FATFUNgenes (FAT cell FUNction genes) V1
Research type
Research Study
Full title
The genetics of adipose tissue function and its link to Type 2 diabetes and heart disease
IRAS ID
257693
Contact name
Timothy Frayling
Contact email
Sponsor organisation
CRF 399
Duration of Study in the UK
2 years, 6 months, 0 days
Research summary
Summary of Research
Obesity is a major risk factor for Type 2 diabetes. However, two obese people of the same height and weight can have very different risks of the condition. As a greater proportion of the population is becoming obese, we need to understand more about why some people develop Type 2 diabetes at lower weight and why some people stay healthy despite being obese. We and others provided evidence for genetic factors associated with higher weight for a given height but lower risk of diabetes, lower cholesterol and fat levels, lower blood pressure, and lower risk of heart disease. We showed that people who carry these genetic factors are able to store extra fat in a safe place, which is under the skin, as they gain weight. The proposed project aims to establish whether or not these genetic factors are associated with better development and function of fat tissue in storing extra fat. We hypothesize that a healthy and functional fat tissue in our body has a key role in modifying the risk of diseases such as Type 2 diabetes, heart disease and hypertension.
We will recruit volunteers from the 'Exeter 10,000' cohort who gave their permission to be contacted for further research. In those that agree, we will collect detailed body size measures, including body composition assessments by the BodPod machine, collect a blood sample and a small subcutaneous abdominal fat biopsy to use to measure fat cell size, from which we will store a sample for future analyses. We will compare the results between people with and without the particular genetic changes that we are interested in.
Knowing more about these genetic changes and how our fat cells work could help us understand factors that predispose, delay or protect obese individuals from Type 2 diabetes and other metabolic disturbances.Summary of Results
Higher adiposity increases the risk of developing type 2 diabetes but not everyone with higher adiposity will develop the condition. Since a large proportion of many populations are overweight or obese, it is important to understand the differences between those who do and do not develop the condition to identify the mechanisms that delay or protect individuals from developing the condition.We recently identified 36 genetic variations associated with higher adiposity but lower risk of type 2 diabetes. Therefore, we named these genes ‘favourable adiposity’ genes. We used MRI scans from the UK Biobank study and provided evidence that these genes are associated with an ability to store the extra fat in a safe place which is under the skin. The main question is whether these genes operate through a healthy fat tissue.
It is proposed that smaller fat cells but in larger numbers represent a healthy and functioning fat tissue. Previous studies have shown that people who do not have type 2 diabetes have smaller fat cells compared to those with the condition. In this study, we aimed to study fat cell size and number to understand: (1) the link between adiposity and a functioning fat tissue; and (2) how genes cause difference in our ability to store fat. We hypothesised that individuals carrying many ‘favourable adiposity’ genes have better functioning fat cells that can expand and store extra fat.
We designed a prospective cohort study that took place from 2019 to 2021. We used the Exeter 10,000 database of research volunteers. We recruited 207 volunteer men who consented to participate in our study. We excluded anyone who had history of bariatric surgery, recent significant weight loss/gain (+/- 3 kgs in the last 3 months), currently prescribed corticosteroid, diuretics, antiplatelet or anticoagulation medication. Costs, including NIHR Exeter Clinical Research Facility (Exeter CRF) nurse and technician costs, sample measurements and analyses were covered by Dr Yaghootkar’s Diabetes UK RD Lawrence fellowship (17/0005594), MRC funding (MR/L020149/1), and for genotypes work European Research Council grant 323195. The Exeter CRF provided project management support.
We invited the volunteers to the Exeter CRF for a one-off visit (approximately 1.5 hours) and collected details of their general health and lifestyle. We measured their height, weight, waist circumference, hip circumference, skin fold thicknesses, and more detailed body size measures using BodPod. We collected two small (pea-sized) samples of fat under the skin from their stomach area to measure fat cell size and gene expression levels.
The mean age of our study participants was 61 years and 10% had type 2 diabetes. Fat cells were larger and in smaller number in those who had type 2 diabetes compared to those who did not have type 2 diabetes. Participants who had higher adiposity (as measured by body fat percentage, skin fold thicknesses from biceps, triceps, subscapular, and suprailiac regions, waist and hip circumference) had larger fat cells but in smaller number. There was no association between fat cell size or cell number and blood pressure, height, and lean mass.
We had both genetic and fat cell size and cell number for 182 participants. To understand the link between obesity and healthy fat tissue, we investigated the genetic link between obesity and fat cell size and number. Participants with higher genetic predisposition to obesity had significantly higher body mass index, larger fat cells and smaller number of cells. We then tested for association between 36 ‘favourable adiposity’ genetic variations and fat cell size and number. We corrected these associations for age and body fat percentage. The majority of the ‘favourable adiposity’ genetic variations (20 out of 36) were associated with smaller fat cell size. This included three ‘favourable adiposity’ genetic variations with statistically significant association with smaller fat cells. One of these three genes is PPARG which is well known to regulate generation of many small fat cells that can get mature and store extra fat under the skin.
We then calculated a genetic risk score for ‘favourable adiposity’ by combining the effect of all the 36 genes. We observed that those with a more ‘favourable adiposity’ genetic risk score had a trend to have relatively smaller fat cells. There was also a positive link between having many ‘favourable adiposity’ genes and a larger number of fat cells.
Our study provided some genetic evidence supporting the role of a healthy fat tissue in mechanisms that protect from type 2 diabetes. However, it was difficult to establish a statistically significant link between ‘favourable adiposity’ and fat cell size and number. There are two possible explanations. First, our sample size is not big enough to detect the true associations. Second, the ‘favourable adiposity’ genes are acting through a mixture of biological mechanisms. For example, in addition to smaller fat cells, less inflamed fat tissue or better blood flow of fat tissue. Knowing more about how our fat cells work could help us understand factors that predispose, delay or protect obese individuals from type 2 diabetes and other metabolic disturbances.
We will combine our results with other similar studies to increase our power. Please check Dr Yaghootkar’s profile page (https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fu2790089.ct.sendgrid.net%2Fls%2Fclick%3Fupn%3DXv3JSvJ-2B3M71ppf7N9agbc-2B7fmUU-2FPqgZbCEQCTkApnjBA7hGmkHNS3nSH5w-2FiBrZwTSNDgxILmAXRfICrlntQ-3D-3DKyrz_E1aO2-2BZlVOSJJV-2FajQqskegTd6IRomHYTi-2Fbt8SH3YJMrerO0lH4G7oCvhkQdiSk02useFNATqHn9PPbmJLkorFSO2gRlAdF63kGJ2ZpYAP2vtCkqlu-2FME6ohECEj9z9iI-2B-2Bbe-2FJV1BIw6ZvFK47ha4h7P1Po5r6Us2crZ4qHaT7oqBhdetHoLOqDpdAIBmKYwm52typRvvAIj3fytdOjw-3D-3D&data=05%7C01%7Capprovals%40hra.nhs.uk%7C469667135aa245ad539a08dac8aebbca%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638042950044741594%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=l7tQhTy1wqOE9EYGKfRvzEACYfP5QAlW6D%2FHKQLjBBE%3D&reserved=0 ) to find more about the outcome of this study. We are preparing a paper and aim to submit it to a peer-reviewed journal for publication. The link to the paper will be shared on Dr Yaghootkar’s profile page.
REC name
South West - Central Bristol Research Ethics Committee
REC reference
19/SW/0012
Date of REC Opinion
14 Feb 2019
REC opinion
Further Information Favourable Opinion