Proposal to enhance linked research in human fat metabolism & pathophysiology between MRC HNR, MRC MDU and MRC EU

Lead Research Organisation: MRC Human Nutrition Research Group

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. However, there is increasing realisation that T2DM is not a homogenous disease and can arise from a number of different pathways related to diet, life style and genetic influences. Because of this there is increasing realisation that ‘one size’ does not fit all in terms of treatment. Indeed, certain individuals may particularly benefit from targeted diet and drug interventions as part of an approach referred to as ‘personalised medicine.’ This initiative sets out to understand the underlying pathways that influence why an individual might develop T2DM using analytical chemistry approaches to define patient groups according to their metabolism. We plan to use metabolic changes, termed biomarkers, to better identify patient groups who would benefit from particular treatments. This personalised medicine approach should improve health of individuals as well as providing a significant financial saving to the healthcare system.

Technical Summary

With the increasing burden that type 2 diabetes (T2DM) and aspects of the metabolic syndrome place on the National Health Service and the wider economy there is a drive to stratify patients into treatment groups to maximise response to interventions to prevent insulin resistance (IR) be it through diet, physical activity or drug intervention. By its very definition the metabolic syndrome is a cluster of disorders. It is also now a widely held view that T2DM is a heterogeneous collection of pathological disorders all sharing the common outcome of hyperglycaemia. There is a growing realisation that effective treatments for complex disorders such as T2DM and dyslipidaemia will require “deep phenotyping” of the individuals to allow the implementation of personalised medicine and nutritional interventions.
This drive towards personalised medicine and nutrition has been impaired by the lack of personalised diagnosis. The limited development and validation of relatively few biomarkers hampers real stratification of individuals, and the majority of the current markers used for the diagnosis of the metabolic syndrome and T2DM are associated with the effects of the clinical endpoint or the clinical endpoint itself. One reason for this lack of translation is the difficulties of performing controlled intervention studies in humans to validate molecular mechanisms of a potential diagnostic biomarker alongside the biomarker discovery studies. As part of the MRC/Wellcome Trust funded Cambridge Initiative in Obesity and Metabolic Disease we are applying human intervention studies in order to better understand the mechanistic basis underpinning potential biomarkers developed within the groups led by Griffin and Bluck as well as collaborators at MRC Units and the University of Cambridge that make up the rest of the Initiative. To achieve this we are applying our world-class specialisms in high resolution mass spectrometry of lipids and stable isotope analysis for kinetic measurement of substrate flux to measure biomarkers and flux changes in well controlled human physiological interventions.
The current focus is in the understanding of the contribution of de novo lipogenesis (DNL) to fatty liver disease in those that are either considered healthy or have mild IR. From our previous work in lipodystrophic patients we know that triglycerides associated with DNL are increased in blood plasma and the activity of the pathway is raised as measured by stable isotope studies. We are currently conducting studies to directly measure DNL alongside blood plasma triglycerides using a combination of stable isotope techniques and high resolution mass spectrometry in different patient groups and at risk individuals.

Publications

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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

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

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Charidemou E (2017) The use of stable isotopes in the study of human pathophysiology. in The international journal of biochemistry & cell biology

 
Description SACN advisory committee on dietary fats
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Amegen Summer studentship - Xavier Fernandez
Amount £3,000 (GBP)
Organisation Amgen Inc 
Sector Private
Country United States
Start 06/2015 
End 08/2015
 
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 High-throughput "omic" science and imaging call
Amount £1,300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2013 
End 07/2014
 
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 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 Wellcome Trust and GSK studentship in translational medicine
Amount £65,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
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 Cambridge Metabolism Network 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution I am a member of the organising committee for the Cambridge Metabolomics Network. This has included two meetings on metabolism. The events have been sponsored by AZ, MedImmune and Novartis and contact with AZ led to a CASE pHD studentship.
Collaborator Contribution To my group they have provided a PhD studentship.
Impact Got a CASE studentship in a multi-disciplinary research area.
Start Year 2015
 
Description Cambridge Metabolism Network 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution I am a member of the organising committee for the Cambridge Metabolomics Network. This has included two meetings on metabolism. The events have been sponsored by AZ, MedImmune and Novartis and contact with AZ led to a CASE pHD studentship.
Collaborator Contribution To my group they have provided a PhD studentship.
Impact Got a CASE studentship in a multi-disciplinary research area.
Start Year 2015
 
Description Collaboration with Cardiovascular medicine, University of Oxford 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We are collaborating with Cardiovascular medicine at Oxford to understand the role metabolism plays in hypertrophic cardiomyopathy (HCM). The focus of this work is a translational medicine study of HCM. Our role is to help understand the metabolic changes that are associated with HCM, and in particular the switch from fat metabolism towards carbohydrates (fetal reprogramming).
Collaborator Contribution We ghave acquired pilot data for grant applications and written grant proposals
Impact None to date
Start Year 2013
 
Description Collaboration with Medimmune 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution We have initated a collaboration with medimmune in terms of making our expertise and facilities in metabolomics and lipidomics available to the cardiovascular and metabolic diseases group and in return we have been offered access to their high throughput cell culture facilities, we are discussing CASE studentships and also access to previously generated mouse models of obesity and fatty liver disease.
Collaborator Contribution See above!
Impact None as yet
Start Year 2014
 
Description Collaboration with the Department of Physiology Development & Neuroscience, University of Cambridge (HNR project 6503) 
Organisation University of Cambridge
Department Department of Physiology, Development and Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Liver metabolome (HNR project 6503), liver, plasma, adipose and intestine samples were collected for a mouse strain and gender comparison of the lipid and low molecular weight species of the liver metabolome (many thanks to JLG, Xinzhu Wang, LR and Frank Sanders for the sample collection.
Collaborator Contribution Andrew Murray's group in the Department of Physiology Development and Neuroscience, UCam oversaw the study
Impact TBC
Start Year 2014
 
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 Lipidomics in a population eating the Mediterranean diet 
Organisation University of Bari
Country Italy 
Sector Academic/University 
PI Contribution FS and MVa have established a collaboration with the University of Bari, Italy, for a project that will translate our murine studies into human research of the link between de novo lipogensis and fatty liver disease. The MTA is now in place and the University of Bari received the final approval from the ethics committee for sending the serum samples. .
Collaborator Contribution Providing blood plasma samples from an on-going Italian cohort
Impact None to date - currently processing data.
Start Year 2015
 
Description Thought Leader Award from Agilent 
Organisation Agilent Technologies
Country United States 
Sector Private 
PI Contribution Agilent have awarded a Thought Leader award to the head of group. This consists of a brand new ion mobility mass spectrometry plus substantial funds for research to develop this new piece of equipment. In turn we will develop new mass spectrometry tools based around ion mobility for lipid detection.
Collaborator Contribution see above.
Impact The collaboration starts in december 2014
Start Year 2014
 
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 BBC filming as part of a news report on fat metabolism 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact With MRC Epidemiology we took part in a documentary by the BBC on fat intake. This has led to a number of other media contacts since then.
Year(s) Of Engagement Activity 2015
 
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 Contact with the BBC about a scientific program on diet and food 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact CW contacted by Milla Harrison from the BBC doing another Horizon programme - The Biology and Environmental factors behind Obesity. Wanted some advice on genes and genotyping.
Year(s) Of Engagement Activity 2015
 
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 Debating matters - regional final judge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Schools
Results and Impact We encouraged students to both debate and think about applying to the University of Cambridge

see above
Year(s) Of Engagement Activity 2014
 
Description Discussion with Trust me I'm a doctor 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact I advised on a program on energy balance and dieting pills.

Still waiting for the program to air!
Year(s) Of Engagement Activity 2014
 
Description French Embassy Seed meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact JLG, LR, AA and ZA were invited to the French Embassy to discuss collaborations with colleagues from INRA on metabolomics. This was following a successful application to the French government to fund the meeting by JLG and his counterparts in France.
Year(s) Of Engagement Activity 2015
 
Description Hosted a visit from Singaporean students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Schools
Results and Impact We hosted a visit from 6th form Singaporean students interested in applying to Cambridge as undergraduates in science related areas.

They gave me a box of chocolates!
Year(s) Of Engagement Activity 2013
 
Description How the fat flies - Science Week 
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 The University of Cambridge Science Festival took place on Saturday 14th and Sunday 15th March. My group had a stand at the Corn Exchange. The stand was split into two, with one half focusing on nutrition and the other on mass spectrometry.
Year(s) Of Engagement Activity 2015
 
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 Metabolomics Workshop at the 20th International Symposium on Microsomes and drug oxidations, stuttgart, germany 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact academics said they would incorporate metabolomics into their future experiments

See above
Year(s) Of Engagement Activity 2014
 
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 Poster presentation at Experimental Biology 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact One of the PhD students attended Experimental Biology and presented a poster entitled "Effects of green tea and coffee polyphenols on cardiometabolic function in women with Polycystic Ovary Syndrome." Experimental Biology Boston, USA, 28 March-1 April 2015.
Year(s) Of Engagement Activity 2015
 
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 Sugar, Fat and the Daily Mail Headlines 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact JLG spoke at the 'Skeptics in the Pub' event on 26th May. The video is on YouTube should anyone want to view it!
Year(s) Of Engagement Activity 2015
 
Description Talk on metabolomics at Bedford School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Gave a talk on metabolomics and systems biology to the biology club at Bedford school.
Year(s) Of Engagement Activity 2015
 
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