Lipid Profiling and Signalling: Macronutrients and Metabolic Health View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2011-2016

FUNDING AMOUNT

4586954.0 GBP

ABSTRACT

According to statistics reported by Diabetes UK in 2010, since 1996 the number of people diagnosed with diabetes has increased from 1.4 million to 2.6 million, and is set to rise to four million people by 2025. The majority of these cases are associated with type 2 diabetes (T2DM), with the increased prevalence arising from an increasingly aged population and the rise in overweight and obese people. The interaction between being overweight and T2DM arises because fats become inappropriately stored in organs such as the liver, pancreas and skeletal muscle, reducing the body’s capacity to respond to the hormone insulin, an important signal which regulates the storage of nutrients. However, one central enigma concerning the interaction between obesity and T2DM is why some individuals appear to have a near limitless capacity for storing fat without proceeding to diabetes, while other appear to be pre-disposed to the disease. The lipid profiling and signalling group are using novel mass spectrometry, nuclear magnetic resonance spectroscopy and computer aided modelling to understand this problem. We have a range of studies that investigate the effects of over-nutrition, and in particular the role that high fat intake plays in inducing disease. The benefits of this work are an improvement in our understanding of the disease process, providing new drug targets, and the identification of ‘biomarkers’, molecular signatures of disease or treatment that could be used for diagnostics. Technical Summary Understanding how fat metabolism is regulated in the human body is essential to understanding a number of major pathologies affecting human health including type II diabetes (T2DM), obesity, atherosclerosis and fatty liver disease. The incidence of both T2DM and obesity are rising rapidly across the globe as a result of over nutrition. The aim of the Lipid Profiling and Signalling programme is to understand why on an individual basis certain people develop insulin resistance and subsequently type 2 diabetes, while others stay metabolically healthy, and in particular how diet interacts with relative risk. We investigate the regulation of lipid metabolism and its interplay with health and diseases of over nutrition using a combination of state of the art mass spectrometry, NMR spectroscopy and bioinformatics to use an individual’s metabolism as a measure of their relative risk of developing disease. The programme consists of four inter-related areas of research. The first involves the understanding of adipose tissue metabolism in health and disease. In particular through work on peroxisome proliferator activated receptors (PPARs), three receptors that play a central role in regulating metabolism at the whole organism level, we have investigated the regulation between lipid storage and fatty acid oxidation in this tissue. This has led us into work understanding small molecule activators of mitochondrial biogenesis in white adipose tissue, so called ‘browning’ agents, which could be used to reduce obesity and restore metabolic health. In addition we have developed a quantitative method for the profiling of lipid mediators, including over 100 eicosanoids and related metabolites. These mediators are important in understanding some of the mechanisms thought to mediate insulin resistance and in particular how the generation of reactive oxygen species produce lipid mediators linked to inflammation of key organs including adipose tissue. The second area of research involves the consequences of ectopic fat deposition in liver and skeletal muscle, and how this influences insulin resistance. In addition to work in global lipidomics and eicosanoid profiling detailed above, we have also developed methods to examine how changes in fat metabolism affect the composition of sub-cellular organelles and cellular function, such as inducing endoplasmic reticulum stress and mitochondrial dysfunction. We are developing mass spectrometry tools to profile the lipid composition of sub-cellular membranes in order to understand how changes in lipid metabolism alter sub-cellular function and hence influence disease at a cellular level. The third area of research is in molecular epidemiology. To assess the impact diet has on T2DM and the metabolic syndrome, we, in conjunction with members of MRC Epidemiology and the Institute of Public Health, University of Cambridge, are using lipidomics and metabolomics to profile individuals at the epidemiological scale and cross correlate changes in metabolism with anthropometric and genome wide association studies. All this work is strongly underpinned by bioinformatics and multivariate statistics. We have developed a range of bioinformatic tools for the processing and storage of lipidomic data. These tools are currently being used in-house in a number of collaborative lipidomic studies into aspects of the metabolic syndrome including large scale epidemiology studies and mass spectrometry imaging of fatty liver disease. More... »

URL

https://gtr.ukri.org/project/EFC3E53D-4230-4169-A9AE-77810E2AAFC4

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However, one central enigma concerning the interaction between obesity and T2DM is why some individuals appear to have a near limitless capacity for storing fat without proceeding to diabetes, while other appear to be pre-disposed to the disease.\nThe lipid profiling and signalling group are using novel mass spectrometry, nuclear magnetic resonance spectroscopy and computer aided modelling to understand this problem. We have a range of studies that investigate the effects of over-nutrition, and in particular the role that high fat intake plays in inducing disease. 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    4 schema:description According to statistics reported by Diabetes UK in 2010, since 1996 the number of people diagnosed with diabetes has increased from 1.4 million to 2.6 million, and is set to rise to four million people by 2025. The majority of these cases are associated with type 2 diabetes (T2DM), with the increased prevalence arising from an increasingly aged population and the rise in overweight and obese people. The interaction between being overweight and T2DM arises because fats become inappropriately stored in organs such as the liver, pancreas and skeletal muscle, reducing the body’s capacity to respond to the hormone insulin, an important signal which regulates the storage of nutrients. However, one central enigma concerning the interaction between obesity and T2DM is why some individuals appear to have a near limitless capacity for storing fat without proceeding to diabetes, while other appear to be pre-disposed to the disease. The lipid profiling and signalling group are using novel mass spectrometry, nuclear magnetic resonance spectroscopy and computer aided modelling to understand this problem. We have a range of studies that investigate the effects of over-nutrition, and in particular the role that high fat intake plays in inducing disease. The benefits of this work are an improvement in our understanding of the disease process, providing new drug targets, and the identification of ‘biomarkers’, molecular signatures of disease or treatment that could be used for diagnostics. Technical Summary Understanding how fat metabolism is regulated in the human body is essential to understanding a number of major pathologies affecting human health including type II diabetes (T2DM), obesity, atherosclerosis and fatty liver disease. The incidence of both T2DM and obesity are rising rapidly across the globe as a result of over nutrition. The aim of the Lipid Profiling and Signalling programme is to understand why on an individual basis certain people develop insulin resistance and subsequently type 2 diabetes, while others stay metabolically healthy, and in particular how diet interacts with relative risk. We investigate the regulation of lipid metabolism and its interplay with health and diseases of over nutrition using a combination of state of the art mass spectrometry, NMR spectroscopy and bioinformatics to use an individual’s metabolism as a measure of their relative risk of developing disease. The programme consists of four inter-related areas of research. The first involves the understanding of adipose tissue metabolism in health and disease. In particular through work on peroxisome proliferator activated receptors (PPARs), three receptors that play a central role in regulating metabolism at the whole organism level, we have investigated the regulation between lipid storage and fatty acid oxidation in this tissue. This has led us into work understanding small molecule activators of mitochondrial biogenesis in white adipose tissue, so called ‘browning’ agents, which could be used to reduce obesity and restore metabolic health. In addition we have developed a quantitative method for the profiling of lipid mediators, including over 100 eicosanoids and related metabolites. These mediators are important in understanding some of the mechanisms thought to mediate insulin resistance and in particular how the generation of reactive oxygen species produce lipid mediators linked to inflammation of key organs including adipose tissue. The second area of research involves the consequences of ectopic fat deposition in liver and skeletal muscle, and how this influences insulin resistance. In addition to work in global lipidomics and eicosanoid profiling detailed above, we have also developed methods to examine how changes in fat metabolism affect the composition of sub-cellular organelles and cellular function, such as inducing endoplasmic reticulum stress and mitochondrial dysfunction. We are developing mass spectrometry tools to profile the lipid composition of sub-cellular membranes in order to understand how changes in lipid metabolism alter sub-cellular function and hence influence disease at a cellular level. The third area of research is in molecular epidemiology. To assess the impact diet has on T2DM and the metabolic syndrome, we, in conjunction with members of MRC Epidemiology and the Institute of Public Health, University of Cambridge, are using lipidomics and metabolomics to profile individuals at the epidemiological scale and cross correlate changes in metabolism with anthropometric and genome wide association studies. All this work is strongly underpinned by bioinformatics and multivariate statistics. We have developed a range of bioinformatic tools for the processing and storage of lipidomic data. These tools are currently being used in-house in a number of collaborative lipidomic studies into aspects of the metabolic syndrome including large scale epidemiology studies and mass spectrometry imaging of fatty liver disease.
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