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.
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