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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 Dapperl/Frodol (Dactl) as a new preadipocyte gene involved in the regulation of murine and human adipogenesis.
RESEARCH DESIGN AND METHODS- Changes in Dactl 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 Dactl action during adipogenesis. The in vivo regulation of Dactl and Wnt/ß-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 - Dactl is a preadipocyte gene that decreases during adipogenesis. However, Dactl knockdown impairs adipogenesis through activation of the Wnt/ß-catenin signaling pathway, and this is reversed by treatment with the secreted Wnt antagonist, secreted Frizzled-related protein 1 (Sfrpl). In contrast, constitutive Dactl 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, Dactl and Wnt/ßcatenin 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 - Dactl regulates adipogenesis through coordinated effects on gene expression that selectively alter intracellular and paracrine/autocrine components of the Wnt/ß-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. Diabetes 58: 609-619, 2009
Dysregulated adipose function, as is observed in obesity, is associated with increased risk of developing diabetes, cardiovascular diseases, and some cancers. Recently, impaired adipose tissue expandability/plasticity has been shown to be an important factor linking obesity to its metabolic complications (1-4). This has led to the hypothesis that specific regulatory mechanisms must exist to ensure that the balance between preadipocyte recruitment and differentiation tightly matches the storage demands imposed by nutritional loads. Understanding the mechanisms that control when, how, and which preadipocytes enter the program of differentiation may aid the development of rational therapeutic strategies to improve adipose tissue functionality and lipid buffering capacity and thereby prevent and/or treat obesity-associated...