A group of researchers from the German Institute of Human Nutrition* led by Hadi Al-Hasani and Hans-Georg Joost has identified a natural mutation in the Tbc1d1 gene that keeps mice lean and also protects against diabetes despite a high-fat diet. The researchers were thus able to gain a deep insight into the function of the gene.
Further clarification of its function would provide a basis for developing new approaches for prevention and treatment, as this gene could also be linked to obesity and diabetes in humans.
The mutation that knocks out the Tbc1d1 gene causes increased fat uptake in skeletal muscle and, at the same time, boosts fat oxidation. On the other hand, glucose uptake of muscles is reduced. “This shows that the normal Tbc1d1 gene has a very important function in fat and glucose metabolism and therefore plays an essential role in regulation of energy metabolism“, explains Hadi Al-Hasani.
“Not only how much food we eat but also how our body uses it is decisive for development of obesity and diabetes“, says Hans-Georg Joost, Scientific Director of DIfE. When the relation between glucose and fat oxidation shifts so that the muscles use more fat and less glucose as a source of energy, this is energetically less efficient. As a result, the body stores less fat. This lowers the risk for obesity and consequently also for diabetes.
In Germany, 66 percent of the men and 50.6 percent of the women are already overweight or obese. In the USA, even three-fourths of adults “break the bathroom scales“, according to the latest reports. Overweight increases significantly the risk of heart attack, stroke, intestinal cancer, and type-2 diabetes. At present, more then seven percent of Germans are diabetic and this number will increase even more due to the growing number of overweight persons.
Studies in animals and humans have shown that there is a relation between overweight, type-2 diabetes, diet, and genes. Researchers suspect that natural variants of at least 50 genes are involved in the development of overweight. As for diabetes, probably more than 100 genes are involved. Only very few of these genes and variants are known to date. In addition, they form a functional, interacting network with environmental variables that is incompletely understood.
Since humans and mice are genetically very similar, the researchers of DIfE use the mouse model to identify genes involved in the development of overweight and diabetes. If an “overweight gene“ has been discovered which plays a role in both species, then the researchers can investigate its function and the basic molecular mechanisms in animal models under controlled conditions. Such studies often cannot be carried out in humans for ethical as well as practical reasons. The results from the animal model studies can then be used to develop new medications for treatment of obesity and diabetes.
About the study: The researchers identified the mutation on the Tbc1d1-gene by means of back-crossing experiments. Then the genetic makeup of two very different mouse strains was compared. The New Zealand obese mouse gains weight rapidly under a high-fat diet (60 percent fat) and develops obesity, whereby the proportion of body fat can increase to over 40 percent. Despite a very high fat diet, the mice of the Swiss Jim Lambert strain did not gain weight but stayed lean, due to their genetic makeup.
Seven base pairs are missing in the mutated Tbc1d1 gene of the Swiss Jim Lambert strain. These changes lead to the synthesis of a shortened Tbc1d1 protein molecule and, most likely, loss of enzyme activity. The Tbc1d1 protein molecule is located mainly in skeletal muscle. Researchers have found smaller amounts in heart, pancreas, intestine, kidney, and hypothalamus. It is not found in fatty tissue or liver.
*Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke, DIfE
The above story is based on materials provided by German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE). Note: Materials may be edited for content and length.
- Chadt et al. Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nature Genetics, October 19, 2008; DOI: 10.1038/ng.244
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