The RNA roots of obesity?

By silencing two microRNAs, researchers were able to improve insulin sensitivity in overweight mice.

By | June 8, 2011

Obese and normal mouseIMAGE: WIKIMEDIA COMMONS, OAK RIDGE NATIONAL LABORATORY

Two upregulated microRNA molecules may lie at the heart of insulin signalling malfunctions, which can lead to obesity and type 2 diabetes, according to researchers in Switzerland. Scientists at ETH Zurich found that silencing the two microRNAs improved glucose sensitivity in obese mice, and in a paper published today (8 June) in Nature, they suggest that the findings may point the way to potential obesity treatments in humans.

“The effects they are showing are quite striking,” said Phillip Scherer, a fat cell physiologist at the University of Texas Southwestern Medical School, who was not involved in the study. The microRNAs studied in the paper were “so blatantly, obviously up-regulated in the obese state.”

MicroRNAs, or small snippets of non-coding RNA, turn off whole gene networks by binding to and silencing messenger RNAs, the templates for protein synthesis. Several studies have implicated microRNAs in cancer, diabetes, heart disease, and neurological disorders. One microRNA sequence is being studied in human trials as a target for a potential Hepatitis C therapy.

Markus Stoffel, an ETH Zurich molecular physiologist, wanted to see whether certain microRNAs were associated with obesity and diabetes. To do so, the he and his colleagues performed gene expression analysis and found two microRNAs, 103 and 107, that were up-regulated in both mice and humans who had fatty liver disease, a precursor to insulin resistance and diabetes.

To show that the microRNAs caused insulin resistance, Stoffel and his colleagues used a viral vector to express the two microRNAs in healthy mice, who soon developed high blood sugar. Next, they silenced the two microRNAs in two groups of obese mice—one group that had been genetically modified to be fat and another that comprised normal mice fed a high-fat diet. Both sets of mice showed improved glucose metabolism in their liver and fat cells.

The researchers then used gene expression experiments to determine that the microRNAs reduced insulin sensitivity by switching off production of a membrane protein called caveolin 1. In fat cells, caveolin 1 stabilizes insulin receptors.

The study sets the stage for the therapeutic silencing the microRNAs in obese patients, said Jens Brüning, an endocrinologist and director of the Max Planck Institute for Neurological Research, who was not involved in the work.

Before the studies can progress to humans, however, researchers need to show that silencing microRNAs 103 and 107 does not disrupt other gene networks, he said.

Another limitation is that the researchers only tracked mice for a few weeks. Follow-up work should test whether the gene silencing effects persisted long term, he said.

Trajkovski, M., et al. “MicroRNAs 103 and 107 regulate insulin sensitivity,” Nature. doi:10.1038/nature10112, 2011.

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