Abstract

Objective: Wnt signalling inhibits adipogenesis but its regulation, physiological relevance, and molecular effectors are poorly understood. Here we identify the Wnt modulator Dact1 (Dapper1/Frodo1) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis.

Research Design and Methods: Changes in Dact1 expression were investigated in three in vitro models of adipogenesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dact1 and Wnt/β-catenin signalling were investigated in murine models of altered nutritional status, pharmacological stimulation of in vivo adipogenesis and during the development of dietary and genetic obesity.

Results: Dact1 is a preadipocyte gene that decreases during adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/β-catenin signalling pathway and this is reversed by treatment with the secreted Wnt antagonist, Sfrp1. In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced anti-adipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/β-catenin signalling also exhibit coordinated expression profiles in response to altered nutritional status, pharmacological stimulation of in vivo adipogenesis and during the development of dietary and genetic obesity.

Conclusions: Dact1 regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/β-catenin signalling pathway. These novel insights into the molecular mechanisms controlling adipose tissue plasticity provide a functional network with therapeutic potential against diseases such as obesity and associated metabolic disorders.