrasound at three time points during pregnancy (14, 19 and 30 weeks) to measure the growth of six fetal dimensions in rural Bangladeshi women participating in the Maternal and Infant Nutrition Interventions, Matlab study. Postnatal ultrasound was used to calculate thymic index (TI) at birth, 2, 6 and 12 m. Of the 3267 women recruited, 2861 participated by providing data at least at one fetal biometry and one TI time point. Patterns of fetal growth were summarized using principal components calculated from fetal dimension z-scores. Random effects regression, controlling for infant size and season of measurement were used to relate these patterns to TI. We found that smaller leg length relative to head circumference, characteristic of head-sparing growth restriction, was predictive of lower TI. This association was significant at all time points but strongest in earlier pregnancy. Each standard deviation increase in leg-head proportion was associated with an increase in TI of ∼5%. We conclude that growth patterns typical of poor fetal nutrition are associated with poor thymic development. The greater strength of this association in the first trimester is consistent with a period of vulnerability during the early ontogeny of the thymus and suggests that preventative intervention would need to be given in early pregnancy.

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.

Haematological effects of multimicronutrient supplementation in non-pregnant Gambian women.

BACKGROUND/OBJECTIVES: The use of multimicronutrient (MMN) supplementation to reduce the burden of anaemia in non-pregnant women of reproductive age has been little studied, particularly in Africa. The objective of the study was to evaluate haematological outcomes in non-pregnant, rural Gambian women of reproductive age, receiving daily MMN supplements for 1 year. SUBJECTS/METHODS: The study in 293 women aged from 17 to 45 years old was nested within a double-blind, randomized placebo-controlled trial of periconceptional MMN supplementation [ISRCTN 13687662], using the United Nations International Multiple Micronutrient Preparation (UNIMMAP), received daily for 1 year or until conception. Red cell parameters and free erythrocyte protoporphyrin concentration were measured at baseline and after 12 months in those women who did not conceive. RESULTS: Anaemic women (haemoglobin concentration <12 g per 100 ml) were more likely to be older and in economic deficit at baseline. Mean change in haemoglobin concentration was +0.6+/-1.4 g per 100 ml in the intervention arm and -0.2+/-1.2 g per 100 ml in the placebo arm (P<0.001). After supplementation with MMN, the relative risk of anaemia (<12 g per 100 ml) was 0.59 (0.46, 0.76) compared with placebo. Anaemic subjects at baseline showed an increase in mean haemoglobin from 10.6 g per 100 ml to 11.8 g/l (P<0.001) after MMN supplementation. CONCLUSIONS: MMN supplementation should be considered as a strategy for improving the micronutrient and haematological status of non-pregnant women of reproductive age.

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.

Frequent feeding delays the gastric emptying of a subsequent meal.

To assess the suitability of the 13C-octanoic acid breath test for measuring gastric emptying in circumstances other than the post-absorptive state, a preliminary study was performed where 6 hourly spaced isoenergetic meals preceded the determination of gastric emptying of a subsequent 2 MJ meal. Emptying was measured in three individuals on four separate occasions, with a reproducibility of 8%. A crossover study was then conducted to test the hypothesis that meal frequency can modulate the gastric emptying of a subsequent meal, with the potential to influence appetite regulation. Sixteen subjects were fed to energy balance, receiving food either as 2 isoenergetic meals 3 h apart or 6 isoenergetic meals fed hourly. Gastric emptying of a subsequent 2 MJ meal was investigated. Visual analogue scales were used throughout to assess appetite. The maximum rate of gastric emptying was unchanged but the onset of emptying was delayed by the more frequent feeding pattern. There was no significant difference in subjective appetite before or after the test meal. In conclusion, short-term increases in feeding frequency delayed the gastric emptying of a subsequent meal, but significant effects on post-meal appetite could not be demonstrated.

Validity of the leg-to-leg bioimpedance to estimate changes in body fat during weight loss and regain in overweight women: a comparison with multi-compartment models.

OBJECTIVES: To investigate changes in body composition and the validity of the leg-to-leg bioimpedance (LTL) method to measure body fat during active weight loss (WL) and weight regain (WR). DESIGN: Longitudinal, 12-week weight loss intervention (3.3-3.8 MJ/day) and subsequent follow-up at 1 year. SUBJECTS: Fifty-eight adult women aged between 24 and 65 years (mean age: 46.8+/-8.9 years) and with a body mass index (BMI) > or =25 kg/m(2) (mean BMI: 31.6+/-2.5 kg/m(2), range=26.0-48.2 kg/m(2)) participated in the study. MEASUREMENTS: Fat mass (FM) was measured at baseline, 12 weeks, 24 weeks and 52 weeks using three- and four-compartment (4-C) models, air displacement plethysmography (ADP), deuterium dilution - total body water (TBW), dual-energy X-ray absorptiometry (DXA), skinfold thickness (SFT), tetrapolar bioelectrical impedance analysis (T-BIA) and LTL. RESULTS: At the end of the weight loss programme, subjects lost 9.9+/-3.5 kg weight (P<0.001) and 7.6+/-0.5 kg fat (P<0.001) but after 1 year they had regained 4.9+/-3.7 kg of weight and 3.7+/-2.9 kg of fat. The 4-C model showed that FM and TBW accounted for 76.2 and 23.6% of the loss in body mass and 81.8 and 17.7% of the tissue accrued during weight regain, respectively. The estimate of body fat change by LTL relative to multi-compartment models (WL(bias+/-2s.d.)=0.51+/-3.26 kg; WR(bias+/-2s.d.)=-0.25+/-2.30 kg) was similar to ADP, DXA and TBW in both phases but it was better than T-BIA (WL(bias+/-2s.d.)=0.17+/-7.90 kg; WR(bias+/-2s.d.)=-0.29+/-7.59 kg) and skinfold thickness (WL(bias+/-2s.d.)=2.68+/-6.68 kg; WR(bias+/-2s.d.)=-0.84+/-3.80 kg). CONCLUSIONS: Weight loss and regain were associated with minimal changes in lean tissue as measured using multi-compartment models. The LTL system is a useful method to measure body composition changes during clinical weight management programmes.

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.