Pramfalk C., et al – Cholesterol Esterifying Enzyme Acat2-A Target for Cardiometabolic DiseasesLay Summary – The cholesterol esterifying enzyme acyl-Coenzyme A: cholesterol acyltransferase 2 (ACAT2) is exclusively expressed in enterocytes and hepatocytes (liver cells). Mice without this gene do not develop atherosclerosis or diet-induced hypercholesterolemia, and accumulate less fat in the liver (hepatic steatosis) when fed a high fat-cholesterol diet. The main component of this paper looks at these mice and whether there are any sex differences, their response to different dietary regimes and this genes association with insulin sensitivity. They did however also look at blood samples from the Oxford Biobank from participants carrying a rare genetic variant of the ACAT2 gene. The mice without this gene, when fed a high fat or high carbohydrate diet showed less accumulation of fat in the liver and were more insulin sensitive. The humans with the rare variant of this gene also had a lower insulin level. Inhibition of ACAT2 may thus be a strategy to treat cardiometabolic diseases
Circulation, V.132 – pp. A15393-A15393
Pramfalk, C., et al – Sex-Specific Differences in Hepatic Fat Oxidation and Synthesis May Explain the Higher Propensity for NAFLD in Men.Lay Summary – Sex-specific differences in liver dietary fatty acid (FA) metabolism have not been well characterized. In this paper the Authors compared fasting and postprandial hepatic FA synthesis (de novo lipogenesis [DNL]) and oxidation in men and women. Eleven men and eleven women were selected from the Oxford Biobank matched for age,BMI and liver fat content and dietary fat oxidation was assessed. Men showed lower dietary fat burning and a prolonged increase in the production fats from other sources (DNL). This may represent a tendency for men store more fat in the liver and thus explain their greater risk of hepatic steatosis than women.
J Clin Endocrinol Metab, V.100 (12) – pp.4425-4433 – PMID: 26414963
Hodson, L., et al. – Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women.Lay Summary –
When a woman becomes menopausal her risk of heart disease is increased, which may be due to a change in body fat distribution or a change in the production of cholesterol risk particles (lipoproteins) made by the liver. Women from the Oxford Biobank, who were aged between 45 – 55 years, took part in this study that investigated the effects of abdominal obesity and menopause status in relation to lipoprotein production by the liver. It was found menopausal women produce more cholesterol-rich particles than pre-menopausal women and this may contribute an increased risk of heart disease.
J of the Am Heart Assoc, V.4(10) – pp.e002258 – PMID: 26432801
Locke, A.E., et al. – Genetic studies of body mass index yield new insights for obesity biology.Lay Summary –
Obesity is heritable and predisposes to many diseases. It is estimated that as much as 20% of the variation in Body mass Index (BMI) can be attributed to genetic variation common with the population. In this study the Oxford Biobank samples are part of a consortium of similar collections of volunteers around the world totaling 340,000 individuals. High-throughput techniques were used to look at the genetic variation in the population and how that may impact obesity. After combining the results from the different collections the analysis identified 97 genetic loci associated with body mass that are estimated to account 2.7% of the total variation in Body mass in the population.
Nature, V.518(7538) – pp.197-206 – PMID: 25673413
Shungin, D., et al. – New genetic loci link adipose and insulin biology to body fat distribution.Lay Summary –
Where we store our fat is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall obesity. A common measure of this is the Waist to Hip ratio, i.e. the ratio between upper body fat (Waist) and lower Body Fat (Hip). In this study the Oxford Biobank DNA samples form part of a consortium of similar collections of volunteers from around the world totaling 224,459 individuals for a genome wide association study (GWAS). 49 Loci were significantly associated with differences Waist to hip ratio with 33 of them being new. 20 of these were different between men and women.
Nature, V.518(7538) – pp.187-96 – PMID: 25673412
Teare, H.J., et al. – Towards ‘Engagement 2.0’: Insights from a study of dynamic consent with biobank participants.Lay Summary –
Over recent years there has been a steady increase in public engagement in research, evident by the growing support of participants in studies such as the Oxford Biobank. There has also been huge developments in technology, communication and methods if engagement. At present the consent process for volunteers is static with very little data fed back. This study involved the recruitment of volunteers from a number biobanks for focus groups (Oxford Biobank is Biobank 2) to gage opinion of new ways of engaging with the participants. The study showcases a “Web 2.0 dynamic consent interface” which allows a 2-way communication channel between participants and researchers.
Digital Health, V.1(0) – pp.1-13
Amisten, S., et al. – An atlas of G-protein coupled receptor expression and function in human subcutaneous adipose tissue..Lay Summary –
Adipose tissue expresses a wide range of proteins called receptors that confer sensitivity of the resident cells to various chemicals, with these proteins also being the target of numerous drugs used clinically. Abdominal and gluteal fat biopsies from the Oxford BioBank were analysed for the presence of a wide range of these receptors to generate an ‘atlas’ of their expression pattern. This comprehensive data set will help our understanding of adipose tissue function in the future whilst also highlighting current gaps in our knowledge. It may also be used to better predict the effect of drugs on adipose function and thereby facilitate the development of safer therapeutic agents.
Pharmacol Ther, V.J6 – pp.61-93 – PMID: 25242198
Loh, N.Y., et al. – LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion..Lay Summary –
This study shows how preadipocytes from the upper and lower body fat depots respond differently to changes in WNT/β-catenin signaling activity because of their different intrinsic LRP5 protein levels, thereby influencing human body-fat distribution. Genotype and body fat distribution data from volunteers of the Oxford Biobank were used to show that individuals with low bone mineral density-associated LRP5 gene variants tend to have increased upper body-fat distribution (apple shape), whereas individuals with high-bone-mass causing LRP5 mutations have greater lower body-fat distribution (pear shape). Cell culture studies used preadipocytes isolated from fat biopsies of volunteers from the Oxford Biobank.
Cell Metab, V.J6 – pp.262-272 – PMID: 25651180
Mahajan, A., et al. – Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus..Lay Summary –
There have been a large number of Genome wide association studies looking at Common genetic variants and their impact on Insulin and Glucose in the human body. However only a very small amount of the variation has been explained using these common variants. In this study the researchers look at whether rare genetic variants may explain some of the, as yet unidentified, inherited contribution of differences in Glucose and Insulin observed with the human population. The Oxford Biobank DNA samples formed part of a consortium of similar collections that were analysed with new Exome Chip technologies specifically looking at 100s of 1000s rare genetic variants. A total of 33,231 DNA samples were analysed of which the Oxford Biobank contributed ~5500. Two new loci were identified, plus potential causative variants were identified for previously known genomic regions. The results did not add significantly to the total % of explained variation in glycemic traits but did add biological insight.
PLoS Genet, V.J6 – pp.e1004876 – PMID: 25625282
Reschen, M.E., et al. – Lipid-Induced Epigenomic Changes in Human Macrophages Identify a Coronary Artery Disease-Associated Variant that Regulates PPAP2B Expression through Altered C/EBP-Beta Binding..Lay Summary –
There are a number of genetic variations that have been shown to increase risk of developing heart disease, but why they do this is unclear. This study investigated how genetic variation affected a key step in the formation of plaques that block blood vessels in to the heart. Using blood from the Oxford Biobank, subjects were recruited with a particular heart disease genetic risk variant (rs72664324). It was found that the risk variant was associated with inflammation that may contribute to the development of heart disease.
PLoS Genet, V.J6 – pp.e1005061 – PMID: 25835000
Karpe F and K.E. Pinnick – Biology of upper-body and lower-body adipose tissue–link to whole-body phenotypes..Lay Summary –
People who store fat on their legs and hips have a reduced risk of developing metabolic diseases, like type 2 diabetes, compared to people who store fat on their upper-body. In this review paper we discuss studies in the reported literature that have looked at the relationship between body shape and disease risk. We include DXA scan measurements of body fat distribution from Oxford Biobank volunteers to support the view that obese individuals who store fat on their lower-body are metabolically “healthier” compared to matched individuals who store fat on their upper-body.
Nat Rev Endocrinol, V.J6 – pp.90-100 – PMID: 25365922
Pinnick KE., et al. – Distinct Developmental Profile of Lower-Body Adipose Tissue Defines Resistance Against Obesity-Associated Metabolic Complications.Lay Summary –
People who store fat on their legs and hips have a reduced risk of developing metabolic diseases, like type 2 diabetes, compared to people who store fat on their upper-body. One explanation is that not all fat is alike. In this study we collected paired abdominal and gluteal subcutaneous fat biopsies from Oxford Biobank volunteers and compared the genes that they express. The levels of many genes were consistently different between the two tissues and a large proportion were identified as genes that control organ development. We showed that one of these genes, TBX5, specifically controls the growth and development of abdominal fat cells. These results suggest that not all fat tissues develop in the same way. This may be an important factor in understanding functional differences between fat tissues.
Diabetes, V.J6 – pp.3785-3797 – PMID: 24947352
Fairfax, B.P., et al. – Innate immune activity conditions the effect of regulatory variants upon monocyte gene expression..Lay Summary –
Genes associated with numerous common diseases are involved in the immune system, meaning investigation of how the immune system is controlled by genetic mechanisms can improve our understanding of disease development. In this study, immune cells obtained from a number of participants from the Oxford Biobank were chemically stimulated to mimic the process of infection. The biological response of these cells was then analysed and cross-referenced with genome-wide analysis data. It was found that the expression of specific genes previously associated with various common diseases was altered in the immune cells after chemical stimulation, thereby validating these genome-wide analysis hits as having potentially functional importance in the development in numerous common diseases.
Science, V.J6 – pp.1246949 – PMID: 24604202
Hodson, L., et al. – Lower resting and total energy expenditure in postmenopausal compared with premenopausal women matched for abdominal obesity..Lay Summary –
When a woman becomes menopausal there is an increased risk of obesity, altered body fat distribution and decreased skeletal muscle mass. Women aged 45 – 55 years from the Oxford Biobank took part in this study that investigated habitual energy intake and expenditure in pre- and postmenopausal women matched for abdominal obesity. It was found that weight maintenance in the post- compared to pre-menopausal women was achieved through a combination of reduced energy intake along with a reduction in total energy expenditure.
J Nutr Sci, V.J6 – pp.e3 – PMID: 25191611
Marinou, K., et al. – Structural and functional properties of deep abdominal subcutaneous adipose tissue explain its association with insulin resistance and cardiovascular risk in men..Lay Summary –
Excess body weight is frequently linked to metabolic complications that increase the risk of type 2 diabetes and cardiovascular disease. The specific location of body fat is more important than the overall quantity of body fat. Abdominal fat stored under the skin, called subcutaneous adipose tissue, have two distinct layers, a deep layer (dSAT) and a superficial layer (sSAT). It is not known whether there are differences between these two layers. In this study, healthy male volunteers were recruited from the Oxford Biobank in order to characterize if there are any functional differences between the two subcutaneous fat layers. The results showed that dSAT expands disproportionally more than sSAT in obesity which then may lead to increased risk of cardiovascular disease.
Diabetes Care, V.J6 – pp.821-829 – PMID: 24186879
McNeil, C.A., et al. – The storage stability and concentration of acetoacetate differs between blood fractions..Lay Summary –
Acetoacetate is a ketone body produced by the liver that in high concentrations can make the blood acidic. This may happen in patients with diabetes. Acetoacetate has been reported to be unstable so is rarely measured. The study investigated different methodologies to measure acetoacetate in the blood from participants in the Oxford Biobank.
Clin Chim Acta, V.J6 – pp.278-283 – PMID: 24721643
Wong, D., et al. – Genomic mapping of the MHC transactivator CIITA using an integrated ChIP-seq and genetical genomics approach..Lay Summary –
The master trans-activator gene CIITA is essential to the regulation of an effective immune response and defects in this gene result in severe immunodeficiency. Using Blood samples from recruited Oxford Biobank volunteers this paper looks at the network of gene interactions involving CIITA within the human genome.
Genome Biol, V.J6 – pp.494 – PMID: 25366989
Berndt, S.I., et al. – Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture..Lay Summary –
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits. In this paper the researchers look at the population extremes for measurements in BMI, Height, waist-hip-ratio and obesity and runs a meta-analysis over 263,407 individuals of European ancestry across over 50 studies looking a genetic variation common in the population. 91 of the top scoring variations were further examined for functional significance using tissue samples from regions of the body. Paired upper and lower fat tissue biopsies from 73 Oxford Biobank volunteers were used. This paper identifies 4 new genes influencing height and 7 influencing obesity.
Nat Genet, V.J6 – pp.501-512 – PMID: 23563607
Drong, A.W., et al. – The Presence of Methylation Quantitative Trait Loci Indicates a Direct Genetic Influence on the Level of DNA Methylation in Adipose Tissue..Lay Summary –
DNA methylation is a simple chemical modification of the genetic material found within our cells that controls which genes are switched on or off. DNA methylation is highly tissue-specific but few studies have investigated DNA methylation in human fat tissue. In this study we collected abdominal subcutaneous fat biopsies from Oxford Biobank volunteers and screened for variation in DNA sequence and DNA methylation between individuals. We found that there are specific sites in the DNA sequence that vary between people and that are associated with differing levels of DNA methylation. This study has extended our understanding of how DNA methylation is regulated in human fat tissue and may be important in understanding between-people differences in fat tissue function.
PLoS ONE, V.J6 – pp.e55923 – PMID: 23431366
Evans, D.M., et al. – Mining the Human Phenome Using Allelic Scores That Index Biological Intermediates..Lay Summary –
Genome-wide association studies typically analyse a relationship between a component of a disease and genetic markers one at a time, with hits identifying molecular pathways that may be importance to the development of said disease. However, single genetic markers typically only explain very small amounts of risk in complex diseases. In an attempt to overcome such a limitation and get more information from a given data set, potential relationships between genetic markers and several biological markers relevant to a selection of diseases were explored simultaneously using a novel scoring system. This involved using a large data database including data provided by the Oxford BioBank. This new approach was validated as it identified numerous previously identified genetic markers associated with specific diseases and predicted they had the expected effect on disease risk. This statistical method can easily be scaled up, meaning that if the vast data sets of genetic and biological information currently available are analysed using this new approach, future analyses might generate larger amounts of more meaningful, informative data.
PLoS Genet, V.J6 – pp.e1003919 – PMID: 24204319
Hodson, L., et al. – Metabolic signatures of human adipose tissue hypoxia in obesity..Lay Summary –
When people put on weight they typically increase their body fatness and this may cause their body fat (adipose tissue) not to get as much oxygen as it needs to function. Participants from the Oxford Biobank were involved in this study that investigated how much oxygen was being delivered and used by the subcutaneous adipose tissue around the abdomen. Results showed that even as people increased body fatness their adipose tissue adapted to having a lower amount of oxygen delivery by using less oxygen; no evidence of changes in metabolism due to oxygen deficiency were found
Diabetes, V.J6 – pp.1417-1425 – PMID: 23274888
Hu, Y.-J., et al. – Meta-analysis of gene-level associations for rare variants based on single-variant statistics..Lay Summary –
The analysis of genetic variation using technologies that cover the whole genome are know as genome wide association studies (GWAS) and the combining of results from multiple datasets is known as Meta-analysis. The statistical methods used are very complex and demanding and each comes with limitations. This paper describes a new statistical approach to analyse GWAS data and GWAS data on the Oxford Biobank samples was used, as part of a consortium of datasets, to test the analysis method described.
Am J Hum Genet, V.J6 – pp.236-248 – PMID: 23891470
Magné, J., et al. – The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans..Lay Summary –
Fat inside the cells is stored in the form of lipid droplets. In different tissues, the surface of lipid droplets is coated by a number of different proteins that are important in the regulation of lipid metabolism. Perilipin 2 is the most abundant lipid droplet protein found in non-fat tissues, but its exact function in humans is not well characterized. In this study, healthy volunteers were recruited from the Oxford Biobank in order to study if genetic variation in Perilipin 2 has an impact on cellular lipid metabolism. We showed that Perilipin 2 influences the accumulation and release of intracellular triglycerides, and that genetic variation may affect the plasma triglycerides levels.
FASEB Journal, V.J6 – pp.3090-3099 – PMID: 23603836
Mughal, S.A., et al. – Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes..Lay Summary –
This study shows that ApoM may be a useful diagnostic tool for distinguishing patients with maturity-onset diabetes of the young (MODY) carrying HNF1A mutation from patients with Type I diabetes. Plasma samples for healthy controls were from the Oxford Biobank.
Diabet Med, V.J6 – pp.246-250 – PMID: 23157689
Randall, J.C., et al. – Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits..Lay Summary –
In this paper the authors investigate whether genetic effects influencing body shape have different effects between men and women. Measurements for height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio were looked at across 94 different studies, of which the Oxford Biobank was one. Genetic variation in or near 5 previously established genes and 3 new genes were identified. In all cases the associations were significant in women but not men and were associated with waist circumference.
PLoS Genet, V.J6 – pp.e1003500 – PMID: 23754948
Rivas, M.A., et al. – Assessing association between protein truncating variants and quantitative traits..Lay Summary –
DNA sequencing methods (process of determining the exact order of nucleotides within a DNA molecule) have significantly accelerated medical research and discovery of genetic causes of disease. DNA encodes for proteins. In rare cases, specific changes in the DNA sequence called protein-truncating variants will lead to the formation of non-functional proteins and this can have biological effects. In this study, healthy participants were recruited from the Oxford Biobank and had their protein-coding genes analysed by using exome sequencing and measurement of plasma triglyceride concentration. Using a statistical model, we discovered a strong association between a protein-truncating variant in a gene responsible for triglyceride processing and low plasma triglyceride levels.
Bioinformatics, V.29 (19) pp.2419-26 – PMID: 23860716
Vimaleswaran, K.S., et al. – Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts..Lay Summary –
Both obesity and deficiency in vitamin D are a large health concern in humans and often occur together, but it is not clear if one causes the other. Using a consortium of data the authors investigated if genetic variation thought to increase body mass index (BMI) had an effect on vitamin D amounts in humans. Using multiple biobank data sets (including that of the Oxford Biobank) we found that it is likely that a high BMI leads to low vitamin D levels rather than low vitamin D levels causing an increase in BMI.
PLoS Med, V.10 (2) pp.e1001383 – PMID: 23393431
Andersson, J., et al. – Association of adipose tissue blood flow with fat depot sizes and adipokines in women..Lay Summary –
The regulation of blood flow through fat tissue is poorly understood but is changed after we eat a meal and is altered in obesity. Where we store fat in our bodies is thought to have different metabolic and health consequences with fat around our organs increasing risk for developing disease. Healthy individuals from the Oxford Biobank were recruited to investigate if the amount of fat and its location had an effect of blood flow through the fat. The Authors found that high levels of fat were associated with reduced blood flow in all fat tissue areas measured.
Int J Obes (Lond), V.36 (6) pp.783-789 – PMID: 21792171
Dastani, Z., et al. – Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals..Lay Summary –
Circulating levels of adiponectin, a hormone predominantly expressed in fat cells, are highly heritable and inversely associated with type 2 diabetes (T2D). Using genetic, biochemical and body measurement data from tens of thousands of individuals, including those from the Oxford Biobank, this study identified new genes that may influence adiponectin levels, and therefore influence the risk of a person developing T2D and insulin resistance.
PLoS Genet, V.8 (3) pp.e1002607 – PMID: 22479202
Fairfax, B.P., et al. – Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles..Lay Summary –
As well as directly affecting the structure of a protein, genetic variation in the genome can affect the levels that a protein is expressed at a nearby gene, this is called a cis-eQTL (expression quantitative trait loci). Furthermore, genetic variation that effects one protein can also affect the levels that another protein is expressed, this is known as a Trans-eQTL and can be on a completely separate chromosome. Understanding how these cis and trans eQTLs is crucial to understanding the biological and medical significance of genetic variation. In this study the researchers sought to determine physiologically active cell type-specific eQTLs of high relevance to immunity and inflammation in paired samples of monocytes and B-cells. Immune cells from bloods attained from Oxford Biobank volunteers were purified. Using paired purified primary monocytes and B-cells novel, predominantly cell-specific, cis- and trans-eQTL were identified and provides insights into the genetic basis of disease susceptibility.
Nat Genet, V.44 (5) pp.502-510 – PMID: 22446964
Fox, C.S., et al. – Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women..Lay Summary –
Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. In this paper the authors looked at genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution. The top results of this GWAS study were then validated with a consortium of datasets of which the Oxford Biobank is one. The main comparisons were with Visceral and subcutaneous fat. When comparing the results with previous publications looking at more conventional measures such as BMI, waist circumference or waist to hip ratio 7 out of the 14 regions associated with fat distribution were also found in this study but only 7 of the 32 regions previously associated with BMI were seen.
PLoS Genet, V.8 (5) pp.e1002695 – PMID: 22589738
Frayn, K.N. and S.M. Humphreys. – Metabolic characteristics of human subcutaneous abdominal adipose tissue after overnight fast..Lay Summary –
Under skin (Subcutaneous) adipose tissue is one of the largest fat depots and contributes to the major proportion of circulating nonesterified fatty acids (NEFA). Using collated data from 331 experiments in 255 healthy Oxford Biobank volunteers over a 23-year period, in which subcutaneous abdominal fat tissue metabolism was studied by measuring the arterio-venous differences in different metabolites after an overnight fast, we get better insight into what happens to glucose taken up by this fat tissue, and what metabolites that are released.
Am J Physiol Endocrinol Metab, V.302 (4) pp.E468-E475 – PMID: 22167523
Manolopoulos, K.N., F. Karpe, and K.N. Frayn. – Marked resistance of femoral adipose tissue blood flow and lipolysis to adrenaline in vivo..Lay Summary –
Storage of fat (adipose tissue) around the hips (femoral) is healthier than storage around the abdomen. One reason for this may be because fat is released less easily from the hips, leading to reduced accumulation of fat in organs which can lead to insulin resistance (associated with cardiovascular disease and type 2 diabetes). This study recruited participants from the Oxford Biobank and stimulated the release of fat with adrenaline in both abdominal and femoral sites. Fat release was lower in femoral adipose tissue, supporting the study’s hypothesis.
Diabetologia, V.55 (11) pp.3029-3037 – PMID: 22898765
Min, J.L., et al. – Coexpression network analysis in abdominal and gluteal adipose tissue reveals regulatory genetic loci for metabolic syndrome and related phenotypes..Lay Summary –
Metabolic Syndrome (MetS) has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in the progression of MetS a set of fat tissue samples and blood samples from both MetS individuals and healthy controls (Oxford Biobank participants) were analysed. Both the genetic variation and expression levels of genes were analysed in tandem. This analysis allowed for both genetic differences between MetS and controls to be identified but also genetic differences that effect the amount of a gene product produced in the cell.
PLoS Genet, V.8 (2) pp.e1002505 – PMID: 22383892
Pal, A., et al. – PTEN mutations as a cause of constitutive insulin sensitivity and obesity..Lay Summary –
People with mutations in a gene which controls cell growth, called PTEN, have an increased risk of developing certain forms of cancer. The role of PTEN has also been shown to be important in type 2 diabetes and obesity through its involvement in insulin signalling. In order to test the link between cancer, type 2 diabetes and obesity, patients with a PTEN mutation, were recruited and compared to healthy volunteers from the Oxford Biobank. Our data shows that people with the PTEN mutation had increased risks of obesity and cancer but a decreased risk of type 2 diabetes, showing a complex relationship between cancer, obesity and type 2 diabetes.
N Engl J Med, V.367 (11) pp.1002-1011 – PMID: 22970944
Pinnick, K.E., et al. – Gluteofemoral adipose tissue plays a major role in production of the lipokine palmitoleate in humans..Lay Summary –
People who store fat on their legs and hips have a reduced risk of developing metabolic diseases, like type 2 diabetes, compared to people who store fat on their upper-body. In this study we collected fat biopsies and blood samples from Oxford Biobank volunteers to examine whether lower-body fat produces a “releasable” factor which could be responsible for the protective effects of this tissue. We found that lower-body fat synthesises higher amounts of a lipid, called palmitoleate, than upper-body fat. Palmitoleate was released from the fat tissue into the bloodstream. It is proposed that palmitoleate exerts beneficial properties on other tissues in the body such as the liver and muscle.
Diabetes, V.61 (6) pp.1399-1403 – PMID: 22492525
Trachtenberg, A.J., et al. – The effects of APOE on the functional architecture of the resting brain..Lay Summary –
A well-established risk factor for the development of Alzheimer’s disease is the type of APOE gene an individual possesses. Individuals were selected from the Oxford BioBank and grouped by their APOE gene type before undergoing a brain scan using magnetic resonance imaging. By measuring the flow of oxygenated blood in specific areas of the brain it was found that the activity of specific neural networks relating to hearing, vision and memory was different between individuals of various APOE gene types. However, the patterns of brain activity observed did not translate intuitively to the expected effect that each APOE gene type and their associated effect on Alzheimer’s disease risk. Given this finding, it has been proposed that the risk of developing Alzheimer’s disease associated with APOE gene type relates to its role in brain development.
NeuroImage, V.59 (1) pp.565-572 – PMID: 21851856
Trachtenberg, A.J., et al. – The effects of APOE on brain activity do not simply reflect the risk of Alzheimer’s disease..Lay Summary –
Among the various factors implicated in the development of Alzheimer’s disease, two specific types of the APOE gene have been associated with opposite effects on the risk of developing the disease. Individuals were selected from the Oxford BioBank and grouped based on the type of APOE gene they possessed. These individuals then underwent magnetic resonance imaging to assess specific brain functions that can be used to predict Alzheimer’s disease risk. By measuring the flow of oxygenated blood in specific areas of the brain it was found that brain activity was different between the two groups, albeit in an unexpected manner. This finding highlights that the biological mechanisms linking APOE gene type to brain function and Alzheimer’s disease risk are far more complex than previously appreciated, but this knowledge can be used to inform future investigations that aim to better understand this phenomenon.
Neurobiol Aging, V.33 (3) pp.618.e1-618.e13 – PMID: 21232817
Antoniades, C., et al. – Induction of vascular GTP-cyclohydrolase i and endogenous tetrahydrobiopterin synthesis protect against inflammation-induced endothelial dysfunction in human atherosclerosis..Lay Summary –
Vascular disease is a common cause of heart disease and promotes inflammation and damage to blood vessels. This can cause decreases in enzymes involved in health of blood vessels. Genetic variation may play a role in how our bodies respond to inflammation. DNA from the Oxford Biobank was used to recruit subjects with variations in one particular gene, GCH1, so its effect on blood vessels could be assessed. It was found that GCH1 is important for the body’s ability to cope with inflammation and that genetic variation may affect the body’s ability to protect against damage to blood vessels.
Circulation, V.124 (17) pp.1860-1870 – PMID: 21969008
Chambers, J.C., et al. – Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma..Lay Summary –
Enzymes that are released from the liver into the blood can be predictors of liver disease caused by alcohol, obesity and drug toxicity. However, our genes may also influence the amount of liver enzymes in the blood. Using DNA from the Oxford Biobank (and other large consortiums of data) the authors found a number of genetic variants that may impact on liver enzymes. This work provides the basis for future work to study how and why liver damage occurs.
Nat Genet, V.43 (11) pp.1131-1138 – PMID: 22001757
Collins, J.M., et al. – De novo lipogenesis in the differentiating human adipocyte can provide all fatty acids necessary for maturation..Lay Summary –
The main role of human adipose tissue is to provide a site for the safe storage of excess dietary fats. In this study we used abdominal subcutaneous fat biopsies from Oxford Biobank volunteers to show that adipose tissue also has the ability to convert some non-lipid precursors, such as sugars and amino acids, into fats.
J Lipid Res, V.52 (9) pp.1683-1692 – PMID: 21677304
Marinou, K., et al. – Young women partition fatty acids towards ketone body production rather than VLDL-TAG synthesis, compared with young men..Lay Summary –
Before the menopause, women are relatively protected against heart disease compared with men. The reasons for this are not completely understood, but liver fat metabolism may play a role. Healthy lean men and women from the Oxford Biobank were recruited for this study to analyse any differences in how man and women handle fats. The study identified that man and women do indeed partition fats differently and this may contribute to their more advantageous metabolic profile.
Br J Nutr, V.105 (6) pp.857-865 – PMID: 21251339
McQuaid, S.E., et al. – Downregulation of adipose tissue fatty acid trafficking in obesity: A driver for ectopic fat deposition?..Lay Summary –
Fat stored in tissues other than fat tissue can have a negative impact on health. Whether this ectopic fat comes from fat tissue or directly from dietary fat is however not known. Nine abdominally obese and ten lean male volunteers from the Oxford Biobank were recruited for a 24-hour study to track the partition of fats in the body. It was shown that the obese men showed an impaired storage of Dietary fat in their adipose tissue.
Diabetes, V.60 (1) pp.47-55 – PMID: 20943748
Neville, M.J., et al. – Comprehensive human adipose tissue mRNA and MicroRNA endogenous control selection for quantitative real-time-PCR normalization..Lay Summary –
The accurate quantification of the levels that genes are expressed is reliant upon the selection of suitable stable endogenous control transcripts for normalizing quantitative real-time-PCR (qRT-PCR) data. In this paper the authors present data on a selection of fat samples, including biopsies from Oxford Biobank participants and compares some of the most commonly used endogenous control transcripts and some novel candidates. It presents some suitable candidates for analysing gene expression in fat tissue and cells plus outcomes of selecting inappropriate genes.
strong>Obesity, V.19 (4) pp.888-892 – PMID: 20948521
Rantalainen, M., et al. – MicroRNA Expression in Abdominal and Gluteal Adipose Tissue Is Associated with mRNA Expression Levels and Partly Genetically Driven..Lay Summary –
MicroRNAs are small non-coding RNA molecules that can regulate the protein levels of their target genes. In this paper the Authors analyse MicroRNAs found in Fat tissue in the upper and lower fat depots together with healthy individuals from the Oxford Biobank and a panel of individuals with Metabolic syndrome. 12% of MicroRNAs were found to be significantly different between upper and lower fat depots and 14 microRNAs were associated with metabolic syndrome. The paper also looked at genetic variation and levels of microRNA expression (eQTLs) and whether the microRNA expression levels correlate to expression levels seen for their predicted target mRNAs. Six significant eQTLs were identified.
PLoS ONE, V.6 (11) pp.e27338 – PMID: 22102887
Speliotes, E.K., et al. – Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits..Lay Summary –
Non-alcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. This GWAS study aimed to identify additional genetic variants that influence NAFLD. Using a collection of different datasets and relevant Cohorts of individuals five gene loci were identified. These loci were then assesses for association with, lipid, glycemic and anthropometric traits in further consortia of datasets, including the Oxford Biobank. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits.
PLoS Genet, V.7 (3) pp.e1001324 – PMID: 21423719
Strawbridge, R.J., et al. – Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes..Lay Summary –
In this study the authors present the combined results from a number of GWAS studies (Meta-analysis) looking at fasting proinsulin levels in 10,701 non-diabetic individuals of European Ancestry with ~2.5million genetic variants within the human genome (SNPs). 23 significant variants identified were analysed on a further 16,387 individuals, including the Oxford Biobank participants. Nine SNPs at eight loci were associated with proinsulin levels, two of which had not been associated with metabolic traits previously.
Diabetes, V.60 (10) pp.2624-2634 – PMID: 21873549
Zhu, H., et al. – The Lin28/let-7 axis regulates glucose metabolism..Lay Summary –
It is well appreciated that metabolic health influences the risk of developing cancer but the mechanisms involved remain poorly understood. Using a genetically modified mouse, two interacting molecular partners – Lin28 and Let7 – previously implicated in controlling cancer formation were found to also be central regulators of glucose metabolism. Analysis of genetic data, including that contributed by the Oxford BioBank, identified numerous genes that Let7 acts through to exert its effect on glucose metabolism. Understanding this genetic pathway may identify new targets for future treatments of metabolic disease.
Cell, V.147 (1) pp.81-94 – PMID: 21962509
Ahmed, M., et al. – Proteomic analysis of human adipose tissue after rosiglitazone treatment shows coordinated changes to promote glucose uptake..Lay Summary –
By comparing the protein profiles from fat tissue samples obtained from ten moderately obese Oxford Biobank volunteers before and after treatment with rosiglitazone, an oral diabetes medicine that controls blood sugar levels, this study identified a group of proteins whose levels changed after rosiglitazone treatment. This information provides insights into how fat cells increase their efficiency in glucose uptake and insulin sensitivity in response to rosiglitazone treatment.
Obesity, V.18 (1) pp.27-34 – PMID: 19556978
Andersson, J., et al. – Dysregulation of subcutaneous adipose tissue blood flow in overweight postmenopausal women..Lay Summary –
In post-menopausal women, particularly those who are overweight, fat has been found to accumulate in organs (ectopic fat), which can lead to insulin resistance (associated with cardiovascular disease and type 2 diabetes). This may be because blood flow and fat delivery to fat-specific storage sites (adipose tissue) is reduced; meaning fat is stored in organs instead. This study recruited participants from the Oxford Biobank and measured adipose tissue blood flow during fasting and after a meal. Being overweight always reduced blood flow to adipose tissue, while being post-menopausal reduced blood flow in normal weight women after eating, suggesting the menopause could affect ectopic fat accumulation under certain conditions.
Menopause, V.17 (2) pp.365-371 – PMID: 19940788
Collins, J.M., et al. – De novo lipogenesis and stearoyl-CoA desaturase are coordinately regulated in the human adipocyte and protect against palmitate-induced cell injury..Lay Summary –
Dietary fats are made up of a mixture of saturated and unsaturated fats. When we consume fats they are normally stored safely in the adipose tissue. However, there is evidence that very high levels of saturated fats can have adverse effects on cell function and health. In this study we isolated fat cells from abdominal subcutaneous fat biopsies from Oxford Biobank volunteers and looked at the effects of exposure to high levels of a saturated fat (palmitate). The results were unexpected, even though palmitate levels were high, the cells switched on a pathway to make more fat from non-lipid precursors, such as sugars. However, the newly formed fats were different in that they were more unsaturated. This may be a compensatory mechanism to protect cell function in the presence of high levels of saturated fats.
J Biol Chem, V.285 (9) pp.6044-6052 – PMID: 20032470
Dupuis, J., et al. – New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk..Lay Summary –
In this study the authors present the combined results from 21 GWAS studies (Meta-analysis) in an initial 46,186 non-diabetic individuals to identify new loci influencing glycemic traits. A follow-up of 25 significant variants were then analysed on a further 76558 individuals, including the Oxford Biobank participants. Sixteen SNPs were associated with fasting glucose and HOMA-B and two loci additional loci were associated with fasting insulin and HOMA-IR. Five loci were also associated with type 2 diabetes.
Nat Genet, V.42 (2) pp.105-116 – PMID: 20081858
Funada, J.-I., et al. – Regulation of subcutaneous adipose tissue blood flow is related to measures of vascular and autonomic function..Lay Summary –
In obesity, blood flow to the fat store under the skin (subcutaneous adipose tissue) is impaired. This could be related to problems with blood vessels enlarging (dilation), which allows increased blood flow, or heart function, which is controlled by the nervous system. In this study, participants were recruited from the Oxford Biobank and had their adipose tissue blood flow (ATBF), blood vessel dilation and heart function measured. Reduced ATBF and dilation were associated with obesity, and both dilation and heart function contributed to ATBF. These results indicate a complex relationship between obesity, blood vessel function and the nervous system.
Clin Sci (Lond), V.119 (8) pp.313-322 – PMID: 20518748
Harnden, K.E., K.N. Frayn, and L. Hodson. – Dietary Approaches to Stop Hypertension (DASH) diet: applicability and acceptability to a UK population..Lay Summary –
The Dietary Approaches to Stop Hypertension (DASH) diet is widely promoted in the USA for the prevention and treatment of high blood pressure. However this diet has not been assessed in a UK population. Fourteen healthy participants were recruited from the Oxford Biobank for a 30-day diet intervention study following a DASH style diet. The diet successfully and significantly reduced blood pressure.
J Hum Nutr Diet, V.23 (1) pp.03-10 – PMID: 19843201
Heid, I.M., et al. – Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution..Lay Summary –
Your distribution of body fat can influence your risk of conditions associated with obesity. One measure of fat distribution is waist to hip ratio (WHR). In this study the authors present the combined results from 32 GWAS studies (Meta-analysis) in an initial 77,167 non-diabetic individuals to identify new loci influencing WHR. A follow-up of 16 significant variants were then analysed on a further 113636 individuals over 29 studies, including the Oxford Biobank participants. Thirteen loci were found to be significantly associated, seven of which exhibited marked differences between genders, showing a stronger effect in women.
Nat Genet, V.42 (11) pp.949-960 – PMID: 20935629
Hodson, L., et al. – Does the DASH diet lower blood pressure by altering peripheral vascular function?..Lay Summary –
Specific components of the foods we eat may alter our blood pressure. The Dietary Approaches to Stopping Hypertension (DASH) diet which consists of eating lots of fruits and vegetables, whole grain foods, and low salt foods, has been clearly demonstrated to lower blood pressure but is unclear if it has other beneficial effects on parameters related to vascular health. Participants from the Oxford Biobank consumed a DASH diet for 30 days to investigate whether decreasing blood pressure altered other vascular factors that may be related to risk of cardiovascular disease. It was found the DASH diet notably lowered blood pressure and other factors related to heart disease risk, such as plasma total cholesterol concentrations, but it did not change vascular function.
J Hum Hypertens, V.24 (5) pp.312-319 – PMID: 19657359
Hodson, L., et al. – Greater dietary fat oxidation in obese compared with lean men: An adaptive mechanism to prevent liver fat accumulation?..Lay Summary -Obesity is associated with an increase of fat in the liver and fat known as VLDL-TG being secreted from the liver that increases the risk of cardiovascular disease. When fatty acids enter the liver they can either be secreted as VLDL-TG, stored or oxidised for energy. Healthy lean and obese males recruited from the Oxford Biobank were fed three meals over 24 hours. The results showed that obese compared to lean males had a greater amount of dietary fat entering oxidation pathways which may be an initial metabolic adaption to try and prevent fat being stored in the liver. Am J Physiol Endocrinol Metab, V.299 (4) pp.E584-E592 – PMID: 20628024
McQuaid, S.E., et al. – Development of an arterio-venous difference method to study the metabolic physiology of the femoral adipose tissue depot..Lay Summary –
Fat stored around the hips (gluteofemoral adipose tissue) is beneficial to metabolic health, however, little is known about it due to the complex methodologies required to assess the molecules being released from adipose tissue. In this study, participants were recruited from the Oxford Biobank and had the blood draining their gluteofemoral adipose tissue measured using a new ultrasound method. Leptin (an appetite-suppressing hormone secreted from fat) and fat molecules were released, whereas creatinine (released from muscle) was not, as expected in adipose tissue. These results show that the method was accurately locating and measuring blood from gluteofemoral fat, establishing this technique for use in future studies which will allow comparison with fat stored in other locations.
Obesity, V.18 (5) pp.1055-1058 – PMID: 20057374
McQuaid, S.E., et al. – Femoral adipose tissue may accumulate the fat that has been recycled as VLDL and nonesterified fatty acids..Lay Summary –
Lower body fat, in contrast to abdominal, fat accumulation appears protective against diabetes and cardiovascular disease. In this study the authors investigate whether this difference in disease susceptibility is due to differences in the different fat depots ability to store fat. Participants from the Oxford Biobank were recruited to study where fats from a meal end up and how local blood flow in the fat tissue responds to a meal. Blood flow increased in both fat depots in response to a meal however lower body fat showed a lower movement of fats and a different preference than the upper body fat.
Diabetes, V.59 (10) pp.2465-2473 – PMID: 20682685
Speliotes, E.K., et al. – Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index..Lay Summary –
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, the authors examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals, including the Oxford Biobank participants. The authors confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass.
Nat Genet, V.42 (11) pp.937-948 – PMID: 20935630
Lindgren, C.M., et al. – Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution..Lay Summary –
In this study the authors present the combined results from 16 GWAS studies (Meta-analysis) in an initial 38580 individuals to identify new loci influencing central obesity and fat distribution. A follow-up of 26 significant variants were then analysed on a further 70689 individuals, including the Oxford Biobank participants. Two loci were associated with central obesity and a third loci with body fat distribution.
PLoS Genet, V.5 (6) pp.e1000508 – PMID: 19557161
Madani, R., et al. – RANTES release by human adipose tissue in vivo and evidence for depot-specific differences..Lay Summary –
Obesity is associated with increased activity of the immune system. This activity can be assessed by measuring levels of specific chemicals released by immune cells. RANTES is a chemical that was chosen due to previously work suggesting it can negatively impact the function of fat at the cellular level and thereby influence overall metabolic health. By analysing blood samples taken from individuals from the Oxford BioBank displaying different extents of obesity it was found that RANTES is released by fat tissue in different parts of the body to varying extents. However, due to the small amount detected it was concluded that fat is probably not the main contributor to the total amount of RANTES circulating in the blood.
Am J Physiol Endocrinol Metab, V.296 (6) pp.E1262-E1268 – PMID: 19240255
Perez-Matute, P., et al. – Transcriptional control of human adipose tissue blood flow..Lay Summary –
The regulation of blood flow through fat tissue is poorly understood but clearly an important aspect of tissue function. We know that there is acute regulation (increased blood flow) after meal intake, but little is known about the distinct and reproducible differences between individuals. Genes believed to regulate blood flow were analysed in a small cohort of individuals from the Oxford Biobank in whom blood flow regulation had been measured. One expected (nitric oxide synthase) gene and one new gene (natriuretic peptide receptor A) were positively associated with the increase in blood flow seen after a meal. As a high blood flow in fat tissue is associated with good metabolic function of the tissue, the identification of the natriuretic peptide receptor A as a novel putative regulator of blood flow could be of importance.
Obesity, V.17 (4) pp.681-688 – PMID: 19165164
Roberts, R., et al. – Markers of de novo lipogenesis in adipose tissue: Associations with small adipocytes and insulin sensitivity in humans..Lay Summary –
Fat tissue is normally considered the tissue that stores the excess of our dietary fat, but in this study we observe clear signals that fat tissue can also convert sugar to fat. Such a conversion is also seen in the liver but then often associated with obesity and metabolic problems. In contrast, in fat tissue it seems the conversions takes place in healthy small fat cells and is a normal feature of tissue function.
Diabetologia, V.52 (5) pp.882-890 – PMID: 19252892
Ruge, T., et al. – Fasted to fed trafficking of fatty acids in human adipose tissue reveals a novel regulatory step for enhanced fat storage..Lay Summary –
Healthy lean men recruited from the Oxford Biobank were studied over a 24-hour period; during this time they were given three meals. The findings showed that fat storage was enhanced during the day and extrapolating to whole body values suggested that a large proportion of fat from each meal was stored in fat tissue and a large proportion of carbohydrate went into skeletal muscle.
strong>J Clin Endocrinol Metab, V.94 (5) pp.1781-1788 – PMID: 19223522
Christodoulides, C., et al. – Circulating Fibroblast Growth Factor 21 Is Induced by Peroxisome Proliferator-Activated Receptor Agonists But Not Ketosis in Man.Lay Summary –
The gene FGF21 has been shown to play a critical role in regulating metabolism during ketosis in Mice but little is known of its function in Humans. The aim of the study was to measure plasma FGF21 during fasting, ketogenic diet, and PPAR agonist treatment in humans. The study involved the use of material from three patient groups and a subset of Oxford Biobank partisipants that had undergone another study looking at the effect of the Rosiglitazone drug. It was concluded that FGF21 does not play a major role in regulating the fasting response or ketosis in man. However, plasma FGF21 is elevated in response to pharmacological activation of PPARα and PPARδ, e.g. by Rosiglitazone, and may contribute to the beneficial metabolic effects observed in response to pharmacotherapy with these compounds.
J Clin Endocrinol Metab, V.94 (9) pp.3594-3601 – PMID: 19531592
Bickerton, A.S.T., et al. – Adipose tissue fatty acid metabolism in insulin-resistant men..Lay Summary –
Circulating non-esterified fatty acid (NEFA) originate from fats stored and released from fat cells. This process is suppressed by insulin in the period following a meal. However, the systemic and adipose tissue NEFA metabolism in insulin-resistant status were rarely investigated. At the population level data held on the Oxford biobank was interrogated. For a metabolic investigation 20 over weight men were recruited from the oxford biobank. The results indicated that NEFA release, i.e. fat released from fat tissue is suppressed in high fasting insulin concentrations.
Diabetologia, V.51 (8) pp.1466-1474 – PMID: 18504545
Chong, M.F.-F., et al. – Parallel activation of de novo lipogenesis and stearoyl-CoA desaturase activity after 3 d of high-carbohydrate feeding..Lay Summary –
Excess sugars in the diet can be converted into fats, this is known as de novo lipogenesis (DNL), therefore high high-carbohydrate diets increase DNL. Another important component is the modification of lipid synthesised by DNL. One important gene involved in this is stearoyl-CoA desaturase (SCD) but its effects are not well understood. In a crossover study eight participants recruited from the Oxford Biobank were fed either a high carbohydrate or high fat diet. Analysis of lipids from blood then enabled the quantification of DNL and SCD action. It was found that parallel activation of DNL and SCD was found after a short period of high-carbohydrate feeding.
Am J Clin Nutr, V.87 (4) pp.817-823 – PMID: 18400702
Freathy, R.M., et al. – Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on bmi..Lay Summary –
One of the most published Loci associated with obesity and Type 2 Diabetes is the FTO gene. This paper looks at whether the common variants associated with BMI in this gene are also associates with metabolic traits known to be diabetes risk factors, such as raised insulin, glucose, and triglycerides. Ten metabolic traits were analysed using data from 17037 individuals across 7 studies, including those from the Oxford Biobank. The FTO variant rs9939609 was associated with metabolic changes consistent with an increase in BMI but not independent of BMI.
Diabetes, V.57 (5) pp.1419-1426 – PMID: 18346983
Loos, R.J.F., et al. – Common variants near MC4R are associated with fat mass, weight and risk of obesity..Lay Summary –
This Genome wide association study (GWAS) analysed 16,876 individuals of European ancestry looking for new loci associated with Body Mass (BMI). The initial analysis was then followed up in a further 60352 adults, which included the Oxford Biobank and 5988 children. In addition to the previously identified FTO gene a new susceptibility locus near the MC4R gene was identified.
Nat Genet, V.40 (6) pp.768-775 – PMID: 18454148
Roberts, R., et al. – Reduced oxidation of dietary fat after a short term high-carbohydrate diet..Lay Summary –
The effects of short term high-carbohydrate diet on tissue-specific alterations in fatty acid metabolism are not well established. Eight healthy individuals were recruited from the Oxford Biobank. Participants had calorie balanced diets containing a high percentage of energy from carbohydrates or a higher percentage of energy from fat for 3 day in a randomized crossover dietary intervention study. On the study day fatty acids were labelled with stable isotope tracers and given via meals and intravenous infusion. Breath samples and regional blood samples were collected before the meal and for 6 hours after. The findings showed that there was a significant shift in the utilisation of fats from energy expenditure to energy storage when on a high-carbohydrate diet.
Am J Clin Nutr, V.87 (4) pp.824-831 – PMID: 18400703
Savage, D.B., et al. – A prevalent variant in PPP1R3A impairs glycogen synthesis and reduces muscle glycogen content in humans and mice..Lay Summary –
The uptake of glucose by muscle is tightly regulated and some of the glucose is stored as glycogen for later use. We discovered a variant in a gene coding for a protein specifically involved in glycogen storage in muscle. Carriers of this variant appears healthy but if the variant exists in people who have other faulty genes, this can lead to early diabetes. In this study we demonstrate that carriers of the gene variant have problem in storing glucose as glycogen in muscle. It is both surprising and interesting that this defect is not associated with any ill effects, not least because defects in glycogen storage has been described as a hallmark finding in people with Type 2 diabetes.
PLoS Med, V.5 (1) pp.e27 – PMID: 18232732
Tan, G.D., et al. – Fatty acid metabolism in patients with PPARγ mutations..Lay Summary –
This study describes fat transport in blood in a patient who is lacking the ability to store fat appropriately in fat tissue (lipodystrophy) and their data compared to a selected group of controls form the Oxford Biobank. A minor fat transport pathway seen in everyone was found to be vastly up-regulated and this pathway (spill over pathway) could be possibly explain some of the metabolic problems patients with lipodystrophy have.
J Clin Endocrinol Metab, V.93 (11) pp.4462-4470 – PMID: 18713822
Bickerton, A.S.T., et al. – Preferential uptake of dietary fatty acids in adipose tissue and muscle in the postprandial period..Lay Summary –
The means by which dietary fat is stored in either fat tissue or skeletal muscle are not clear. Volunteers from the Oxford Biobank gave blood samples before and for 6 hours after eating a mixed meal; various components of fat released from this meal were measured in the blood samples. The most striking finding was that after eating one of the components of fat released from the meal into the blood was preferentially taken up by fat tissue; in muscle this was not the case.
Diabetes, V.56 (1) pp.168-176 – PMID: 17192479
Frayling, T.M., et al. – A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity..Lay Summary –
Obesity is a serious international health problem that increases the risk of several common diseases. In this paper an initial GWAS search for type 2 diabetes susceptibility genes identified the FTO gene locus. This was then replicated in 13 cohorts, including the Oxford Biobank. Homozygous carries of the rare allele were about 3kg heavier and reflects a specific increase in fat mass.
Science, V.316 (5826) pp.889-894 – PMID: 17434869
Heath, R.B., et al. – Dietary fatty acids make a rapid and substantial contribution to VLDL-triacylglycerol in the fed state..Lay Summary –
Elevated fat and cholesterol lipoprotein levels in the blood after eating are associated with Heart disease and type 2 diabetes yet few studies have examined the effect of sequential meals on this fat metabolism. This study investigated fat metabolism after eating. Eight healthy individuals were recruited from the Oxford Biobank. By using 13C-labeled fatty acids in breakfast and lunch meals, the authors were able to trace the process of fat metabolism and showed that there is a rapid flux of fatty acids from the diet into stored fat depots.
Am J Physiol Endocrinol Metab, V.292 (3) pp.E732-E739 – PMID: 17090753
Hodson, L., et al. – The contribution of splanchnic fat to VLDL triglyceride is greater in insulin-resistant than insulin-sensitive men and women: Studies in the postprandial state..Lay Summary –
Fatty acids that are present within the liver originate from a number of different sources including those consumed (dietary fat), those already present in the body (coming from adipose tissue or stored within the liver) and those synthesised within the liver from non-lipid precursors. These fatty acids from different sources are then used to synthesise very low density lipoprotein triglyceride (VLDL-TG). We recruited healthy insulin sensitive and insulin resistant individuals from the Oxford Biobank and fed them a mixed test meal and used specially labelled molecules (isotopes) to determine if VLDL-TG was produced from the same fatty acid sources in insulin sensitive and insulin resistant individuals. The only difference we found was a notably greater amount of fatty acids from splanchnic sources (that is fatty acids from visceral adipose tissue, those already stored in the liver and those synthesised in the liver) were used to produce VLDL-TG in insulin resistant compared to insulin-sensitive individuals. These results help to explain why VLDL-TG concentrations may increase when an individual become insulin resistant.
Diabetes, V.56 (10) pp.2433-2441 – PMID: 17601988
Neville, M.J., et al. – Absence of relationship between MTTP haplotypes and longevity..Lay Summary –
Polymorphisms for the microsomal triglyceride transfer protein (MTTP) gene have been associated with longevity and with lower risk for cardiovascular mortality. However there is conflicting data in the literature. In this paper detailed analysis of the genetics within the MTTP gene were used to compared an elderly population of a mean age of 78 to those within the Oxford Biobank Cohort (mean age 40). No significant association could be seen between MTTP genetic variants and longevity.
J Gerontol A Biol Sci Med Sci, V.62 (2) pp.202-205 – PMID: 17339647
Tan, G.D., et al. – The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: The first use of the Oxford Biobank..Lay Summary –
In this Paper the Authors describe the first use of the Oxford Biobank and the utility of using a Recruit-by-Genotype approach in biomedical research and translational medicine. The study described looks at a gene integral to fat tissue function, a gene called peroxisome proliferator-activated receptor (PPAR). The Authors hypothesise that the Ala12 carriers of a Pro12Ala polymorphism in this gene demonstrate greater adipose tissue metabolic flexibility and insulin sensitivity. After genotyping DNA from Oxford Biobank participants twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,1-(13)C]tripalmitin. The results confirmed previous observation that the PPAR Ala12 allele protects against the development of type 2 diabetes. Plus this study highlights the power of using Recruit-by-Genotype studies and demonstrates the value of collections of volunteers such as the Oxford Biobank.
Diabetologia , V.49 (1) pp.158-168 – PMID: 16362285
Ledmyr, H., et al. – The microsomal triglyceride transfer protein gene-493T variant lowers cholesterol but increases the risk of coronary heart disease..Lay Summary –
Between-people variations in genes can explain differences in fat transport. In this study we studied the effect of a fat transfer protein in the heart and its relationship to heart attacks in a large cohort. It is The gene variant otherwise associated with lowering cholesterol in the blood was in this study associated with more heart attacks. It is believed that this might be explained fat transport within cells in the heart that predisposes the heart to performing badly if there is a heart attack for any other reason.
Circulation , V.109 (19) pp.2279-2284 – PMID: 15136504