The Cambridge Initiative: Proposal to enhance linked research in human fat metabolism and pathophysiology between MRC HNR, MRC MDU and MRC Epi

Obesity is one of the causes of type 2 diabetes. However, some people with obesity do not develop type 2 diabetes, while others seem particularly vulnerable to the disease. This project sets out to examine human fat metabolism to understand this.
Mass spectrometry is an analytical technique used to identify different chemicals by how much they weigh. We can also use naturally occurring, non-radioactive heavy nuclei of certain elements (called 'stable isotopes') to label chemicals, and detect where these labels end up in the body. These techniques are helping us develop the concept of personalised nutrition and medicine - the tailoring of diets and treatments to an individual to maximise their effects. The aim of this project is to investigate how fats are absorbed by the body from the body, processed in the liver, metabolised and stored. People will be fed meals containing labelled fats to see where the label goes and what effects the fat has on metabolism. We will also study how different foods affect the fate of the fat eaten in a meal - for example whether fats from milk are treated differently to those from meat. By understanding how fat metabolism is controlled in healthy and diabetic people we will understand better the causes of type 2 diabetes and identify new ways to prevent and treat the disease.

A central question in diabetes and nutrition research is why some individuals are predisposed to developing type 2 diabetes, while others are remarkably resistant to the disease despite similar levels of obesity and activity. While genetics plays a role, there is growing evidence that there are clear associations between insulin resistance and the handling of dietary lipids, in particular the uptake, synthesis and storage of lipids.
This proposal is to develop a platform in human pathophysiology of fat metabolism using a combination of HNR's state-of-the-art high-resolution mass spectrometry for lipidomics and world-class facilities in stable isotope labelling to directly measure turnover of fats. This work will provide a collaborative bridge between MRC Human Nutrition Research, the proposed MRC Metabolic Disease Unit and MRC Epidemiology, by facilitating the translation of fundamental cellular and animal studies through into population and policy-relevant outcomes and clinical treatments. We will examine fat metabolism in small, well-defined patient groups which will inform the modelling of specific aspects of the Metabolic Syndrome including fatty liver disease, polycystic ovary syndrome, non-obese diabetic individuals and obese insulin sensitive individuals. We will use stable isotope labelled fats to probe lipid handling and metabolism, conducting stable isotope techniques alongside high resolution mass spectrometry used to detect intact lipids directly, including triglycerides, phospholipids, and cholesterol lipids, as well as lipids thought to be involved in lipotoxicity such as eicosanoids, long-chain carnitines and acyl-CoA derivatives, ceramides, monoacylglycerides and diacylglycerides. In particular, we will develop techniques to investigate (i) differences in de novo lipogenesis, (ii) uptake of fatty acids in different meals to model how lipid absorption changes across individuals, (iii) responses to glucose and insulin in the different patient groups.

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.