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Researchers ID Mouse MicroRNAs Mediating Insulin Sensitivity

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – In a paper appearing online today in Nature, a team of researchers from the US and Switzerland described how they tracked down and started characterizing a pair of microRNAs contributing to insulin sensitivity in mice.

The group used microarray analyses to identify miRNAs from the same family — miR-103 and miR-107 — whose expression is ramped up in two mouse models of obesity. Follow-up studies suggest that elevated expression of these miRNAs corresponds to increased insulin and blood glucose levels and reduced insulin sensitivity in the animals.

On the other hand, when the researchers interfered with the levels of miR-103 and miR-107, they got mice with enhanced insulin sensitivity and glucose homeostasis, hinting that it might be possible to tweak such processes by targeting the miRNAs.

"These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity," senior author Markus Stoffel, a molecular systems biology, systems physiology, and metabolic disease researcher at the Swiss Federal Institute of Zurich (ETH Zurich), and co-authors wrote.

Stoffel and his colleagues tracked down the miRNAs by looking at the miRNA profiles in liver tissue from male mice with diet-induced obesity or with obesity caused by genetic glitches that prevent the animals from producing the hormone leptin using miRXplore arrays targeting 584 mouse, 426 rat, 122 viral, and 728 human miRNAs.

From their microarray data, the team found that miR-103 and miR-107, nearly identical miRNAs from the same miRNA family, were among the most highly expressed miRNAs in both of the mouse models of obesity — findings that they confirmed through northern blot and real-time PCR experiments.

The two miRNAs also seem to be more highly expressed in the liver biopsy samples from humans with several liver conditions associated with diabetes, the researchers reported, but not in samples from those with liver disease caused by hepatitis viruses.

To further explore potential ties between the miRNAs and insulin sensitivity-related processes, researchers injected wild type animals with fluorescently tagged recombinant adenoviruses that caused over-expression of miR-107.

Compared to mice that received a control injection, mice with higher miR-107 levels had several signs pointing to elevated glucose production in the liver, they found.

When they silenced miR-103 and miR-107 using antagomirs, meanwhile, the team saw lower blood glucose levels, increased insulin sensitivity, and better glucose tolerance in the leptin-deficient mice and mice with diet-induced obesity but not in wild type mice. Even so, they noted, decreasing miRNA levels specifically in liver tissue was not enough to shift liver metabolism back to wild type patterns.

"[G]lobal miR-103/107 silencing causes increased insulin signaling in both liver and adipose tissue, although silencing of [liver] miR-103/107 expression in overt obese and insulin-resistant states is insufficient to reverse the metabolic abnormalities," the researchers wrote. "This indicated that silencing of miR-103 in adipocytes is the dominant contributor to enhanced insulin sensitivity.

The group's subsequent studies, including comparisons of gene expression patterns assessed with Affymetrix arrays, suggest that the newly-identified miRNAs contribute to insulin-related processes by curbing the expression of an insulin signaling mediator known as caveolin-1.

When the activity of these miRNAs is impeded in fat cells, they explained, their caveloin-1 levels increase, insulin signaling improves, and size diminishes. Lower miRNA-103 and miR-107 levels also corresponded to insulin receptor stabilization and more pronounced insulin-stimulated glucose uptake by these cells.

"Our findings that silencing miR-103/107 in obese animals improves glucose homeostasis implicated these miRNAs as novel therapeutic targets for the treatment of diabetes," the team concluded.

ETH Zurich researchers collaborated with scientists from Regulus Therapeutics and Alnylam Pharmaceuticals on the study.

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