NEW YORK (GenomeWeb News) – A new Nature study suggests that levels of a microRNA called miR-802 rise in response to obesity, leading to the sorts of metabolic changes and insulin resistance features that foretell type 2 diabetes.
Researchers from Germany, Switzerland, and France used microarrays to profile miRNA patterns in liver samples from mice being used to model obesity and insulin resistance. Among the liver miRNAs that stood out for having elevated expression in these animals was miR-802, which was subsequently found at higher-than-usual levels in the livers of obese humans, too.
Through its follow-up analyses, the team saw that this rise in miR-802 levels is capable of causing type 2 diabetes-related changes in not only insulin sensitivity but also glucose tolerance. Additionally, that effect appears to stem from excessive silencing of the hepatic nuclear factor 1 beta gene Hnf1b by the miRNA.
"Although the mechanism(s) of how Hnf1b controls hepatic glucose metabolism clearly requires further investigation, our study reveals an important role for miR-802- and Hnf1b-dependent regulation of insulin sensitivity and glucose metabolism in vivo," corresponding author Jens Brüning, a researcher affiliated with the Max Planck Institute for Neurological Research and the University of Cologne, and his colleagues said.
Past studies have linked a handful of miRNAs to type 2 diabetes-related traits, the researchers said. For instance, shifts in the regulation of some miRNAs have been shown to sway insulin sensitivity in the liver, which produces glucose in response to insulin cues.
To delve further into potential roles for miRNAs in type 2 diabetes, Brüning and his co-authors began by using microarrays to catalog the miRNAs present in liver samples from mouse models of obesity and insulin resistance/diabetes. The obese mice had subsisted on an especially high fat diet, they reported, while the diabetic mouse models carried mutations affecting both copies of a leptin receptor gene previously linked to the disease.
All told, the team detected 66 miRNAs showing significantly different expression in the livers of obese mice compared to control animals fed a normal diet. Meanwhile, 156 miRNAs were differentially expressed in livers from mice with leptin receptor mutations relative to wild type mice.
Among the miRNAs found at higher-than-usual levels in liver samples from both mouse models of disease was miR-802 — a finding that investigators verified through additional quantitative real-time PCR and northern blot experiments.
Through a series of cell line and mouse model experiments, meanwhile, the researchers demonstrated that a rise in miR-802 levels leads to impaired insulin sensitivity, coupled with glucose intolerance.
In an effort to begin untangling the reason for such effects, the team turned to bioinformatics to search for possible miR-802 targets. In the process, it came up with 26 candidates, including a gene implicated in some past diabetes studies: Hnf1b.
Together, such results led investigators to suspect that obesity-related increases in miR-802 levels might influence insulin sensitivity and glucose metabolism by muting the activity of the Hnf1b gene product.
Turning to mouse models once more, the researchers showed that dialing down Hnf1b activity in the liver did lead to aberrant insulin and glucose features, along with a boost in glucose production by the liver. On the other hand, Hnf1b over-expression corresponded with enhanced insulin sensitivity, they reported, even in mouse models of diabetes.
While more research is needed to tease apart the details of this obesity-induced pathway, those involved in the study argued that the work "defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity."