Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms

Kennell, Jennifer; MacDougald, Ormond A.

doi:10.1074/jbc.m501080200

Cited by 232 publications

(174 citation statements)

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“…Drosophila Kc167 cells were routinely cultured as described (10). Mouse ST2 marrow-derived stromal cells were cultured and induced to differentiate into adipocytes as described (27). To visualize lipid accumulation, cells were stained with Oil Red-O 6 days after induction of differentiation (26).…”

Section: Methodsmentioning

confidence: 99%

“…5B). Mutation of either site alone gave only a partial rescue, suggesting that both sites are functionally important (data not shown We chose to study these mammalian miR-8 family members in ST2 marrow stromal cells because it has been shown that Wnt signaling potently inhibits the differentiation of ST2 cells into adipocytes (25)(26)(27). Suppression of endogenous Wnt signaling in ST2 cells promotes adipogenesis, and ectopic treatment with Wnts blocks the differentiation process (data not shown) (25).…”

Section: Mir-8 Directly Targets Cg32767 a Positive Regulator Of The Wgmentioning

confidence: 99%

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The microRNA miR-8 is a conserved negative regulator of Wnt signaling

Kennell

Gerin

MacDougald

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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178

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Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.adipogenesis ͉ TCF ͉ Wntless

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Section: Methodsmentioning

confidence: 99%

Section: Mir-8 Directly Targets Cg32767 a Positive Regulator Of The Wgmentioning

confidence: 99%

The microRNA miR-8 is a conserved negative regulator of Wnt signaling

Kennell

Gerin

MacDougald

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

178

151

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“…This effect appears to be mediated by BMP-dependent effects on the Wnt signaling pathway. Wnt signaling controls commitment of mesenchymal progenitors to the osteoblastic lineage and stimulates the expression of the osteoclast inhibitor OPG (Glass et al 2005;Hill et al 2005;Kennell and MacDougald 2005;Rodda and McMahon 2006;Kamiya and Mishina 2011;Baron and Kneissel 2013). Wnt activating gene mutations cause high bone mass, whereas inactivating mutations cause osteopenia characterized by severely reduced bone mineral density (Gong et al 2001;Boyden et al 2002;Little et al 2002;Patel and Karsenty 2002;Babij et al 2003;Winkler et al 2003).…”

Section: Tgf-b Family Signaling In Connective Tissuesmentioning

confidence: 99%

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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“…As an inhibitor of WNT signalling, DKK1 can be expected to promote adipogenesis, since active WNT signalling prevents both precursor cells from entering the adipose lineage and the normal differentiation of committed pre-adipocytes [11][12][13]. DKK1 binds to both Kremen and the LRP receptor, thus preventing WNT from binding and activating the WNT signal [14].…”

Section: Introductionmentioning

confidence: 99%

Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis

2009

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Aims/hypothesis Dickkopf-1 (DKK1) is a secreted inhibitor of canonical wingless-type MMTV integration site family (WNT) signalling; the key pathway for cell fate and development. Inhibition of WNT signalling by DKK1 in precursor cells promotes adipogenesis and inhibits osteogenesis. Previous studies have shown that treatment of type 2 diabetic patients with thiazolidinediones (TZDs) reduces bone density and increases risk of bone fractures, while body fat is increased. Methods We examined the effect of TZDs on secretion and DKK1 levels in pre-adipocytes and mature adipose cells and also measured circulating DKK1 levels in 11 patients with type 2 diabetes before and after treatment with the TZD rosiglitazone for 90 days. Results TZDs added in vitro rapidly increased DKK1 protein levels and secretion in both fully differentiated adipose cells and pre-adipocytes undergoing differentiation. In parallel, β-catenin levels, a marker of canonical WNT signalling, were reduced. Serum levels of DKK1 were also increased in several of the patients with type 2 diabetes after treatment with rosiglitazone for 90 days. Conclusions/interpretation These results provide a novel mechanism whereby peroxisome proliferator-activated receptor-γ activation can terminate WNT signalling and promote adipogenesis. Furthermore, they provide an explanation for why TZD treatment can lead to reduced bone formation and increased risk of fractures, since inhibited WNT signalling in progenitor cells promotes adipogenesis while osteogenesis is reduced.

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Wnt Signaling Inhibits Adipogenesis through β-Catenin-dependent and -independent Mechanisms

Cited by 232 publications

References 51 publications

The microRNA miR-8 is a conserved negative regulator of Wnt signaling

The microRNA miR-8 is a conserved negative regulator of Wnt signaling

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Thiazolidinediones increase the wingless-type MMTV integration site family (WNT) inhibitor Dickkopf-1 in adipocytes: a link with osteogenesis

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