Friday, November 11, 2011

Gene blocking improves metabolism and endurance

One gene makes a significant difference in the health status of mice, two groups of scientists have determined in collaboration with each other. A Swiss group of scientists showed that knocking out the NCoR1 gene renders mice able to run for much longer than normal. In fact, their endurance doubles, as the mice in the experiment where found to run twice as far as without the genetic adaptation. A group of scientists from California found, in collaboration with those in Switzerland, that knocking out the same gene results in a decreased chance of developing diabetes. That is an interesting duality, for just a single gene.

The difference lies in where the gene gets knocked out. If it is done in muscle tissue, the mouse increases its endurance. However, when the scientists knocked NCoR1 out in fat cells, they found that a surplus of fat tissue didn't lead to development of diabetes.

NCoR1 inhibits certain transcription factors, that are able to regulate gene expression, in muscle cells. A downregulation of NCoR1 leads to an increase of these transcription factors, which can in turn activate genes that causes muscle mass to increase. In addition, the energy generating machinery of the cells, called mitochondria, were increased in number and activity.

In the fat cells however, knocking down NCoR1 resulted in increase of insulin sensitivity. That causes increased uptake of glucose by cells from various organs, a mechanism that is found to be broken in diabetes patients. In addition, there was less tissue inflammation, another symptom which is prevalent in diabetes. NCoR1 repression turns on genes that are vital for insulin sensitivity, which consequently leads to glucose tolerance in many tissues.

The difference in cellular effects is caused by different cellular interactions that NCoR1 is involved with. In muscle cells it interacts with certain transcription factors, while in fat cells, NCoR1 represses a pathway involved with signalling required for the upregulation of genes that are important to prevent diabetes. In both cell types the mechanism is the same: NCoR1 represses certain molecules involved with cell signaling, but the outcome differs greatly.

It is interesting to see how a single gene can play different roles in different cell types. There are more of these genes however, but NCoR1 is still quite special, as it has such a profound effect on the health status of the mice that were used in the experiment. It is also known that NCoR1 plays an important role in embryonic development, as foetuses that lack NCoR1 in all tissues cease to develop prior to birth. Future studies need to reveal how additional roles of NCoR1 can account for the failure of the foetus to develop.

If the same mechanism is found in humans, doctors could treat patients by inhibiting the NCoR1 protein in fat tissue. Athletes could train their muscles by the same mechanism, but I am quite sure that is a less favourable development.

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