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‘Master regulator’ gene for obesity and diabetes discovered


Researchers have found that a gene linked to type 2 diabetes and cholesterol levels acts as a ‘master regulator’, controlling the behaviour of other genes found within fat tissue in the body.

The study highlights the regulatory gene as a possible target for future treatments to fight metabolic diseases such as obesity, heart disease and diabetes.

Published today in ’Nature Genetics’, the study is part of a large multinational collaboration funded by the Wellcome Trust, known as the Multiple Tissue Human Expression Resource (MuTHER) study. It involves researchers from King’s College London, the University of Oxford, the Wellcome Trust Sanger Institute and the University of Geneva. DeCODE Genetics also contributed to the results reported in the paper.

The gene KLF14 has previously been linked to type 2 diabetes and cholesterol levels but until now, the part it plays in controlling other genes located further away on the genome was unknown.

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

These other genes found to be controlled by KLF14 are linked to a range of metabolic traits, including body mass index (and hence obesity), cholesterol, insulin and glucose levels, highlighting how these metabolic traits are connected.

The KLF14 gene is unusual in that its activity is inherited from the mother. Each person inherits a set of all genes from both parents, but in this case, the copy of KLF14 from the father is switched off and only the copy from the mother is active - a process known as imprinting.

Professor Tim Spector from the Department of Twin Research at King’s, who coordinates the MuTHER project, says: “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.”

Professor Mark McCarthy from the University of Oxford, who co-led the study, adds: “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.”

Image: The regulatory gene KLF14 could be a target for future treatments for a variety of diseases. Image credit: Matthew McVickar on Flickr.

Small KS. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet 2011 [ePub ahead of print]


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