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

Lead Research Organisation: University of Cambridge
Department Name: Biochemistry

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

10 25 50
publication icon
Acharjee A (2017) The translation of lipid profiles to nutritional biomarkers in the study of infant metabolism. in Metabolomics : Official journal of the Metabolomic Society

publication icon
Ament Z (2016) Metabolomics dataset of PPAR-pan treated rat liver. in Data in brief

publication icon
Atzori L (2017) How to bridge metabolomics and genomics. in The international journal of biochemistry & cell biology

publication icon
Auffray C (2019) Ten years of Genome Medicine. in Genome medicine

publication icon
Bond NJ (2017) : an R package for annotation and interpretation of mass spectrometry imaging data for lipidomics. in Metabolomics : Official journal of the Metabolomic Society

 
Description SACN advisory committee on dietary fats
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Astra Zeneca CASE studentship
Amount £40,000 (GBP)
Organisation AstraZeneca 
Sector Private
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description BHF Intermediate fellowship for KT
Amount £250,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description GSK-Astra Zeneca partnership awards
Amount £417,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 04/2017 
End 03/2020
 
Description Medimmune industrial studentship
Amount £100,000 (GBP)
Organisation MedImmune 
Department MedImmune Cambridge
Sector Private
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description NIH-Cambridge Studentship in translational medicine
Amount £100,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 10/2017 
End 09/2020
 
Description Technology Development Grant, MetaboFlow - the development of standardised workflows for processing metabolomics data to aid reproducible data sharing and big data initiatives
Amount £900,000 (GBP)
Funding ID 202952/B/16/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2016 
End 11/2019
 
Description Unilever CASE funded studentship
Amount £40,000 (GBP)
Funding ID NA 
Organisation Unilever 
Department Unilever Research and Development
Sector Private
Country United Kingdom
Start 10/2017 
End 09/2020
 
Title Data supporting "Metabolic Basis to Sherpa Altitude Adaptation" 
Description Data supporting "Metabolic Basis to Sherpa Altitude Adaptation" 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
 
Description Antonio Moschetta. Lipidomics and Bile Acid profiling in liver disease 
Organisation University of Bari
Country Italy 
Sector Academic/University 
PI Contribution Collaborating on understanding the role bile acids play in fatty liver disease
Collaborator Contribution Provided animal models for the collaboration.
Impact None to date
Start Year 2017
 
Description Collaboration with UCB Pharma 
Organisation UCB Pharma
Country United Kingdom 
Sector Private 
PI Contribution We have profiled the metabolic outcome of a number of antibodies used as treatments for aspects of metabolic disease.
Collaborator Contribution Financial
Impact Financial
Start Year 2017
 
Description Collaborations with Newcastle University on fatty liver disease 
Organisation Newcastle University
Department Institute of Health and Society
Country United Kingdom 
Sector Academic/University 
PI Contribution Fiona Oakley. Metabolic control of liver regeneration and hepatocellular carcinogenesis Q Anstee. SNPs in NASH affecting lipidome
Collaborator Contribution Fiona Oakley. Metabolic control of liver regeneration and hepatocellular carcinogenesis Q Anstee. SNPs in NASH affecting lipidome
Impact Still in progress
Start Year 2017
 
Description 2nd Metabolomics Sardinian Scientific School 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact 2nd Metabolomics Sardinian Scientific School was aimed at post-grad students new to the field of metabolomics. We gave seminars and workshops in various tools and techniques in metabolomics.
Year(s) Of Engagement Activity 2016
 
Description Cambridge Science Week 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact took part in Cambridge Science week and put on a display on personalised medicine and health using advanced biochemical techniques.
Year(s) Of Engagement Activity 2017
 
Description Danish-UK Metabolism meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Taught postgrads how to use metabolomics and lipidomics to study aspects of type 2 diabetes and related disorders.
Year(s) Of Engagement Activity 2017
 
Description King's College Natural Sciences Taster session 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Gave a mini lecture to sixth formers interested in coming to Cambridge University. Held a question and answers session after the lecture and discussed the teaching at the University.
Year(s) Of Engagement Activity 2018
 
Description MetaboFlow and Cambridge Metabolomics 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Held a Metabolomics Interest group for the East Anglia/London region to increase interest in this research area.
Year(s) Of Engagement Activity 2017
 
Description Metabolic Complications in Obesity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A conference/workshop to promote new methods for understanding the causes and consequences of obesity.
Year(s) Of Engagement Activity 2017
 
Description Organised Metabomeeting 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Organised a national meeting in Metabolomics for the UK community, encouraging collaborations between participants - both academics and industry.
Year(s) Of Engagement Activity 2018
 
Description Pint of science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talked about the research behind the debate about whether it is increased carbohydrate or saturated fat intake that is driving the obesity and type 2 diabetes epidemics.
Year(s) Of Engagement Activity 2017
 
Description Sardinian summer school: Metabolomics and more. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Sardinian summer school to spread the use of tools in metabolomics and lipidomics.
Year(s) Of Engagement Activity 2017
 
Description Science Week cambridge 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact : volunteering on 13th March 2016 Cambridge science festival HNR stand: Blood, Fat & the Future
Year(s) Of Engagement Activity 2016
 
Description The Naked Scientist Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Talked about my research while in a punt going along the river Cam as part of the Naked scientist Podcast.
Year(s) Of Engagement Activity 2018
 
Description West African Centre for cell Biology of Infectious Pathogens College of Basic and Applied Sciences, Ghana Research Conference 2017 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Took part in a 3 day conference/workshop to discuss advances in Biology that could be applied within Western Africa to treat human disease.
Year(s) Of Engagement Activity 2017
 
Description Work experience for two school boys 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Work experience for two school boys: two school boys spent a week in my lab following members around to get some experience of what its like being a scientist.
Year(s) Of Engagement Activity 2016