Genetic master switch identified in obesity and diabetes

Professor Mark McCarthy

A gene linked to type 2 diabetes and cholesterol levels has been identified as a ‘master regulator’ by a team at King’s College London and the University of Oxford.

The researchers found that the gene controls the behaviour of other genes found within fat tissues in the body.

As fat plays a key role in susceptibility to metabolic diseases such as obesity, heart disease and diabetes, the regulatory gene could be a possible target for future treatments to fight these diseases.

The study published is part of a large multinational collaboration funded by the Wellcome Trust, known as the MuTHER study. It involves researchers from King’s College London, Oxford University, the Wellcome Trust Sanger Institute, and the University of Geneva. DeCODE Genetics also contributed to the reported results.

The KLF14 gene was already known to be linked to type 2 diabetes and cholesterol levels but, until now, its role or function was unknown.

The researchers examined over 20,000 genes in subcutaneous fat biopsies from 800 UK female twin volunteers. They found an association between the KLF14 gene and the expression levels of multiple distant genes found in fat tissue, suggesting it acts as a master switch to control these genes. This finding was then confirmed in an independent sample of 600 subcutaneous fat biopsies from Icelandic subjects.

"We are working hard right now to understand these processes and how we can use this information to improve treatment of these conditions"

Professor Mark McCarthy

The genes found to be controlled by KLF14 are linked to a range of metabolic traits, including obesity, cholesterol, insulin and glucose levels, highlighting the interconnectedness of metabolic traits.

Moreover, the ability of KLF14 to control other genes was entirely dependent on the copy of KLF14 inherited from the mother – the copy inherited from the father had no effect. This is due to a process called imprinting. While each person inherits a set of all genes from both parents, in this case the copy of KLF14 from the father is switched off. This leaves the copy from the mother as the active gene.

Professor Tim Spector from the Department of Twin Research at King’s, who led the MuTHER project, said: ‘This is the first major study that shows how small changes in one master regulator gene can cause a cascade of other metabolic effects in other genes. This has great therapeutic potential particularly as by studying large detailed populations such as the twins we hope to find more of these regulators.’

Professor Mark McCarthy from the Wellcome Trust Centre for Human Genetics at the University of Oxford, who co-led the study, said: ‘ KLF14 seems to act as a master switch controlling processes that connect changes in the behaviour of subcutaneous fat to disturbances in muscle and liver that contribute to diabetes and other conditions. We are working hard right now to understand these processes and how we can use this information to improve treatment of these conditions.’