The role of wnt signalling network in adipose tissue development and plasticity

Obesity and diabetes are becoming increasingly prevalent in the western world. Individuals that are obese and diabetic are at high risk of dying at an early age from heart attacks. Hence, obesity and the related metabolic diseases represent a significant public health issue. The ideal strategy would be to prevent individuals from becoming obese, but it is clear that current efforts have been ineffective at curbing this epidemic. By increasing our understanding of how normal fat tissue develops and adjusts its size in response to environmental changes, we may identify more effective strategies for maintaining their health despite increased body weight. We think that adipose tissue does not have an unlimited capacity to store fat and it is when this level is surpassed that clinical problems arise. Our research aims to identify and study a group of proteins (Wnts) that are related to tissue development and alter the program of fat cell formation. These proteins can act as messengers to control the size and recruitment of new fat tissue. How these proteins bring about these changes in human fat tissue remains unclear. We have shown that key Wnt signalling molecules are co-ordinately regulated in human fat cell formation. We have also identified a human mutation in one of these molecules, in an obese individual. This mutation appears to render the molecule signalling defective and may be related to their obesity. Herein, we propose to identify and characterise the full complement of these molecules and identify their roles in altering fat tissue size in specific experimental models of obesity and fat cell development. We will also generate a new model that will allow us to investigate the role of this novel wnt mutant in whole body energy storage. We hypothesise that the wnt signalling network orchestrates the balance between fat cell recruitment and size. Alterations in this network may result in increased fat tissue size and cell number that ultimately may have important metabolic consequences.

A fundamental question in adipose tissue biology is the nature of the signals determining 'when' and 'how' preadipocytes differentiate. The Wnt signalling network is particularly suited to regulate this. Although, a few Wnts are implicated in murine adipogenesis, the involvement of the wnt network in human adipogenesis and tissue plasticity remains unclear. We have shown that key Wnt signalling molecules are co-ordinately regulated in human adipogenesis and facilitate differentiation. We have also identified a human wnt10b mutant, which is signalling defective and cannot maintain the preadipocyte phenotype. Herein, we propose to 1) identify differentially regulated wnt signals in an in vivo model of hypertrophic adipose tissue (PPAR gamme2-KO), 2) characterise their effects on adipogenesis and 3) generate a wnt10b loss of funcion mutant knock-in mouse. We hypothesise that the wnt signalling network orchestrates the balance between adipocyte maturation and preadipocyte recruitment. Alterations in this network may result in hyperplasic/hypertrophic adipose tissue with important metabolic consequences.