In research published in PNAS, a team of researchers has shown that loss of the gene called ‘TMEM18’ causes weight gain, while specifically overexpressing this gene in a small part of the hypothalamus results in weight loss.
An understanding of the mechanisms underlying body-weight regulation is crucial to tackle the growing problem of obesity. Although significant changes in lifestyle and environmental factors have undoubtedly driven the recent rise in the prevalence of obesity worldwide, there are equally compelling data indicating that inherited biological factors play a major role in determining an individual’s susceptibility to obesity.
The growing size and sophistication of human genetic studies has led to the identification of many variants in regions of our genetic code that are clearly and reliably associated with obesity. One such region is located on chromosome 2, near to the gene TMEM18. However, even when such a region has been unequivocally associated with obesity, there remains a real challenge in understanding how such genetic variance actually influences how food is consumed or how fat is stored.
We believe our study directly addresses an important gap in knowledge, turning statistical association into a deeper understanding of biology. We show for the first time that changing the amount of TMEM18 within a very discrete region of the hypothalamus can reduce food intake and body weight.
Dr Tony Coll, MRC Metabolic Diseases Unit.
Working with colleagues from the Wellcome Trust Sanger Institute and the Universitat Autònoma de Barcelona (UAB), the team used a range of mouse models to help them determine if this gene had a role in body weight regulation. As well as studying a mouse genetically engineered to lack the gene coding for TMEM18, they used a modified virus to overexpress the gene in the paraventricular nucleus, a region of the brain well recognised to have a crucial role in controlling body weight. The team also used a number of cultured cell models designed to contain labelled versions of TMEM18 to enable them to see where in the cell this protein was working.
“There are still several important unanswered questions”, says Dr Coll. “There are a lot of different cell types in the hypothalamus and we need to find what kind of cells contain TMEM18. In addition, there is still much more to learn about the other genes found close to TMEM18; they too could also play a part in controlling body weight. However, these studies have strengthened the candidacy of TMEM18 as mediator of the association between genetic variation in this region of chromosome 2 and human adiposity and again show the importance of the brain in the control of body weight.”