Molecular Medicine Israel

Gene tweak creates supermouse – and prevents diabetes

Cell, Volume 147, Issue 4, 815-826, 11 November 2011; DOI 10.1016/j.cell.2011.09.050.
P. Li, W. Fan, J. Xu, M. Lu, H. Yamamoto, J. Auwerx, D.- D. Sears et al.
“Adipocyte NCoR Knockout Decreases PPARγ Phosphorylation and Enhances PPARγ Activity and Insulin Sensitivity”.

Faster, longer, further… fatter? Knocking out a particular gene in muscle lets mice run twice as far as normal. Knocking out the same gene in fat cells allows the animals to put on weight without developing type-2 diabetes.
The discoveries could lead to new treatments for diabetes or for invigorating muscles in elderly people and in those with wasting diseases, say Johan Auwerx of the Federal Polytechnic School of Lausanne, Switzerland, and colleagues. Auwerx warns that cheats may exploit the potential for increase athletic performance, however.

Auwerx and his colleagues used a targeted virus to knock out the gene that makes a protein called nuclear receptor corepressor 1 (NCoR1) in the muscle of mice. Without NCoR1, mitochondria, which power cells, keep working at full speed. “Effectively, the mice go further, faster, on the same amount of gas,” says Auwerx.

“The treated mice ran an average of 1600 metres in 2 hours, compared with 800 metres for untreated mice,” he says.

Fattened up

In a separate experiment, Auwerx found that knocking out NCoR1 in fat cells exclusively made the mice get fatter, but they didn’t develop type-2 diabetes. He hopes that by giving drugs that control NCoR1 in fat to people who are already obese, it may be possible to stop them developing diabetes as well.

Auwerx has already identified fatty acids in common foods that suppress NCoR1. If similar compounds can be found that target specific tissues, then it may be possible to treat diseases specific to muscle or fat.

Auwerx warns athletes not to try to grow their muscles and stamina illicitly by somehow targeting the NCoR1 protein, however.

“We only know what happens if it’s knocked out either in fat or muscle, and it could have serious side effects on other organs,” he says. Also, he points out that without NCoR1, all fetuses perish, so it plays a vital but undiscovered role in fetal development.


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