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ESR Project 3: Trib3-mediated control of macrophage phenotype and impact on adipose tissue inflammation

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Laura Martinez Campasino

Obesity related diseases cause significant morbidity and mortality worldwide. Obese patients have chronic inflammation, which increases their susceptibility to metabolic disorders such as type 2 diabetes mellitus or cardiovascular disease as well as cancer.

The close relationship between the immune system and the whole-body metabolism is most apparent in tissues such as the adipose tissue, which is comprised of adipocytes, immune and endothelial cells.

During the establishment of chronic inflammation in obesity, infiltrating monocyte-derived macrophages and resident adipose tissue macrophages show a pro-inflammatory phenotype. The process of macrophage recruitment into adipose tissue as well as how these cells promote the formation of new adipocytes, their alteration of adipocyte function and contribution to chronic inflammation is not entirely understood.

Tribbles pseudokinase 3 (TRIB3) is an evolutionarily conserved member of the pseudokinase tribbles family of proteins that has a critical role in controlling immune responses, energy homeostasis and cancer development. Previous work in our lab has shown that TRIB3 deficiency in mice promotes inflammation and obesity.

The aim of this project is to study the impact of TRIB3 expression on the interplay between immune cells and adipocytes.

To approach that, two mouse strains will be used: full body TRIB3 knock out and macrophage-specific-TRIB3 deficient mice treated with high fat diet. Phenotypic changes produced by myeloid specific alterations of TRIB3 will be assessed. On the other hand, alterations in the adipocyte formation and function and the macrophage differentiation process might be affected as well, therefore different methods and techniques will be used along the project. As an example of them: immunohistochemistry for macrophage and adipocyte staining, histology and FACS for assessing adipocyte formation, metabolic analysis or protein and gene expression profiling.

In conclusion, the overall objectives of this project will be to establish the immune-metabolic profile of the TRIB3 full body and myeloid specific KO mice, define the adipocyte and macrophage cell profiles of adipose tissue depots in these two animal models and finally, validate in vitro the effects of Trib3 gene-silencing on metabolome and gene expression.