WNT ADIPOSE TISSUE · Wnt signalling and adipose tissue plasticity
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-04-01 → 2008-12-31
- EU contribution
- €167,664
- Participants
- 1
- Scheme
- EIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
Obesity resulting from hypertrophy of adipocytes is more deleterious metabolically than obesity resulting from hyperplasia of new adipocytes. Our aim is to understand the role of Wnt signalling network regulating the balance between hypertrophy and hyperplasic adipose tissue. We hypothesise that over nutrition activates Wnts regulatory mechanisms in adipose tissue to facilitate fat storage in pre-existing adipocytes or inducing differentiation of new adipocytes. Whereas overexpression of Wnts in preadipocyte s prevents adipogenesis, inhibition of Wnt signalling canonical pathway stimulates adipogenesis. Wnt signalling is also involved in the activation of proadipogenic transcription factors such as PPARgamma. Therefore our hypothesis is that Wnt network could control the balance between hypertrophy and hyperplasia in adipose tissue. The laboratory of my sponsor has characterised a PPARg2 Knock-out mouse showing hypertrophic changes in the adipose tissue of these mice in response to a high fat diet. In this proposal, I will use this model to investigate the role of Wnts in adipocyte hypertrophy or hyperplasia in vivo. In parallel I will also be able to learn the technology to generate a knock in mouse model of the first human mutant in a wnt related molecule detected in an obese subject. The specific objectives are: a) To identify genes from Wnt signalling network involved in adipocyte hypertrophy/hyperplasia using adipose tissue from PPARg2 KO using a Systems Biology approach involving gene expression profiling a nd advanced bioinformatic analysis. b) To characterise in vitro the role of Wnts signalling proteins identified in a) using gain and loss of function (RNAi) experiments. c) To generate and characterise a knock-in mouse expressing a non-functional human wnt 10 mutants identified in a cohort of human obese individuals (Goose cohort). This project will provide new insights on mechanisms regulating adipose tissue plasticity and their impact in energy homeostasis.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTER AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGECoordinatorCity levelUnited Kingdom
Links
Data: CORDIS, © European Union