The role of chain length in fatty acid uptake in both health and disease: a combined experimental-theoretical modelling approach
Lead Research Organisation:
University of Birmingham
Department Name: Inst of Metabolism & Systems Research
Abstract
Heart disease, type 2 diabetes and obesity (collectively known as metabolic syndrome) are three of the most serious health conditions facing the UK today. They affect one in four adults in the UK, costing the NHS over £10 billion annually. These figures are rising rapidly, with 1 in 2 people predicted to be affected by 2050, with an associated cost of £50 billion. Sadly, we do not know the basic mechanisms of how type 2 diabetes (and many other obesity-related conditions) occur. Establishing the mechanics and role of fats is critical since too many entering our cells can contribute to the development of diabetes. This then poses the question: how do fats enter cells? At present, we know very little. Identifying how fats enter cells will pave the way for the development of new diets and drug treatments to reduce fat uptake. In the long term, this will help to slow and potentially halt the development of type 2 diabetes, obesity and heart disease.
I will use imaging techniques to measure how much fat crosses into cells, how quickly this happens, and how this changes with different types of fats. I will then use this information to build mathematical models that explain the mechanisms behind fat uptake. Although it may seem surprising that mathematics can be used to answer questions in biology, recent progress has shown that combining these two areas can lead to great advances in physiology and medicine. In this project, I will take advantage of my mathematical model to make predictions about the ways in which fats enter cells. I can then confirm or reject these predictions through experiments in the lab. With a good understanding of fat uptake, I will be able to start testing drug treatments and diets in rodents to prevent the progression of type 2 diabetes and obesity.
I will use imaging techniques to measure how much fat crosses into cells, how quickly this happens, and how this changes with different types of fats. I will then use this information to build mathematical models that explain the mechanisms behind fat uptake. Although it may seem surprising that mathematics can be used to answer questions in biology, recent progress has shown that combining these two areas can lead to great advances in physiology and medicine. In this project, I will take advantage of my mathematical model to make predictions about the ways in which fats enter cells. I can then confirm or reject these predictions through experiments in the lab. With a good understanding of fat uptake, I will be able to start testing drug treatments and diets in rodents to prevent the progression of type 2 diabetes and obesity.
Technical Summary
Metabolic syndrome refers to a range of conditions including obesity, diabetes and high blood pressure, which increases an individual's risk of developing cardiovascular disease. These conditions are typically preceded by elevated levels of circulatory free fatty acids (FFAs), which are taken up by cells, subsequently leading to cellular dysfunction and death. This work will identify the mechanisms by which FFAs cross the plasma membrane (PM) and how FFA size alters the rate and mode of transport. This is important as it is often the longer chained FFAs that exert a toxic phenotype. By identifying such mechanisms, therapies can ultimately be developed to regulate cellular FFA entry, thus providing potential targeted therapies for metabolic syndrome. Raman spectroscopy will be used to image FFAs crossing the PM of cells. These experiments will determine the FFA flux and rate constants, which will then be incorporated into a biophysical model of FFA uptake, based on reaction-diffusion equations. The mathematical model will describe the movement of FFAs both outside and inside the cell, and FFA transport across the PM by both passive diffusion and facilitated transport. By fitting the mathematical model to the data, it will be determined: a) if FFA uptake is facilitated, passive or some combination of the two, b) how FFA size and concentration affect the mode of uptake, and c) how this mechanism is altered in metabolic syndrome. The mathematical modelling predictions will then be validated in a human hepatocyte cell line, a cell that contributes towards insulin resistance, a central characteristic of metabolic syndrome. Hepatocytes will be genetically engineered to over- or under-express components of FFA transport, and then exposed to FFAs of increasing chain length for different durations and at different concentrations. These experimental results will then be used to refine the mathematical model, generating fresh predictions and suggesting further experiments.
Planned Impact
N/A. Not completed as advised by Dr Anke Davis, Programme Manager for non-clinical careers at the MRC.
Publications
Clavelo-Farrow C
(2023)
The role of candidate transport proteins in ß-cell long-chain fatty acid uptake: Where are we now?
in Diabetic Medicine
Thomas P
(2021)
Long-chain saturated fatty acid species are not toxic to human pancreatic ß-cells and may offer protection against pro-inflammatory cytokine induced ß-cell death.
in Nutrition & metabolism
Thomas P
(2023)
Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding
in Frontiers in Endocrinology
Thomas P
(2022)
Differential routing and disposition of the long-chain saturated fatty acid palmitate in rodent vs human beta-cells.
in Nutrition & diabetes
Title | Differential routing and disposition of long chain saturated fatty acids in rodent vs human beta cell |
Description | Informative summary video of my research |
Type Of Art | Film/Video/Animation |
Year Produced | 2021 |
Impact | Currently about to go into circulation. |
Title | Website |
Description | Personal website for research |
Type Of Art | Artefact (including digital) |
Year Produced | 2023 |
Impact | Not known |
URL | https://patriciathomas.art |
Description | Institute Environmental and Sustainability lead |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | More labs have joined the University Green Scheme for sustainable labs and actively recycling more in labs. |
Description | Additional year of funding |
Amount | £137,000 (GBP) |
Organisation | University of Birmingham |
Sector | Academic/University |
Country | United Kingdom |
Start | 06/2022 |
End | 05/2023 |
Description | Quantification of candidate fatty acid transport proteins in human pancreatic beta cells |
Amount | £2,110 (GBP) |
Organisation | Society for Endocrinology |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2022 |
End | 06/2023 |
Description | Research Experience Placement Award |
Amount | £3,000 (GBP) |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2021 |
End | 08/2021 |
Description | The role of chain length in fatty acid uptake in both health and disease: a combined experimental-theoretical modelling approach |
Amount | £27,635 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 06/2022 |
End | 12/2022 |
Description | UKRI Covid-19 grant allocation scheme |
Amount | £37,490 (GBP) |
Organisation | United Kingdom Research and Innovation |
Sector | Public |
Country | United Kingdom |
Start | 01/2021 |
End | 08/2021 |
Description | Wellcome Trust Institutional Stategic Support Fund: Career Development Hub |
Amount | £24,537 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2021 |
End | 09/2022 |
Description | Catherine Arden |
Organisation | Newcastle University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of a MRes student in bioinformatics. I joint led the project investigating the role of autophagy in pancreatic beta cell dysfunction using a bioinformatic analysis of single-cell RNA sequencing data. I am continuing to analyse the data. |
Collaborator Contribution | Co-supervision of a MRes student in bioinformatics. Catherine joint led the project and will validate my computational findings in post-mortem pancreatic slices. Joint writing of paper + reviewers revisions |
Impact | MRes student received the Newcastle Dean award for her dissertation. Publication: 1. P Thomas, C Arden, J Corcoran, C Hacker, HJ Welters, NG Morgan. (2022). Differential routing and disposition of the long-chain saturated fatty acid palmitate in rodent vs human beta-cells. Nutrition & Diabetes 12:22. |
Start Year | 2021 |
Description | Collaboration with Cavendish laboratories Cambridge |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration with Professor Ulrich Keyser at the University of Cambridge to determine the rate of fatty acid uptake in artificial membranes. |
Collaborator Contribution | My collaborators at Cambridge will provide expertise in constructing artificial membranes (giant unilamellar vesicles), suspending candidate transport proteins within the artificial membranes, and microfludic techniques to determine the rate of fatty acid uptake in artificial membranes. . |
Impact | C Clavelo-Farrow, KA Leslie, M Fletcher, FM Docherty, I Akerman, MT Gallagher, P Thomas. (2022). Characterisation of the mechanism of long-chain fatty acid uptake in human-derived pancreatic beta cells. Endocrine Abstracts 86: P225. DOI: 10.1530/endoabs.86.P225. C Clavelo-Farrow, KA Leslie, FM Docherty, I Akerman, MT Gallagher, P Thomas. (2023). Studies of long-chain fatty acid uptake in human pancreatic beta cells. In publication Diabetic Medicine. Nominated for Diabetes UK (2023) Basic Science Poster Award. |
Start Year | 2021 |
Description | Roland Stein and Xin Tong |
Organisation | Vanderbilt University |
Country | United States |
Sector | Academic/University |
PI Contribution | Exchange of ideas and knowledge. Plans to collaborate in the future. |
Collaborator Contribution | Exchange of ideas and knowledge. Plans to collaborate in the future. |
Impact | Presentation to Vanderbilt University lab |
Start Year | 2021 |
Description | Scott Soleimanpour, University of Michigan |
Organisation | University of Michigan |
Country | United States |
Sector | Academic/University |
PI Contribution | Collaboration to use EndoC-BH3 cell line for LC-FFA uptake experiments + build collaborative network |
Collaborator Contribution | Collaborator cultured and provided cells, and reagents throughout the duration of my visit. |
Impact | Manuscript in preparation |
Start Year | 2022 |
Description | AMIGO day (patient group workshop) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | ~30 participants attended a patient focus group to discuss research and communication skills to the lay public. I presented my research and that of my immediate group, which sparked questions and discussions afterwards. |
Year(s) Of Engagement Activity | 2021 |
Description | DUK press release for UN International Women and Girls in Science day |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interview and media piece for Diabetes UK UN International Day of Women and Girls in Science |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.diabetes.org.uk/about_us/news/international-day-women-and-girls-science-2023-meet-our-in... |
Description | Diabetes UK (patient and funder lab visit) |
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 | Patients, carers and/or patient groups |
Results and Impact | Diabetes UK patient and funder engagement day. I was a lab tour lead, presenting my research and demonstrating how we use super-resolution microscopy in diabetes research. Patients and funders asked questions and were engaged in the experience. |
Year(s) Of Engagement Activity | 2022 |
Description | Institute for Metabolism and Systems Research community day - chair and panellist |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I chaired and organised a session surrounding diet and fatty acids and their implications in the development of type 2 diabetes. It was an international audience who, following an hours worth of talks from 4 different researchers asked 30 minutes of questions. |
Year(s) Of Engagement Activity | 2021 |
Description | Metabolism, Obesity and Diabetes session chair at the Society for Endocrinology conference, Edinburgh |
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 | Metabolism, Obesity and Diabetes session chair at the Society for Endocrinology conference 2021, Edinburgh |
Year(s) Of Engagement Activity | 2021 |
Description | Panel member for World Diabetes Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Panel member for world diabetes day. We presented our research to an international audience and then answered questions related to diabetes and current research in the field. |
Year(s) Of Engagement Activity | 2020 |