Obesity gene NEGR1 associated with white matter integrity in healthy young adults

Obesity is a crucial public health issue in developed countries, with implications for cardiovascular and brain health as we age. A number of commonly-carried genetic variants are associated with obesity. Here we aim to see whether variants in obesity-associated genes - NEGR1, FTO, MTCH2, MC4R, LRRN6C, MAP2K5, FAIM2, SEC16B, ETV5, BDNF- AS, ATXN2L, ATP2A1, KCTD15, and TNN13K - are associated with white matter microstructural properties, assessed by high angular resolution diffusion imaging (HARDI) in young healthy adults between 20 and 30. years of age from the Queensland Twin Imaging study (QTIM). We began with a multi-locus approach testing how a number of common genetic risk factors for obesity at the single nucleotide polymorphism (SNP) level may jointly influence white matter integrity throughout the brain and found a wide spread genetic effect. Risk allele rs2815752 in NEGR1 was most associated with lower white matter integrity across a substantial portion of the brain. Across the area of significance in the bilateral posterior corona radiata, each additional copy of the risk allele was associated with a 2.2% lower average FA. This is the first study to find an association between an obesity risk gene and differences in white matter integrity. As our subjects were young and healthy, our results suggest that NEGR1 has effects on brain structure independent of its effect on obesity.

Alzheimer's disease risk gene, GAB2, is associated with regional brain volume differences in 755 young healthy twins

The development of late-onset Alzheimer's disease (LOAD) is under strong genetic control and there is great interest in the genetic variants that confer increased risk. The Alzheimer's disease risk gene, growth factor receptor bound protein 2-associated protein (GAB2), has been shown to provide a 1.27- 1.51 increased odds of developing LOAD for rs7101429 major allele carriers, in case-control analysis. GAB2 is expressed across the brain throughout life, and its role in LOAD pathology is well understood. Recent studies have begun to examine the effect of genetic variation in the GAB2 gene on differences in the brain. However, the effect of GAB2 on the young adult brain has yet to be considered. Here we found a significant association between the GAB2 gene and morphological brain differences in 755 young adult twins (469 females) (M = 23.1, SD = 3.1 years), using a gene-based test with principal components regression (PCReg). Detectable differences in brain morphology are therefore associated with variation in the GAB2 gene, even in young adults, long before the typical age of onset of Alzheimer's disease.

Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene

Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro- and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.

Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, highangular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Somali perspectives on physical activity: PhotoVoice to address barriers and resources in San Diego

Although many immigrants enter the United States with a healthy body weight, this health advantage disappears the longer they reside in the United States. To better understand the complexities of obesity change within a cultural framework, a community-based participatory research (CBPR) approach, PhotoVoice, was used, focusing on physical activity among Muslim Somali women. The CBPR partnership was formed to identify barriers and resources to engaging in physical activity with goals of advocacy and program development. Muslim Somali women (n = 8) were recruited to participate, trained and provided cameras, and engaged in group discussions about the scenes they photographed. Participants identified several barriers, including safety concerns, minimal culturally appropriate resources, and financial constraints. Strengths included public resources and a community support system. The CBPR process identified opportunities and challenges to collaboration and dissemination processes. The findings laid the framework for subsequent program development and community engagement.

Use of Skin-Fold Thickness in Sri Lankan Children: Comparison of Several Prediction Equations

Objective There are many prediction equations available in the literature for the assessment of body composition from skinfold thickness (SFT). This study aims to cross validate some of those prediction equations to determine the suitability of their use on Sri Lankan children. Methods Height, weight and SFT of 5 different sites were measured. Total body water was assessed using the isotope dilution method (D2O). Percentage Fat mass (%FM) was estimated from SFT using prediction equations described by five authors in the literature. Results Five to 15 year old healthy, 282 Sri Lankan children were studied. The equation of Brook gave Ihe lowest bias but limits of agreement were high. Equations described by Deurenberg et al gave slightly higher bias but limits of agreement were narrowest and bias was not influence by extremes of body fat. Although prediction equations did not estimate %FM adequately, the association between %FM and SFT measures, were quite satisfactory. Conclusion We conclude that SFT can be used effectively in the assessment of body composition in children. However, for the assessment of body composition using SFT, either prediction equations should be derived to suit the local populations or existing equations should be cross-validated to determine the suitability before its application.

Segmental bioelectrical impedance in the assessment of body composition of Sri Lankan children

Abstract: Over the years bioelectrical impedance assay (BIA) has gained popularity in the assessment of body composition. However, equations for the prediction of whole body composition use whole body BIA. This study attempts to evaluate the usefulness of segmental BIA in the assessment of whole body composition. A cross sectional descriptive study was conducted at the Professorial Paediatric Unit of Lady Ridgeway Hospital, Colombo, involving 259 (M/F:144/115) 5 to 15 year old healthy children. The height, weight, total and segmental BIA were measured and impedance indices and specific resistivity for the whole body and segments were calculated. Segmental BIA indices showed a significant association with whole body composition measures assessed by total body water (TBW) using the isotope dilution method (D2O). Impedance index was better related to TBW and fat free mass (FFM), while specific resistivity was better related to the fat mass of the body. Regression equations with different combinations of variables showed high predictability of whole body composition. Results of this study showed that segmental BIA can be used as an alternative approach to predict the whole body composition in Sri Lankan children.

Exercise, Appetite Control, and Body Weight Regulation

Exercise has many health benefits and should be an effective weight loss strategy because it increases energy expenditure. However, the success of exercise in producing and sustaining weight loss is influenced by compensatory changes in energy intake and non-exercise activity, among other factors (see King et al. Obesity 15(6):1373–1383, 2007 for a detailed review). The aim of this chapter is to discuss the evidence describing the relationship between exercise and body weight regulation, with a particular focus on appetite control. Evidence is discussed which demonstrates that weight loss responses to exercise are highly variable between individuals. The mechanisms underlying the relationship between exercise, appetite and energy intake, and hence body weight are also discussed. Some people experience an increase in fasting hunger in response to 12 weeks of supervised exercise. However, this is offset by an increase in meal-related satiety in overweight and obese individuals. It is worth noting that weight loss should not be considered as the only successful outcome of an exercise program. Indeed, exercise, even in the absence of weight loss, is associated with numerous health benefits. Nevertheless, an improved understanding of compensatory responses to exercise is vital so that exercise can be more effectively used in weight management; such an understanding may assist us to devise strategies to sustain greater long-term participation in physical activity.

Molecular and functional characterizations of a Kunitz-type serine protease inhibitor FcKuSPI of the shrimp Fenneropenaeus chinensis

Serine proteinase inhibitors play important and diverse roles in biological processes such as coagulation, defense mechanisms, and immune responses. Here, we identified and characterized a Kunitz-type proteinase inhibitor, designated FcKuSPI, of the BPTI/Kunitz family of serine proteinase inhibitors from the hemocyte cDNA library of the shrimp Fenneropenaeus chinensis. The deduced amino acid sequence of FcKuSPI comprises 80 residues with a putative signal peptide of 15 amino acids. The predicted molecular weight of the mature peptide is 7.66 kDa and its predicted isoelectric point is 8.84. FcKuSPI includes a Kunitz domain containing six conserved cysteine residues that are predicted to form three disulfide bonds. FcKuSPI shares 44e53% homology with BPTI/Kunitz family members from other species. FcKuSPI mRNAwas expressed highly in the hemocytes and moderately in muscle in healthy shrimp. Recombinant FcKuSPI protein demonstrated anti-protease activity against trypsin and anticoagulant activity against citrated human plasma in a dose-dependent manner in in vitro assays.

The relationship between number of fruits, vegetables, and noncore foods tried at age 14 months and food preferences, dietary intake patterns, fussy eating behavior, and weight status at age 3.7 years

Objective We examined whether exposure to a greater number of fruits, vegetables, and noncore foods (ie, nutrient poor and high in saturated fats, added sugars, or added salt) at age 14 months was related to children’s preference for and intake of these foods as well as maternal-reported food fussiness and measured child weight status at age 3.7 years. Methods This study reports secondary analyses of longitudinal data from mothers and children (n=340) participating in the NOURISH randomized controlled trial. Exposure was quantified as the number of food items (n=55) tried by a child from specified lists at age 14 months. At age 3.7 years, food preferences, intake patterns, and fussiness (also at age 14 months) were assessed using maternal-completed, established questionnaires. Child weight and length/height were measured by study staff at both age points. Multivariable linear regression models were tested to predict food preferences, intake patterns, fussy eating, and body mass index z score at age 3.7 years adjusting for a range of maternal and child covariates. Results Having tried a greater number of vegetables, fruits, and noncore foods at age 14 months predicted corresponding preferences and higher intakes at age 3.7 years but did not predict child body mass index z score. Adjusting for fussiness at age 14 months, having tried more vegetables at age 14 months was associated with lower fussiness at age 3.7 years. Conclusions These prospective analyses support the hypothesis that early taste and texture experiences influence subsequent food preferences and acceptance. These findings indicate introduction to a variety of fruits and vegetables and limited noncore food exposure from an early age are important strategies to improve later diet quality.

The vertebral venous system in healthy and scoliotic adolescent spines - a 3D MRI investigation

Introduction. The venous drainage system within vertebral bodies (VBs) has been well documented previously in cadaveric specimens. Advances in 3D imaging and image processing now allow for in vivo quantification of larger venous vessels, such as the basivertebral vein. Differences between healthy and scoliotic VB veins can therefore be investigated. Methods. 20 healthy adolescent controls and 21 AIS patients were recruited (with ethics approval) to undergo 3D MRI, using a 3 Tesla, T1-weighted 3D gradient echo sequence, resulting in 512 slices across the thoraco-lumbar spine, with a voxel size of 0.5x0.5x0.5mm. Using Amira Filament Editor, five transverse slices through the VB were examined simultaneously and the resulting observable vascular network traced. Each VB was assessed, and a vascular network recorded when observable. A local coordinate system was created in the centre of each VB and the vascular networks aligned to this. The length of the vascular network on the left and right sides (with a small central region) of the VB was calculated, and the spatial patterning of the networks assessed level-by-level within each subject. Results. An average of 6 (range 4-10) vascular networks, consistent with descriptions of the basivertebral vein, were identifiable within each subject, most commonly between T10-L1. Differences were seen in the left/right distribution of vessels in the control and AIS subjects. Healthy controls saw a percentage distribution of 29:18:53 across the left:centre:right regions respectively, whereas the AIS subjects had a slightly shifted distribution of 33:25:42. The control group showed consistent spatial patterning of the vascular networks across most levels, but this was not seen in the AIS group. Conclusion. Observation and quantification of the basivertebral vein in vivo is possible using 3D MRI. The AIS group lacked the spatial pattern repetition seen in the control group and minor differences were seen in the left/right distribution of vessels.

Letter Reply: Distribution of TNFA haplotypes in healthy Caucasians: Comment on the articles by Newton et al and Zeggini et al

We thank Ploski and colleagues for their interest in our study. The explanation for the difference in our findings is a typographic error in Table 2 of our article, whereby the alleles for marker TNF ⫺1031 were labeled incorrectly...

Maternal pregravid body mass index and child hospital admissions in the first 5 years of life: results from an Australian birth cohort

Objectives: To examine the association of maternal pregravid body mass index (BMI) and child offspring, all-cause hospitalisations in the first 5 years of life. Methods: Prospective birth cohort study. From 2006 to 2011, 2779 pregnant women (2807 children) were enrolled in the Environments for Healthy Living: Griffith birth cohort study in South-East Queensland, Australia. Hospital delivery record and self-report baseline survey of maternal, household and demographic factors during pregnancy were linked to the Queensland Hospital Admitted Patients Data Collection from 1 November 2006 to 30 June 2012, for child admissions. Maternal pregravid BMI was classified as underweight (<18.5 kg m−2), normal weight (18.5–24.9 kg m−2), overweight (25.0–29.9 kg m−2) or obese (30 kg m−2). Main outcomes were the total number of child hospital admissions and ICD-10-AM diagnostic groupings in the first 5 years of life. Negative binomial regression models were calculated, adjusting for follow-up duration, demographic and health factors. The cohort comprised 8397.9 person years (PYs) follow-up. Results: Children of mothers who were classified as obese had an increased risk of all-cause hospital admissions in the first 5 years of life than the children of mothers with a normal BMI (adjusted rate ratio (RR) =1.48, 95% confidence interval 1.10–1.98). Conditions of the nervous system, infections, metabolic conditions, perinatal conditions, injuries and respiratory conditions were excessive, in both absolute and relative terms, for children of obese mothers, with RRs ranging from 1.3–4.0 (PYs adjusted). Children of mothers who were underweight were 1.8 times more likely to sustain an injury or poisoning than children of normal-weight mothers (PYs adjusted). Conclusion: Results suggest that if the intergenerational impact of maternal obesity (and similarly issues related to underweight) could be addressed, a significant reduction in child health care use, costs and public health burden would be likely.

Energy gap in the aetiology of body weight gain and obesity: A challenging concept with a complex evaluation and pitfalls

The concept of energy gap(s) is useful for understanding the consequence of a small daily, weekly, or monthly positive energy balance and the inconspicuous shift in weight gain ultimately leading to overweight and obesity. Energy gap is a dynamic concept: an initial positive energy gap incurred via an increase in energy intake (or a decrease in physical activity) is not constant, may fade out with time if the initial conditions are maintained, and depends on the 'efficiency' with which the readjustment of the energy imbalance gap occurs with time. The metabolic response to an energy imbalance gap and the magnitude of the energy gap(s) can be estimated by at least two methods, i.e. i) assessment by longitudinal overfeeding studies, imposing (by design) an initial positive energy imbalance gap; ii) retrospective assessment based on epidemiological surveys, whereby the accumulated endogenous energy storage per unit of time is calculated from the change in body weight and body composition. In order to illustrate the difficulty of accurately assessing an energy gap we have used, as an illustrative example, a recent epidemiological study which tracked changes in total energy intake (estimated by gross food availability) and body weight over 3 decades in the US, combined with total energy expenditure prediction from body weight using doubly labelled water data. At the population level, the study attempted to assess the cause of the energy gap purported to be entirely due to increased food intake. Based on an estimate of change in energy intake judged to be more reliable (i.e. in the same study population) and together with calculations of simple energetic indices, our analysis suggests that conclusions about the fundamental causes of obesity development in a population (excess intake vs. low physical activity or both) is clouded by a high level of uncertainty.

Living well with diabetes: 24-month outcomes from a randomized trial of telephone-delivered weight loss and physical activity intervention to improve glycemic control

OBJECTIVE: To evaluate the effectiveness of a telephone-delivered behavioral weight loss and physical activity intervention targeting Australian primary care patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Pragmatic randomized controlled trial of telephone counseling (n = 151) versus usual care (n = 151). Reported here are 18-month (end-of-intervention) and 24-month (maintenance) primary outcomes of weight, moderate-to-vigorous-intensity physical activity (MVPA; via accelerometer), and HbA1c level. Secondary outcomes include dietary energy intake and diet quality, waist circumference, lipid levels, and blood pressure. Data were analyzed via adjusted linear mixed models with multiple imputation of missing data. RESULTS: Relative to usual-care participants, telephone counseling participants achieved modest, but significant, improvements in weight loss (relative rate [RR] -1.42% of baseline body weight [95% CI -2.54 to -0.30% of baseline body weight]), MVPA (RR 1.42 [95% CI 1.06-1.90]), diet quality (2.72 [95% CI 0.55-4.89]), and waist circumference (-1.84 cm [95% CI -3.16 to -0.51 cm]), but not in HbA1c level (RR 0.99 [95% CI 0.96-1.02]), or other cardio-metabolic markers. None of the outcomes showed a significant change/deterioration over the maintenance period. However, only the intervention effect for MVPA remained statistically significant at 24 months. CONCLUSIONS: The modest improvements in weight loss and behavior change, but the lack of changes in cardio-metabolic markers, may limit the utility, scalability, and sustainability of such an approach.