Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network

Claire Lagathu; Constantinos Christodoulides; Sam Virtue; William P. Cawthorn; Chiara Franzin; Wendy A. Kimber; Edoardo Dalla Nora; Mark Campbell; Gema Medina-Gomez; Benjamin N. R. Cheyette; Antonio J. Vidal-Puig; Jaswinder K. Sethi

doi:10.2337/db08-1180

Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network

Claire Lagathu, Constantinos Christodoulides, Sam Virtue, William P. Cawthorn, Chiara Franzin, Wendy A. Kimber, Edoardo Dalla Nora, Mark Campbell, Gema Medina-Gomez, Benjamin N. R. Cheyette, Antonio J. Vidal-Puig, Jaswinder K. Sethi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

OBJECTIVE-Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Writ 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 (luring the development of dietary and genetic obesity.

RESULTS-Dact1 is a preadipocyte gene that decreases (luring adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Writ 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 Writs. 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. Diabetes 58: 609-619,2009

Original language	English
Pages (from-to)	609-619
Number of pages	11
Journal	Diabetes
Volume	58
Issue number	3
DOIs	https://doi.org/10.2337/db08-1180
Publication status	Published - Mar 2009

Keywords / Materials (for Non-textual outputs)

INHIBITS ADIPOGENESIS
ADIPOCYTE BIOLOGY
BETA-CATENIN
WNT
FRODO
MICE
INVOLVEMENT
ANTAGONIST
METABOLISM
MECHANISMS

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10.2337/db08-1180

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Lagathu, C., Christodoulides, C., Virtue, S., Cawthorn, W. P., Franzin, C., Kimber, W. A., Nora, E. D., Campbell, M., Medina-Gomez, G., Cheyette, B. N. R., Vidal-Puig, A. J., & Sethi, J. K. (2009). Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network. Diabetes , 58(3), 609-619. https://doi.org/10.2337/db08-1180

@article{6ea537bcea1b4223b4a4469a8f7f3125,

title = "Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network",

abstract = "OBJECTIVE-Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Writ 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 (luring the development of dietary and genetic obesity.RESULTS-Dact1 is a preadipocyte gene that decreases (luring adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Writ 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 Writs. 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. Diabetes 58: 609-619,2009",

keywords = "INHIBITS ADIPOGENESIS, ADIPOCYTE BIOLOGY, BETA-CATENIN, WNT, FRODO, MICE, INVOLVEMENT, ANTAGONIST, METABOLISM, MECHANISMS",

author = "Claire Lagathu and Constantinos Christodoulides and Sam Virtue and Cawthorn, {William P.} and Chiara Franzin and Kimber, {Wendy A.} and Nora, {Edoardo Dalla} and Mark Campbell and Gema Medina-Gomez and Cheyette, {Benjamin N. R.} and Vidal-Puig, {Antonio J.} and Sethi, {Jaswinder K.}",

year = "2009",

month = mar,

doi = "10.2337/db08-1180",

language = "English",

volume = "58",

pages = "609--619",

journal = "Diabetes ",

issn = "0012-1797",

publisher = "AMER DIABETES ASSOC",

number = "3",

}

Lagathu, C, Christodoulides, C, Virtue, S, Cawthorn, WP, Franzin, C, Kimber, WA, Nora, ED, Campbell, M, Medina-Gomez, G, Cheyette, BNR, Vidal-Puig, AJ & Sethi, JK 2009, 'Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network', Diabetes , vol. 58, no. 3, pp. 609-619. https://doi.org/10.2337/db08-1180

TY - JOUR

T1 - Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network

AU - Lagathu, Claire

AU - Christodoulides, Constantinos

AU - Virtue, Sam

AU - Cawthorn, William P.

AU - Franzin, Chiara

AU - Kimber, Wendy A.

AU - Nora, Edoardo Dalla

AU - Campbell, Mark

AU - Medina-Gomez, Gema

AU - Cheyette, Benjamin N. R.

AU - Vidal-Puig, Antonio J.

AU - Sethi, Jaswinder K.

PY - 2009/3

Y1 - 2009/3

N2 - OBJECTIVE-Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Writ 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 (luring the development of dietary and genetic obesity.RESULTS-Dact1 is a preadipocyte gene that decreases (luring adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Writ 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 Writs. 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. Diabetes 58: 609-619,2009

AB - OBJECTIVE-Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Writ 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 (luring the development of dietary and genetic obesity.RESULTS-Dact1 is a preadipocyte gene that decreases (luring adipogenesis. However, Dact1 knockdown impairs adipogenesis through activation of the Wnt/beta-catenin signaling pathway, and this is reversed by treatment with the secreted Writ 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 Writs. 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. Diabetes 58: 609-619,2009

KW - INHIBITS ADIPOGENESIS

KW - ADIPOCYTE BIOLOGY

KW - BETA-CATENIN

KW - WNT

KW - FRODO

KW - MICE

KW - INVOLVEMENT

KW - ANTAGONIST

KW - METABOLISM

KW - MECHANISMS

U2 - 10.2337/db08-1180

DO - 10.2337/db08-1180

M3 - Article

SN - 0012-1797

VL - 58

SP - 609

EP - 619

JO - Diabetes

JF - Diabetes

IS - 3

ER -

Dact1, a Nutritionally Regulated Preadipocyte Gene, Controls Adipogenesis by Coordinating the Wnt/beta-Catenin Signaling Network

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