Macronutrients and Metabolic Health - Understanding how metabolic disease arises at the population level using metabolomics and lipidomics.

Both obesity and type 2 diabetes (T2DM) are increasing in the UK, placing significant pressure on the National Health Service and impacting on the health of the UK. We know that some of the major causes of these increases are associated with increased dietary consumption of fats and sugars, as well as a general decrease in physical activity. While current public health advice is to exercise more and eat less calorie dense foods, this health advice has been unable to halt the increases in either obesity or T2DM. While there are a number of drugs used to treat T2DM and the increased fat concentrations found in the blood of individuals with obesity, many have side effects which complicate their long term use and are costly to administer. One central question to the field of diabetes research is why on an individual basis certain people are predisposed to developing insulin resistance (a pre-diabetic state) and subsequent T2DM while others stay metabolically healthy. Addressing this question could help treat those at risk of progression and have a significant impact on the costs of treating this disease and its complications.

In order to do this we use analytical chemistry techniques, including mass spectrometry and Nuclear Magnetic Resonance (NMR) spectroscopy, to measure the total small molecule complement of tissues, cells and biofluids to develop a fingerprint of those metabolites that are associated with disease using a combination of multivariate statistics and pattern recognition techniques. This approach is termed metabolomics. By modelling changes in these metabolites as disease progresses we build up an 'atlas' of response in terms of the key metabolic perturbations associated with the disease. In particular this approach allows us to look at how food intake influences the metabolism of the body, and we can model these changes to look at diet-genotype interactions induced by over-nutrition (eating too much food).

To achieve this aim we have identified four themes to be developed in parallel.

1. Fat cells in health and disease: It is well established that fat cells (referred to as white adipose tissue) have numerous important roles in maintaining healthy metabolism in addition to their role as a major site for storage of fats, including roles in regulating hormones, maintaining body temperature and even contributing to the body clock. We will apply metabolomics in conjunction with molecular biology tools to investigate the balance between lipid storage and how we might influence fat metabolism to reduce obesity.

2. Ectopic fat deposition: Once the capability of white adipose tissue to store fat has been exceeded, fat deposition occurs inappropriately (ectopically) in other tissues. While the consequences of raised blood glucose are biochemically well defined, we do not understand what the consequences of raised fat concentrations are. We will use comprehensive metabolomic approaches to profile the impact of excessive fat storage in the liver, heart and skeletal muscle, and in particular focus on the progression of fatty liver disease.

3. Lipidomics at the epidemiology scale: While most animal models are caused by rare errors in single genes which cause T2DM, the most common forms found in patients with diabetes are caused by many genes with a strong environmental interaction, particularly as the result of over nutrition and increased sedentary lifestyles. In order to investigate IR and T2DM development in humans we have developed assays that can be performed on a global scale to allow us to address questions about T2DM and diet, ethnicity and age in epidemiology studies.

4. Method development in mass spectrometry and bioinformatics: To be able to conduct these studies we require being at the forefront of developments in both mass spectrometry and mathematical tools for processing the data. We are currently developing tools in mass spectrometry imagining and ion mobility for lipidomics.

Both obesity and type 2 diabetes (T2DM) are increasing in the UK impacting on the nation's health. We aim to address this major health issue by understanding the interactions between over nutrition, subsequent obesity, and the development of insulin resistance (IR), and how this ultimately leads to T2DM and cardiovascular disease. Our global aim is to understand the underlying mechanisms that determine why on an individual basis certain people are predisposed to developing IR and subsequently T2DM, while others stay metabolically healthy. To achieve this aim we have identified four themes to be developed in parallel.
1. White adipose tissue (WAT) function in health and disease: We will apply metabolomics in conjunction with molecular biology tools to investigate the balance between lipid storage and oxidation, and in particular continue our study of the browning of WAT. Furthermore, using measurements of lipid mediators we will investigate further how over nutrition produces adipose tissue dysfunction and inflammation.
2. Ectopic fat deposition: We will use comprehensive metabolomic and lipidomic mass spectrometry approaches to profile the impact of excessive fat storage in the liver, heart and skeletal muscle, and in particular focus on the transition of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and cirrhosis, the development of ER-stress in skeletal muscle, and how diet influences cell membrane composition and ultimately cellular function across the body.
3. Lipidomics at the epidemiology scale: To investigate IR and T2DM development in humans we have developed assays that can be performed on a global scale to allow us to address questions about T2DM and diet, ethnicity and age. These will be applied to large scale studies (n>5000) such as Fenland, PROMIS and INTERVAL.
4. Method development in mass spectrometry and bioinformatics: We are currently developing tools in mass spectrometry imaging and ion mobility for lipidomics.

Both obesity and T2DM are increasing in the UK, placing significant pressure on the NHS and impacting on the health of the UK. We aim to address these major health issues by understanding the interactions between over nutrition, subsequent obesity, the development of insulin resistance (IR) and ultimately type 2 diabetes (T2DM), as well as cardiovascular disease (CVD). Central issues for understanding the increase in obesity are the mechanisms that regulate the set point for energy balance and where macronutrients are stored, and we have been at the forefront in developing tools to measure these factors.

Our work also addresses one of the key priorities identified by the MRC Strategic Review of Nutrition and Energy Balance 2008, which outlined the need for "integrating nutrition and modern biological processes", and specifically metabolomics, into nutrition research. The work also addresses strategic aim one (research priority theme two: living a long and healthy life) of the MRC Strategic Plan 2014-2019, and in particular 'molecular datasets and disease', 'life course perspective' and 'environment and health.' Furthermore, there is an urgent need to provide skills training in these specialist tools for the next generation of nutritional scientists. By providing scientific leadership in metabolomics, lipidomics and stable isotope technology our group has been integral to "the identified centre of excellence for integrative nutrition research in Cambridge." This aspect will also help address the national skill shortage of basic and clinical nutrition researchers. This addresses Strategic Aim Four: Supporting Scientists: Sustaining a robust and flourishing environment for world-class medical research. Our research has great relevance to industrial research and development as demonstrated by the fact that Griffin has industrial funding from Selcia, Unilever, Medimmune, AstraZeneca, Waters Corporation, Agilent, Philips, Syngenta and GSK in T2DM and metabolomics. We are involved in initiatives to turn big data into knowledge, contributing to the MRC's drive to increase the use of big data in understanding complex medical problems.

While we will exploit Knowledge Transfer Exchange (KTE) at all levels we expect to continue to specialise in the two areas we have exploited in the current programme. We will collaborate with industry, the university and MRCT to exploit, and where appropriate commercialise our intellectual property. In addition we will continue our projects focussed on dissemination of knowledge and data to key stakeholders including policy-makers, media and public in addition to scientific audiences. One area to raise is that Griffin currently sits on the SACN working group on saturated fats for Public Health England.

We in the process of exploiting a number of our results with industry as well as using our expertise to assist policy decisions and educate other members of the scientific community and the public. Some of the highlights of this KTE are below:

1. In conjunction with a local company Koulman has developed a novel device to be fitted on the front end of mass spectrometers to enable the analysis of the composition of lipoproteins by LC-MS following size exclusion chromatography. To maximise the potential impact of this work we and MRCT collaborated with a SME through the development process to ensure its applicability to commercial and diagnostic needs.
2. We have been at the forefront of developing open standards for reporting metabolomics and lipidomic data. We have both contributed to and organised workshops and conferences, as well as authoring a number of leading publications in this area. This has culminated in the development of a world-wide repository for metabolomics data which is is housed at the European Bioinformatics Institute.