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ESR Project 4: Nuclear TRIB1/3 in adipocytes and macrophages and their functions

miguel

Miguel Hernandez Quilles

Adipose tissue is in the crossroad between metabolism and cancer. Adipocytes promotes cancer inicitation and progression through different endocrine and paracrine mechanisms. Many adipokines secreted directly from cononical adipose tissue have been related with cancer in previous studies.

Obesity has became a major problem worldwide during the last decades, 1,1 Billion adults are overweight and 500 Million are obese. Moreover, 60% of these obese adults suffer from a metabolic dysregulation called “metabolic syndrome”. Some of the features of this syndrome are insulin resistance, hyperglycemia, dyslipidemias and hypertension. Obesity and metabolic syndrome are highly related with type II diabetes, cardiovascular deseases and cancer. Interestengly, obese individuals who do not develop this metabolic dysregulation also have a lower cancer risk.

While the relationship between cancer and obesity is well established, less is known about how metabolic syndrome affects cancer.

It has been shown that TRIBBLES, a family of pseukinases, plays a crucial role in adipogenesis (by regulating the activity of two nuclear receptors; PPARg and RXRa) and in cancer. Modulation of the activity of these nuclar receptors through TRIB1/3 could represent an important link between adipocytes, AT-resident inmune cells and (distantly located) tumours. While these earlier findings suggest that TRIB1/3 subcellular localization is regulated and these proteins have a specific function in the nucleus, the molecular mechanism remain to be established.

The folowing three lines of investigation will be followed:

  1. We will use fluorescent microscopy to study the localization of TRIB1/3 during adipocytes differentiation. Following this we will investigate if obesity associated factors can affect the localization of these proteins.
  2. To address the TRIB1/3-PPARy interaction in detail, we will generate multiple TRIB1/3 mutants and test their ability to interact with PPARy in vitro and in living cells.
  3. In an unbiased approach we will identify the nuclear TRIB1/3 interactome, using cutting edge technology facilities available in the UMC Utrecht.

 

The aim of this project is to investigate the role of TRIB1/3 in adipose tissue, we will focus our reseach in understanding how is regulated the subcelullular localization of TRIB1/3 during adipogenesis, by investigating the interactome of these proteins. We will also investigate the TRIB1/3-PPARg interaction in detail.