A master regulator gene which causes obesity and is linked to diabetes and cholesterol and controls the behavior of distant genes that exist inside fat cells has been identified, researchers from King’s College London and the University of Oxford wrote in the journal Nature Genetics.

The authors say their discovery may help toward developing more effective treatments for obesity-related illnesses, such as diabetes and heart disease.

This latest study was part of a large multinational collaboration – the MuTHER study – financed by the Wellcome Trust. Scientists from The Wellcome Turst, the University of Oxford, King’s College London, as well as the University of Geneva collaborated. DeCode Genetics also contributed.

Researchers already knew about KLF14, a gene that is linked to cholesterol levels and diabetes type 2 – however, nobody knew what role it played until now.

The scientists explained that while “cis regulatory patterns of gene expression have been extensively explored, the identification of trans regulatory effects in humans has attracted less attention.”

Cis regulatory elements regulate the genes within the same molecule of DNA they are present in. Trans regulatory elements affect the behavior of distant genes.

Tim Spector and team took subcutaneous fat biopsies (fat samples from under the skin) of 776 female twins in Great Britain, and analyzed over 20,000 genes in the fat cells. They found that KLF14 is like a controller – it influences the behavior of distant genes inside fat tissue.

They then took another 600 fat samples from a group of people in Iceland, and confirmed their initial findings.

Fat plays a key role in our susceptibility to obesity, heart disease and diabetes – otherwise known as metabolic diseases.

The KLF14 gene is inherited from the mother. We inherit a set of all genes from both our mother and father. But in the case of KLF14, the father’s copy is switched off, making the copy from the mother the active gene – this is called imprinting. KFL14’s ability to control other genes depends entirely on the KFL14 copy inherited from the mother – the father’s copy has no effect.

If medications could be developed to target KLF14, treatments for several metabolic diseases could be much more effective, the authors believe.

Tim Spector, of King’s College London, 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.”

Study co-leader, Mark McCarthy, from the University of Oxford, 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.”

There are twice as many obese people worldwide today than there used to be in the 1980s. Today, half a billion people are obese, or one in every ten adults.

10% of America’s health care budget is taken up by obesity-related illnesses – a total of $147 billion each year. In the UK nearly two-thirds of the adult population is either obese or overweight.

KLF14 appears to regulate the behaviour of distant genes that influence BMI (body mass index), glucose levels, insulin levels, cholesterol and obesity.

“Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes”
Kerrin S Small, Åsa K Hedman, Elin Grundberg, Alexandra C Nica, Gudmar Thorleifsson, Augustine Kong, Unnur Thorsteindottir, So-Youn Shin, Hannah B Richards, Nicole Soranzo, Kourosh R Ahmadi, Cecilia M Lindgren, Kari Stefansson, Emmanouil T Dermitzakis, Panos Deloukas, Timothy D Spector, Mark I McCarthy
Nature Genetics. Year published: (2011) DOI: doi:10.1038/ng.833

Written by Christian Nordqvist