Transfer RNAs (tRNAs) have a central role in protein translation. Recently, tRNAs have been discovered to play also a crucial role as mediators of cellular responses to environmental cues. tRNAs molecules are transcribed, post-transcriptionally modified and cleaved by endonucleases giving rise to functionally active tRNA-derived fragments (tRFs): the ensemble of these processes constitutes the tRNA epitranscriptome, strictly regulated by nutrient availability and environmental factors. The important role of tRNA homeostasis and tRF biogenesis in the context of diabetes has recently emerged. Mutations in the tRNA methylase TRMT10A have been linked to tRNA hypomodification and fragmentation contributing to pancreatic β-cells death. β-cells constitute the only cells in the body able to secrete insulin in response to glucose. Moreover, β-cells from newborn and adult rats exhibit peculiar tRF signatures, which are essential for the postnatal maturation of the insulin-secreting cells. However, the effect of environmental factors contributing to the development of diabetes on the tRNA epitranscriptome has not yet been investigated. Obesity represents the strongest risk factor for type 2 diabetes (T2D) and has become a major public health concern due to the diffusion of malnutrition and overnutrition. The rise of glycaemia in T2D derives from the loss of insulin sensitivity of peripheral organs such as muscle, liver, and adipose tissue, combined with defective insulin secretion from pancreatic β-cells, occurring as a result of chronic stress. In this context, the immune cells macrophages (Mφs) resident in pancreatic islets appear to hold a crucial role. In response to obese environment and β-cell distress, islet Mφs proliferate and undergo transcriptional and metabolic changes, to counteract the excess of nutrient intake and the increased need of insulin. The mechanisms underlying the metabolic modulation of islet Mφs and β-cell function during obesity remain elusive. I hypothesized that changes in tRNA epitranscriptome affect the tRF profile and permit a prompt response to environmental cues in islet cells during obesity. The overall objectives of this project were 1) to investigate whether tRNA epitranscriptome is modulated during obesity in macrophages; 2) to study the consequences of tRNA cleavage modulation on macrophage activation and 3) to understand whether tRNA derived fragments could be part of cell-to-cell crosstalk between macrophages and pancreatic beta cells.
