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Wnt signalling and adipose tissue plasticity

Final Activity Report Summary - Wnt ADIPOSE TISSUE (Wnt signalling and adipose tissue plasticity)

Obesity is a disorder of energy balance where energy intake chronically exceeds energy expenditure resulting in excessive accumulation of white adipose tissue. We proposed that an inability of adipose tissue to expand in the face of continuous positive energy balance, rather than adipose tissue accumulation per se, might underlie the association between obesity and insulin resistance.

Recently, we and others demonstrated that a specific signalling pathway termed the Wnt /beta-catenin pathway was important for limiting the differentiation of preadipocytes into mature adipose cells, responsible for fat storage in adipose tissue. In this project we focussed on the role of specific components of the beta-catenin/Wnt pathway, some of which were not previously identified in adipose tissue. We assessed whether the loss or gain of function of these proteins modulated this pathway and had any effect on adipogenesis. Moreover, we undertook a study evaluating the role of these proteins in the development of obesity and diabetes.

For this purpose, we firstly had to identify Wnt signalling molecules that were differentially regulated in preadipocytes and adipocytes. This allowed us to identify two major pro-adipogenic genes of the Wnt/beta-catenin pathway, namely Dact1 and SFRP1. Gain and loss of function experiments involving SFRP1 and Dact1 were carried out in preadipocytes’ cell lines. We clearly demonstrated that both Dact1 and SFRP1 were antagonists of the Wnt signalling and could promote adipogenesis. Additionally, our in vivo studies showed, for the first time, that both genes were regulated during the onset of adiposity but were dysregulated in obesity associated insulin resistance and diabetes.

We also presented evidence for a functional network formed by Dact1, sFRP1 and other signalling molecules of the Wnt signalling pathway. We speculated that dysregulation of this network night result in altered balance between the processes of adipocyte growth versus preadipocyte recruitment and could be of metabolic relevance in the context of obesity.