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OBJECTIVE: Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dapper1/Frodo1 (Dact1) 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/beta-catenin signaling were investigated in murine models of altered nutritional status, of 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/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrp1). In contrast, constitutive Dact1 overexpression promotes adipogenesis and confers resistance to Wnt ligand-induced antiadipogenesis through increased expression of endogenous Sfrps and reduced expression of Wnts. In vivo, in white adipose tissue, Dact1 and Wnt/beta-catenin signaling also exhibit coordinated expression profiles in response to altered nutritional status, in response to 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/beta-catenin signaling 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.

Original publication

DOI

10.2337/db08-1180

Type

Journal article

Journal

Diabetes

Publication Date

03/2009

Volume

58

Pages

609 - 619

Keywords

3T3-L1 Cells, Adaptor Proteins, Signal Transducing, Adipocytes, Adipose Tissue, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Differentiation, Gene Expression Regulation, Genes, Reporter, Humans, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Nerve Tissue Proteins, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, TCF Transcription Factors, Wnt Proteins, beta Catenin