Wnt5b partially inhibits canonical Wnt/β-catenin signaling pathway and promotes adipogenesis in 3T3-L1 preadipocytes

Kanazawa, Akio; Tsukada, Sachiyuki; Kamiyama, Masumi; Yanagimoto, Toru; Nakajima, Miki; Maeda, Shiro

doi:10.1016/j.bbrc.2005.03.007

Cited by 139 publications

(101 citation statements)

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“…This is consistent with the previous finding that the differentiation of preadipocytes into adipocytes requires suppression of the Wnt/␤-catenin pathway (3,25,36). In this regard, Wnt-5b has been recently reported to promote adipogenesis by antagonizing the Wnt/␤-catenin pathway (15,16). During differentiation of 3T3-L1 preadipocytes, nuclear ␤-catenin levels decrease; however, it remains present at basal levels in mature adipocytes (25).…”

Section: Discussionsupporting

confidence: 92%

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: Discussionsupporting

confidence: 92%

Chibby Promotes Adipocyte Differentiation through Inhibition of β-Catenin Signaling

Li¹,

Singh

Mofunanya

et al. 2007

Molecular and Cellular Biology

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“…Peroxisome proliferator -activated receptor g. WNT10B activates the canonical WNT signaling pathway to inhibit adipogenesis (33), whereas Wnt5b partially inhibits the canonical WNT signaling pathway to promote adipogenesis (34). Peroxisome proliferator -activated receptor g (PPARg) is a nuclear receptor predominantly expressed in adipose tissues to induce adipocyte differentiation and h-catenin degradation (35), and is also expressed in intestinal epithelium.…”

Section: Recent Advances In Wnt Signaling Pathwaymentioning

confidence: 99%

WNT Signaling Pathway and Stem Cell Signaling Network

Katoh¹,

Katoh²

2007

Clinical Cancer Research

704

584

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WNTsignals are transduced to the canonical pathway for cell fate determination, and to the noncanonical pathway for control of cell movement and tissue polarity. Canonical WNT signals are transduced through Frizzled family receptors and LRP5/LRP6 coreceptor to the h-catenin signaling cascade. Microtubule affinity^regulating kinase (PAR-1) family kinases, casein kinase Iq (CKIq), and FRAT are positive regulators of the canonical WNT pathway, whereas APC, AXIN1, AXIN2, CKIa, NKD1, NKD2, hTRCP1, hTRCP2, ANKRD6, Nemo-like kinase (NLK), and peroxisome proliferator^activated receptor g (PPARg) are negative regulators. Nuclear complex, consisting of T-cell factor/lymphoid enhancer factor, h-catenin, BCL9/BCL9L, and PYGO, activates transcription of canonical WNT target genes such as FGF20, DKK1, WISP1, MYC, CCND1, and Glucagon (GCG). Noncanonical WNT signals are transduced through Frizzled family receptors and ROR2/RYK coreceptors to the Dishevelled-dependent (Rho family GTPases and c-jun NH 2 -terminal kinase) or the Ca 2+ -dependent (NLK and nuclear factor of activated T cells) signaling cascades. WNT signals are context-dependently transduced to both pathways based on the expression profile of WNT, SFRP, WIF, DKK, Frizzled receptors, coreceptors, and the activity of intracellular WNT signaling regulators. Epigenetic silencing and loss-of-function mutation of negative regulators of the canonical WNT pathway occur in a variety of human cancer. WNT, fibroblast growth factor (FGF), Notch, Hedgehog, and transforming growth factor h/bone morphogenetic protein signaling network are implicated in the maintenance of tissue homeostasis by regulating self-renewal of normal stem cells as well as proliferation or differentiation of progenitor (transit-amplifying) cells. Breakage of the stem cell signaling network leads to carcinogenesis. Nonsteroidal anti-inflammatory drugs and PPARg agonists with the potential to inhibit the canonical WNT signaling pathway are candidate agents for chemoprevention. ZTM000990 and PKF118-310 are lead compounds targeted to the canonical WNT signaling cascade. Anti-WNT1and anti-WNT2 monoclonal antibodies show in vitro effects in cancer treatment. After the optimization, derivatives of small-molecule compound and human monoclonal antibody targeted to the WNTsignaling pathway could be used in cancer medicine.

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“…Although Wnt5a inhibits the transition of cells from zone I to zone II, Wnt5b promotes the transition from zone I to zone II and thus has an antagonistic effect in regulating chondrocyte proliferation 127. A functional role for Wnt5b in adipogenesis was elucidated in 3T3‐L1 preadpiocytes, where Wnt5b overexpression promoted adipogenesis by antagonizing the Wnt3a‐mediated Wnt/β‐catenin pathway 128. In subsequent studies in the same preadipocyte cell line, both Wnt5a and Wnt5b inhibited β‐catenin–dependent Wnt signaling; however, Wnt5b overexpression, in particular, was determined to be a potent stimulator of adipogenesis via inhibition of canonical Wnt signaling and increased PPARγ expression 129.…”

Section: Implication Of Noncanonical Wnt Signaling In Vcmentioning

confidence: 99%