Diet & Cardiovascular Health
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The group have also pioneered research into the effect of triglyceride structure on postprandial lipid metabolism. More recently we have been investigating the effect of different types of fat and food structure on the release of gut hormones that promote insulin secretion and have effects on satiety.
Over the years, we have acquired a high level of expertise in carrying out dietary intervention trials. Our current goal is to determine the optimum dietary intervention on the cardiovascular disease risk factors associated with the metabolic syndrome. We are investigating whether maternal obesity can programme the offspring to develop metabolic syndrome. We are particularly interested in why obesity causes metabolic syndrome in some people and not others.
The ability of fatty acids and retinoids to cross the placenta is critically important for proper fetal growth and development. A protein mediated multi-step mechanism by which essential lipids are selectively transported from maternal to fetal circulation via the trophoblast layer is proposed. To investigate, a combination of mathematical, biochemical, cell and molecular biological approaches are being used.
In vivo function of zinc-alpha2 glycoprotein (ZAG)
ZAG is believed to participate in the chronic weight loss and muscle wasting exhibited by certain cancer patients. ZAG's true in vivo function is as yet undetermined although given that the protein binds long chain fatty acids, it is likely that ZAG participates in lipid homeostasis. Using a series of biochemical and molecular biology based techniques attempts are being made to identify and characterize ZAG's cell surface receptor. Possible clinical applications of this research would be the development of drugs that inhibit or modulate ZAG:receptor binding, thus reducing or eliminating the drastic weight loss exhibited by some cancer patients during physiologically demanding therapies.
Subsequently I undertook a series of cross-sectional studies to measure intramyocellular lipid storage in human subjects characterised by insulin resistance or sensitivty, for example type 2 diabetic subjects, vegan subjects and subjects undergoing weight loss.
Furthermore, I performed human intervention studies to investigate the effects of low glycaemic index dietary manipulations on insulin sensitivity and intramyocellular lipid. This work showed that intramyocellular lipid storage is elevated in insulin resistant subjects compared to insulin sensitive subjects. Dietary manipulations were shown to impact on insulin sensitivity and muscle lipid storage but not in a dependent manner.
My postdoctoral research at Imperial College involved running a large multi-centre, dietary intervention trial; the RISCK trial, in which the effects of dietary manipulations of quantity and quality of dietary fat and carbohydrate on insulin sensitivity and cardiovascular risk were investigated in 650 subjects.
Recently my main focus has been the peroxisome proliferator-activated receptor genes, PPARα and PPARγ and the PPARγ target gene adiponectin. We have explored the effect of dietary fatty acid interaction with PPARG and PPARA variants on plasma lipids in the RISCK study, a randomised control trial in which a high SFA diet was replaced by MUFA or carbohydrate. We found significant diet x ADIPOQ gene x age interaction in determination of serum adiponectin. Habitual dietary P:S ratio x PPARG gene interaction and dietary fat x PPARA and PPARG gene interaction in determination of plasma lipids has also been shown. Ongoing investigations are centred on gene x diet interactions on lipid profiles and vascular properties related to n3-PUFA intake in the MARINA study.
2. PPARγ function in mitigation of lipodystrophic effects of anti-retroviral therapy (in collaboration with Dr Anne Mullen).
The use of anti-retroviral therapy can lead to HIV-associated lipodystrophy syndrome (HALS). There is some evidence that the activity of PPARγ is down-regulated by anti-retroviral drugs. Pharmacological PPARγ ligands such as rosiglitazone, have shown positive effects on HALS in some RCTs. We aim to investigate whether pre-treatment of cultured adipocytes with PUFAs alters the level of activated PPARγ extracted from cells exposed to anti-retrovirals. Promising results in vitro are expected to lead to human trials.
3. Functional and genomic changes following activation of TRPA1 receptors in the normal and hypertensive peripheral vasculature (in collaboration with Prof Sue Brain, Cardiovascular Sciences).
Research in mouse transcriptomics was initiated in an attempt to identify new players in energy regulation and obesity susceptibility. We originally investigated differential expression of hypothalamic genes in the dietary-induced obesity model C57BL6 mouse on high-fat and standard diets, using microarrays. The aim of our current collaboration is to determine how activation of peripheral vascular responses by transient receptor potential (TRP) ankyrin 1 (TRPA1) influences blood flow in the normal and angiotensin-II mouse model of hypertension to investigate the molecular and genetic changes that occur before and after activation of TRPA1 in the ear vasculature. We aim to identify genes and pathways that are affected by hypertension and/or exhibit selective altered expression following stimulation and are linked to the TRPA1 neurogenic peripheral responses in hypertension. Possible functional analysis in vivo will involve WT and TRPA1KO mice.
Recent publications
AlSaleh A, O'Dell SD, Frost GS, Griffin BA, Lovegrove JA, Jebb SA, Sanders TA (2011) Single nucleotide polymorphisms at the ADIPOQ gene locus interact with age and dietary intake of fat to determine serum adiponectin in subjects at risk of the metabolic syndrome. Am J Clin Nutr 94:1-8.
Lee AK, Kyriakou T, Weston AJ, O'Dell SD (2010) Functional single nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter. DNA Cell Biol 29:703-12.
Lee AK, Mojtahed-Jaberi M, Kyriakou T, Aldecoa-Otalora Astarloa E, Arno M, Marshall NJ, Brain SD, O'Dell SD (2010) Effect of high-fat feeding on expression of genes controlling availability of dopamine in mouse hypothalamus. Nutrition 26: 411-422.
Liu G, Riese H, Spector TD, O'Dell SD, Stolk R, Snieder H (2009). Bivariate genetic modeling of the response to an oral glucose tolerance challenge: A gene-environment interaction approach. Diabetologia 52:1048-1055.
Goyenechea E, Collins LJ , Parra D, Abete I, Crujeiras AB, O'Dell SD, Alfredo Martínez J. (2009) The -11391 G/A polymorphism of the adiponectin gene promoter is associated with metabolic syndrome traits and the outcome of an energy-restricted diet in obese subjects. Horm Metab Res 41:55-61.
Goyenechea E, Collins LJ , Parra D, Liu G, Snieder H, Swaminathan R, Spector TD, Alfredo Martínez J, O'Dell SD (2008) CD36 gene promoter polymorphisms are associated with low density lipoprotein-cholesterol in normal twins and after a low-calorie diet in obese subjects. Twin Res Hum Genet 11:621-628.
Kyriakou T, Collins LJ, Spencer-Jones NJ, Malcolm C, Wang X, Snieder H, Swaminathan R, Hart DJ, Spector TD, O'Dell SD (2008) Adiponectin gene ADIPOQ SNP associations with serum adiponectin in two female populations and effects of SNPs on promoter activity. J Hum Genet 53:718-727.
Ge D, Gooljar SB, Kyriakou T, Collins LJ, Swaminathan R, Snieder H, Spector TD, O'Dell SD (2008) Association of common JAK2 variants with body fat, insulin sensitivity and lipid profile. Obesity (Silver Spring)16:492-449.
Snieder S, Wang X, Shiri-Sverdlov R, van Vliet- Ostaptchouk JV, Hofker MH, Spector TD, O'Dell SD (2008) Associations with general and central obesity in post-menopausal women confirm TUB as a candidate gene for late-onset obesity in humans. Diabetologia 51:54-61.
My postdoctoral research involved running a community based dietary trial of increased fruit and vegetable consumption on blood pressure and vascular function in subjects with pre-hypertension/mild hypertension (DRFRUITNVEG). This work involved investigating the potential mechanisms by which fruit and vegetable intake may influence vascular function, including the influence of potassium, which is found in high amounts in fruit and vegetables.
My current research continues in the broad theme of diet and cardiovascular risk, with particular focus on dietary lipids and the effects and mechanisms by which dietary fat acutely affects endothelial function, in collaboration with the Cardiovascular Division at St Thomas' Hospital.
Wherever possible, we try to take a holistic view with regard to dietary intake and are interested in the effects of overall dietary patterns. We have a long-standing interest in comparing the health of vegans with vegetarians, who consume milk and eggs, and omnivores, who eat meat/or fish in addition to milk and eggs. We also have an interest in the acute effects resulting from the consumption of certain foods as well as the longer term effects.
Our group has specific expertise in the measurement of polyunsaturated fatty acids and other lipids including eicosanoids. Perhaps what differentiates the work of our group from other groups working on dietary lipids is that we have tended to focus on the interaction between the effects of dietary lipids and changes in haemostasis. Our work was among the first to show that meals high in fat induce activation of clotting factor VII and impair endothelial function. Our most recent work in this area indicates that meals high in oleic acid may have adverse effects on procoagulant activity and endothelial function compared with meals containing stearic acid.
We endeavour to foster cross-disciplinary research and seek to work with people with expertise that complements our own. We have much experience in the design and execution of controlled dietary intervention trials.
