Final Report Summary - METABOLOMIRS (Elucidation of MicroRNAs as Regulators of Metabolism and Targets for Therapeutic Intervention)
MicroRNAs (miRNAs) are small (approximately 18-24 nucleotides in length), non-coding RNA molecules encoded in the genomes of plants and animals. In certain instances, highly conserved, endogenously expressed miRNAs regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs. More than 1000 different miRNAs have been identified in plants and animals. Functional analyses of miRNAs have revealed that these small non-coding RNAs contribute to different physiological processes in animals, including developmental timing, organogenesis, differentiation, patterning, embryogenesis, growth control and programmed cell death. Examples of particular processes in which miRNAs participate include stem cell differentiation, neurogenesis, angiogenesis, hematopoiesis, and exocytosis Deregulation of miRNA-networks can result in inappropriate responses to pathological stress and represents the basis of several disease conditions. In pancreatic β-cells, little is known on the role of specific miRNAs in the regulation of glucose-stimulated insulin secretion (GSIS) and how these molecules impact on the adaptation of β-cell function to metabolic stress. With the help of this ERC grant we were able to identify several miRNAs that are dysregulated in pancreatic beta cells, liver and fat in obesity and type 2 diabetes and demonstrated a direct role in the pathogenesis of these diseases. We showed that miR-7 is a negative regulator of glucose-stimulated insulin secretion in β-cells. Using miR-7a deficient mice, we reveal that miR-7a2 controls β-cell function by directly regulating genes controlling late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. In contrast, expression of the miR-200 family is upregulated in oxidative and ER stress and regulated cell survival during chronic metabolic stress. In the liver and adipose tissue miR-103/107 is upregulated in obese mice and humans. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat was sufficient to induce impaired glucose homeostasis. We identified caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrated that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrated the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity that is currently in preclinical development.