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Identification of Obesity Genes Points to New Ways of Preventing Diabetes

 

Two genes that are overexpressed in adipose tissue of morbidly obese people have now been identified by renowned scientists working within the framework of the German Center for Diabetes Research (DZD). This is a result of a new study of the German Institute of Human Nutrition (DIfE) in Potsdam-Rehbrücke, one of the partners in the DZD, and of the University Hospital of Leipzig. These genes promote fat deposits in visceral adipose tissue* in the abdominal cavity. As other results of the study indicate, increased expression of the two genes promotes the release of an enzyme in adipose tissue which is responsible for the formation of cortisol. Cortisol is known as a stress hormone, but it also plays a role in the regulation of energy balance.

Obesity is a complex disease based on the combination of multiple genes and their interaction with the environment. Scientists hope that by learning more about the genes and their function, they will also learn more about the molecular mechanisms that contribute to the development of the disease. This will help them develop new approaches to more effective drug treatments.

Since humans and mice are genetically very similar, the researchers at the German Institute of Human Nutrition (DifE) first used mouse models to identify genes that contribute to the development of obesity. In their current study– similar to Gregor Mendel with his peas – they conducted intercross experiments with mice. They crossed mice with an inclination towards obesity and mice from a normal-weight strain** with each other. By comparing the external traits of the offspring with the quantitative trait loci (QTL) they could map a chromosomal region that is strongly associated with obesity. Further analyses of this region finally led to the identification of the Ifi202b gene, which belongs to the Ifi200 gene family, as obesity gene.

Cortisol contributes to obesity
Mouse offspring that inherited the intact gene from their parents rapidly became overweight. In contrast, the offspring sustained normal weight if, through natural mutation, they had inherited a variant of the gene which had lost its function. As subsequent studies of adipose tissue and cells in culture showed, the protein derived from the intact Ifi202b gene regulates a specific enzyme in the adipose tissue. This converts the biologically inactive cortisone into the active hormone cortisol. The stronger the Ifi202b gene was expressed, the more enzymes the researchers detected in the adipose tissue. This is an important indication that the cortisol produced in the tissue also plays a role in the pathogenesis of obesity. “Once we had identified the critical gene family, we focused on investigating the respective genes in 53 normal weight and 221 morbidly obese individuals, and we were successful,” said lead author Heike Vogel. Two genes of the human Ifi gene family, IFI16 and MNDA, are also associated with obesity. They are expressed much more abundantly in the visceral adipose tissue of obese individuals, whereby the adipose cells increase in size in correlation with increased gene expression of IFI16 and MNDA.

New strategies for diabetes prevention
“Further elucidation of the cellular function of Ifi202b will also lead us to new strategies of diabetes prevention,” said Professor Hans-Georg Joost, scientific director of the DIfE. High quantities of visceral fat in the abdominal cavity represent a risk factor for type 2 diabetes. Professor Annette Schürmann, who led the study, added, “The fact that the identified gene family plays a role both in humans and in mice is a critical advantage. Thus, we can study the gene functions and the underlying molecular mechanisms in model systems such as the mouse or in specific cell lines under controlled conditions. In humans, such studies are often not possible for ethical or practical reasons. ”


Publication: Vogel,H et al. Loss of function of Ifi202b by a microdeletion on chromosome 1 of C57BL/6J mice suppresses 11β-hydroxysteroid dehydrogenase type 1 expression and development of obesity. Human Molecular Genetics; Advance Access published June 12, 2012
http://hmg.oxfordjournals.org/content/early/2012/06/12/hmg.dds213.full.pdf?keytype=ref&ijkey=RjgTKzKy5acnzh0


Background information

*Visceral fat is fat that is deposited in the abdomen around the intestines. It is more metabolically active than subcutaneous fat tissue. People with extensive visceral fat usually have an increased risk for type 2 diabetes, cardiovascular disease and certain types of cancer such as colon cancer.

**The mouse strains used for the intercross experiments: The New Zealand Obese (NZO) mouse gains weight rapidly when put on a high-fat diet and thus becomes obese. The body fat percentage can rise to over 40 percent. Due to their genetic predisposition, the mice of the C57BL/6J (B6) strain gain significantly less weight and stay slim, despite a very high proportion of fat in their diet.