MicroRNAs and Glucose Metabolism

Obesity-associated microRNA-802 regulates hepatic glucose metabolism

MicroRNAs are small, 21-22nt-long noncoding RNAs that modulate the stability and translational capability of their cognate mRNA target(s). According to modern prediction algorithms, mammalian genomes encode for >1000 microRNAs, with each microRNA targeting up to hundreds of protein-coding transcript. More than 60 percent of all mammalian mRNAs are predicted to be regulated by miRNA-evoked posttranscriptional inhibition. Thus, the regulatory spectrum of microRNA-based gene regulation is enormous.

Whereas most studies concentrated on transcriptional regulation of glucose metabolism, a conceptual void exists regarding the role of post-transcriptional gene silencing by microRNAs in control of energy metabolism in healthy individuals as well as obesity-associated diseases like type 2 diabetes mellitus (T2D). We recently identified and characterized a glucoregulatory microRNAs called miR-802 and demonstrated that obesity-associated rises in miR-802 deteriorate hepatic glucose metabolism via silencing of the diabetes risk gene hepatocyte nuclear factor 1 beta (Hnf1b). An excessive miR-802-Hnf1b tone leads to uncurbed glucose production, hyperglycemia and impairment of glucose homeostasis in mice and, presumably, human T2DM patients. The identification of tissue-specific and disease-associated microRNAs and long, noncoding RNAs (lncRNAs) as well as the efficacy of microRNA inhibitors offers the unique prospect of designing and applying noncoding RNA loss-of-function regimens in the future.