Dact1, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the Wnt/beta-catenin signaling network.
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.


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.
Lagathu
Claire
C
Institute of Metabolic Science-Metabolic Research Laboratories and Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.
Christodoulides
Constantinos
C
Virtue
Sam
S
Cawthorn
William P
WP
Franzin
Chiara
C
Kimber
Wendy A
WA
Nora
Edoardo Dalla
ED
Campbell
Mark
M
Medina-Gomez
Gema
G
Cheyette
Benjamin N R
BN
Vidal-Puig
Antonio J
AJ
Sethi
Jaswinder K
JK
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017667:Adipocytes / Q000166:cytology / Q000502:physiology*; D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051820:TCF Transcription Factors / Q000235:genetics; D000073940:Transcription Factor 4; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C491683:DACT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051820:TCF Transcription Factors; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051153:Wnt Proteins; D051176:beta Catenin; C508545:frodo protein, mouse