Modulation of tRNA pool and tRNA fragments in obesity and diabetes; focus on their role in macrophage activation and exosome-mediated crosstalk with pancreatic beta cells

Obesity is a major public health concern and represents the strongest risk factor for type 2 diabetes (T2D) development. In T2D pathogenesis, inflammation contributes to multi-organ insulin resistance and pancreatic β-cell failure.

Macrophages (Mφs) in adipose tissue and pancreatic islets play an important role in organ homeostasis, however their metabolic switch leads to chronic inflammation in obese individuals.

The functional profile of obese Mφs reflects a high complexity, not explained by the classical model of pro-inflammatory activation.

This suggests that unknown molecular modulators, higly sensitive to environmental changes, might control the activation of Mφs.

Here I propose to investigate the role of transfer RNAs (tRNA) and tRNA fragmentation in in Mφ activation and diabetes pathogenesis.

The ensemble of tRNAs in the cell is under strict regulation of nutrient availability and directly controls protein translation; also, tRNA fragmentation is controlled by stress factors and leads to the formation of tRNA fragments (tRFs), highly functional non-coding RNAs.

I propose to study changes in tRNA pool and tRF signature in Mφs from adipose tissue and pancreatic islet using the db/db mouse model.

I will analyse how protein translation is associated with tRNA pool, using ribosome profiling and computational methodologies.

In addition, I will investigate the function of tRFs in the crosstalk between Mφs and β-cells via exosomes and their role in modulating β-cell function.

I will use a Mφ-specific mouse model allowing the labeling of small RNAs in Mφs and the detection of the transferred molecules in β-cells.

I will therefore combine high-throughput and in vivo innovative approaches to achieve the following aims: 1) Analyze the modulation of tRNA pool and translational in obese macrophages; 2) Investigating tRNA fragmentation and tRFs function in Mφs and β-cells during diabetes pathogenesis; 3) Study tRFs role in exosome-mediated Mφ to β-cell signaling.