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Dactl, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the wnt/β-catenin signaling network

Dactl, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the wnt/β-catenin signaling network
Dactl, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the wnt/β-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 Dap- per1/Frodo1 (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 adipo- genesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dactl and Wnt/(β-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, Dact1 knockdown impairs adipogenesis through activation of the Wnt/(β-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, Dactl and Wnt/(β- 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 intracellu- lar and paracrine/autocrine components of the Wnt/p-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.

0012-1797
609-619
Lagathu, Claire
a5c17148-6f7d-4062-a44f-284aa1a923a1
Christodoulides, Constantinos
f5ad503b-bd23-4f57-8e5f-4a7d9ab6c7e5
Virtue, Sam
5a5860ed-b7a9-4bee-a2cc-50a019b5bc5c
Cawthorn, William P.
3eadef28-0866-4a73-81e7-f08db6f7d731
Franzin, Chiara
3b5bcea2-682b-4a2b-a8b7-c85d0081932d
Kimber, Wendy A.
dc4348d3-d6bf-45e2-96d1-7e34653e091d
Nora, Edoardo Dalla
cbcd3d38-cac3-4e4d-80e0-b67ef0ea41dc
Campbell, Mark
ed49d284-9484-44c4-9bb0-5a661309e60f
Medina-Gomez, Gema
9e8167bb-cfac-4bec-8e25-da1b42120e26
Cheyette, Benjamin N.R.
c77ddd7f-ddbd-4fba-a972-930b4e10d103
Vidal-Puig, Antonio J.
bd6ec045-f9b8-48ff-ae86-a86a6a513435
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Lagathu, Claire
a5c17148-6f7d-4062-a44f-284aa1a923a1
Christodoulides, Constantinos
f5ad503b-bd23-4f57-8e5f-4a7d9ab6c7e5
Virtue, Sam
5a5860ed-b7a9-4bee-a2cc-50a019b5bc5c
Cawthorn, William P.
3eadef28-0866-4a73-81e7-f08db6f7d731
Franzin, Chiara
3b5bcea2-682b-4a2b-a8b7-c85d0081932d
Kimber, Wendy A.
dc4348d3-d6bf-45e2-96d1-7e34653e091d
Nora, Edoardo Dalla
cbcd3d38-cac3-4e4d-80e0-b67ef0ea41dc
Campbell, Mark
ed49d284-9484-44c4-9bb0-5a661309e60f
Medina-Gomez, Gema
9e8167bb-cfac-4bec-8e25-da1b42120e26
Cheyette, Benjamin N.R.
c77ddd7f-ddbd-4fba-a972-930b4e10d103
Vidal-Puig, Antonio J.
bd6ec045-f9b8-48ff-ae86-a86a6a513435
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85

Lagathu, Claire, Christodoulides, Constantinos, Virtue, Sam, Cawthorn, William P., Franzin, Chiara, Kimber, Wendy A., Nora, Edoardo Dalla, Campbell, Mark, Medina-Gomez, Gema, Cheyette, Benjamin N.R., Vidal-Puig, Antonio J. and Sethi, Jaswinder K. (2009) Dactl, a nutritionally regulated preadipocyte gene, controls adipogenesis by coordinating the wnt/β-catenin signaling network. Diabetes, 58 (3), 609-619. (doi:10.2337/db08-1180).

Record type: Article

Abstract

OBJECTIVE-Wnt signaling inhibits adipogenesis, but its regulation, physiological relevance, and molecular effectors are poorly understood. Here, we identify the Wnt modulator Dap- per1/Frodo1 (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 adipo- genesis. In vitro gain- and loss-of-function studies were used to investigate the mechanism of Dact1 action during adipogenesis. The in vivo regulation of Dactl and Wnt/(β-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, Dact1 knockdown impairs adipogenesis through activation of the Wnt/(β-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, Dactl and Wnt/(β- 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 intracellu- lar and paracrine/autocrine components of the Wnt/p-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.

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Published date: March 2009

Identifiers

Local EPrints ID: 415308
URI: http://eprints.soton.ac.uk/id/eprint/415308
ISSN: 0012-1797
PURE UUID: dda21624-7410-472d-bb32-a6b6ef42c550
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475

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Date deposited: 07 Nov 2017 17:30
Last modified: 16 Mar 2024 04:31

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Contributors

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

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