Role of Wnt10b and C/EBPα in spontaneous adipogenesis of 243 cells

Bennett, Christina N.; Hodge, Christina; MacDougald, Ormond A.; Schwartz, Jessica

doi:10.1016/s0006-291x(03)00092-5

Cited by 38 publications

(28 citation statements)

References 16 publications

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“…Recent studies established that Wnt/␤-catenin signals inhibit adipogenesis (3,5,7,25,35). Wnt-10b is likely to mediate this effect, since it is highly expressed in preadipocytes, but its expression declines upon adipogenic differentiation (5,36).…”

Section: Discussionmentioning

confidence: 99%

“…Wnt binding to the seven transmembrane Frizzled receptors and the low-density lipoprotein receptorrelated protein (LRP) coreceptors, LRP5 and LRP6, leads to inhibition of GSK-3␤ activity, resulting in stabilization of cytoplasmic ␤-catenin. Subsequently, stabilized ␤-catenin translocates into the nucleus and binds to the T-cell factor/lymphoid enhancer factor (Tcf/Lef) family of transcription factors, leading to activation of target genes (1,2,6,26,43).The Wnt/␤-catenin pathway has been shown to inhibit adipogenesis (3,5,7,36). Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of C/EBP␣ and PPAR␥.…”

mentioning

confidence: 99%

“…The Wnt/␤-catenin pathway has been shown to inhibit adipogenesis (3,5,7,36). Wnt signaling maintains preadipocytes in an undifferentiated state through inhibition of C/EBP␣ and PPAR␥.…”

mentioning

confidence: 99%

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Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Li¹,

Singh

Mofunanya

et al. 2007

Molecular and Cellular Biology

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The canonical Wnt/␤-catenin signaling pathway plays diverse roles in embryonic development and disease. Activation of this pathway, likely by Wnt-10b, has been shown to inhibit adipogenesis in cultured 3T3-L1 preadipocytes and in mice. Here, we report that the ␤-catenin antagonist Chibby (Cby) is required for adipocyte differentiation. Cby is expressed in adipose tissue in mice, and Cby protein levels increase during adipogenic differentiation of 3T3-L1 cells. Ectopic expression of Cby induces spontaneous differentiation of these cells into mature adipocytes to an extent similar to that of dominant-negative Tcf-4. In contrast, depletion of Cby by RNA interference potently blocks adipogenesis of 3T3-L1 and mouse embryonic stem cells. In support of this, embryonic fibroblasts obtained from Cby-deficient embryos display attenuated differentiation to the adipogenic lineage. Mechanistically, Cby promotes adipocyte differentiation, in part by inhibiting ␤-catenin, since gain or loss of function of Cby influences ␤-catenin signaling in 3T3-L1 cells. Our results therefore establish Cby as a novel proadipogenic factor required for adipocyte differentiation.Adipose tissue plays critical roles in the regulation of energy homeostasis by storing and releasing fuel as a reservoir and by secreting a number of hormones and cytokines as an endocrine organ (37). Excess body fat, or obesity, is a major public health problem, particularly in industrialized countries, increasing the risk of diabetes, cardiovascular diseases and several types of cancers (28, 37). Conversely, lipoatrophy, the lack of adipose tissue, is also associated with diabetes and a number of other metabolic abnormalities (32). Hence, understanding the signaling pathways that govern adipocyte differentiation is necessary to develop comprehensive therapeutic strategies for the prevention and treatment of these disorders.Adipogenesis involves the formation of preadipocytes from mesenchymal progenitor cells and their differentiation into adipocytes (29,33,34). The cellular and molecular mechanisms of adipocyte differentiation have been extensively studied using preadipocyte culture systems, such as 3T3-L1 and 3T3-F442A cell lines (10,31,33,34). In response to hormonal stimuli of adipogenesis, two transcription factors, CCAAT/ enhancer-binding protein ␤ (C/EBP␤) and C/EBP␦, are rapidly and transiently induced. These proteins then stimulate expression of the key adipogenic transcription factors, C/EBP␣ and peroxisome proliferator-activated receptor ␥ (PPAR␥), which act synergistically to induce expression of various adipocyte-specific genes.Intracellular signaling by the Wnt family of secreted glycoproteins regulates cell proliferation, differentiation, and polarity throughout vertebrate embryonic development (27,44,46). ␤-Catenin plays a pivotal role as a transcriptional coactivator in the canonical Wnt pathway (39). In the absence of Wnt signaling, cytoplasmic ␤-catenin becomes phosphorylated by glycogen synthase kinase-3␤ (GSK-3␤) in a complex containing Axin and t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Li¹,

Singh

Mofunanya

et al. 2007

Molecular and Cellular Biology

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“…Wnt signaling represses preadipocyte differentiation, the alternative mesenchymal differentiation pathway, which is accompanied by the downregulation of master adipogenic transcription factors, such as C/EBPα and PPARγ [12,13]. Therefore, we examined whether the activation of Wnt/β-catenin signaling by SKL2001 suppressed adipogenic differentiation.…”

Section: Skl2001 Suppresses Preadipocyte Differentiationmentioning

confidence: 99%

“…Recent studies have implicated Wnt signaling in the commitment of mesenchymal stem cells to their various lineages. For example, the Wnt/β-catenin pathway promotes osteogenesis by stimulating Runx2 gene expression [11] and represses adipogenic differentiation of mesenchymal stem cells through the downregulation of adipogenic factors [12,13]. Wnt signaling also suppresses the induction of Sox9, a key regulator of chondrogenesis, which results in the inhibition of mesenchymal stem cell differentiation to chondrocytes [14,15].…”

Section: Introductionmentioning

confidence: 99%

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Gwak

Hwang

Park³

et al. 2011

Cell Res

113

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The Wnt/β-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/β-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated β-catenin responsive transcription by increasing the intracellular β-catenin protein level and inhibited the phosphorylation of β-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3β enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/β-catenin interaction, which is a critical step for CK1-and GSK-3β-mediated phosphorylation of β-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/β-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/β-catenin pathway.

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Diseases of Energy and Lipid Metabolism and Bone: Emerging Therapeutics

Urs

Rosen

2012

Bone-Metabolic Functions and Modulators

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Role of Wnt10b and C/EBPα in spontaneous adipogenesis of 243 cells

Cited by 38 publications

References 16 publications

Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Small molecule-based disruption of the Axin/β-catenin protein complex regulates mesenchymal stem cell differentiation

Diseases of Energy and Lipid Metabolism and Bone: Emerging Therapeutics

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