Growth differentiation factor 11 inhibits adipogenic differentiation by activating TGF‐beta/Smad signalling pathway

Luo, Hang; Guo, Yuchen; Liu, Yuting; Wang, Yuan; Zheng, Rixin; Ban, Y.; Lin, Peng; Yuan, Quan; Liu, Weiqing

doi:10.1111/cpr.12631

Cited by 42 publications

(42 citation statements)

References 30 publications

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“…Little research has been performed on GDF11, but a recent article discussed the effect of GDF11 on adipocyte commitment. The data indicated that GDF11 inhibited adipogenic differentiation in human MSCs by activating SMAD2/3-dependent TGF-β signaling [75]. It is becoming clear that R-SMADs have an impact on the commitment of MSCs, but we still know very little about Co-SMAD (SMAD4).…”

Section: Resultsmentioning

confidence: 99%

TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment

2020

Stem Cell Res Ther

119

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Adipocytes arising from mesenchymal stem cells (MSCs) requires MSC adipocyte commitment and differentiation of preadipocytes to mature adipocytes. Several signaling and some cytokines affect the adipogenesis of MSCs. This review focuses on the roles of TGF-β/SMAD signaling in adipocyte commitment of MSCs. BMP4 and BMP7 signaling are sufficient to induce adipocyte lineage determination of MSCs. The roles of BMP2, TGF-β, and myostatin signaling in this process are unclear. Other TGF-β/SMAD signaling such as BMP3 and BMP6 signaling have almost no effect on commitment because of limited research available, while GDF11 signaling inhibits adipocyte commitment in human MSCs. In this review, we summarize the available information on TGF-β/SMAD signaling regulation of MSCs in adipocyte commitment. Deeper study of this commitment mechanism will offer new approaches in treating obesity, diabetes mellitus, and obesity-related metabolism syndrome.

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Section: Resultsmentioning

confidence: 99%

TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment

2020

Stem Cell Res Ther

119

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“…Transforming Growth Factor-β (TGF-β) family ligands, which include TGF-β, Activin, GDF, and BMP family growth factors, have known roles in both adipogenesis and adipocyte hypertrophy (Lee, 2018, Tang & Lane, 2012, Zamani & Brown, 2011. Thus, TGF-β1, GDF-8, and Activins A and B inhibit adipogenesis (Choy, Skillington et al, 2000, Hirai, Yamanaka et al, 2005, Hoggard, Cruickshank et al, 2009, Ignotz & Massague, 1985, Kim, Liang et al, 2001, Lee, Pickering et al, 2019, Luo, Guo et al, 2019, Sparks, Allen et al, 1992, whereas several BMPs have been shown to promote adipogenesis and/or adipocyte hypertrophy (Gustafson, Hammarstedt et al, 2015, Huang, Song et al, 2009, Modica & Wolfrum, 2017, Schreiber, Dorpholz et al, 2017, Tang, Otto et al, 2004, Tseng, Kokkotou et al, 2008. Yet in spite of a large body of work in this area, fundamental questions remain unresolved, including what steps of adipogenesis are regulated by specific TGF-β family pathways, how are intracellular signaling pathways activated to direct adipocyte development, and can extracellular TGF-β family inhibitors help control adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

TGF-Β Family Inhibitors Blunt Adipogenesis Via Non-Canonical Regulation Of SMAD Pathways

Aykul

Maust

Floer

et al. 2020

Preprint

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Adipose tissues (AT) expand in response to energy surplus through adipocyte hypertrophy and hyperplasia (i.e., adipogenesis). The latter is a process by which multipotent precursors differentiate into mature adipocytes. This process is directed by growth factors and cytokines, including members of the TGF-β family, which regulate intracellular signaling pathways that control adipogenic transcriptional programs. As ectopic adipogenesis has been linked with metabolic syndrome and other pathological conditions, we undertook to establish how TGF-β family growth factors and their inhibitors regulate this process in a 3T3-L1 adipogenesis model. We found that intracellular SMAD1/5/8 signaling pathways are activated while SMAD2/3 pathways are suppressed in differentiating cells. Addition of SMAD1/5/8 pathway activating ligands promoted cell proliferation, while SMAD2/3 pathway activating ligands suppressed adipocyte formation. We identified several ligand traps that blunted 3T3-L1 adipogenesis. Strikingly, anti-adipogenic traps and ligands exploited the same mechanism of regulation involving a negative feedback loop that links SMAD2/3 activation with SMAD1/5/8 hyper-phosphorylation, cytoplasmic retention, and reduced signaling. The identified anti-adipogenic traps could be used to control hyperplastic AT expansion and its associated pathological conditions.

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“…Selecting the appropriate signaling pathway downstream of RARγ is very important. The Smad2/3 signaling pathway has recently been shown to be central to the regulation of adipogenesis [ 55 – 57 ]. In addition, this signaling pathway involved in non-coding RNA has also been shown to play an essential role in the context of cancers, cell differentiation, and migration [ 58 – 60 ].…”

Section: Discussionmentioning

confidence: 99%

A novel tsRNA-16902 regulating the adipogenic differentiation of human bone marrow mesenchymal stem cells

Wang

Mei

et al. 2020

Stem Cell Res Ther

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Background: Transfer RNA-derived small RNAs (tsRNAs) are a recently discovered form of non-coding RNA capable of regulating myriad physiological processes. The role of tsRNAs in hMSC adipogenic differentiation, however, remains incompletely understood. The purpose of this study was to identify the novel tsRNA-16902 as a regulator of hMSC adipogenic differentiation. Methods: In this study, we conducted transcriptomic sequencing of hMSCs after inducing their adipogenic differentiation, and we were thereby able to clarify the molecular mechanism underlying the role of tsRNA-16902 in this context via a series of molecular biology methods. Results: When we knocked down tsRNA-16902 expression, this impaired hMSC adipogenic differentiation and associated marker gene expression. Bioinformatics analyses further revealed tsRNA-16902 to target retinoic acid receptor γ (RARγ). Luciferase reporter assays also confirmed the ability of tsRNA-16902 to bind to the RARγ 3′untranslated region. Consistent with this, RARγ overexpression led to impaired hMSC adipogenesis. Further analyses revealed that Smad2/3 phosphorylation was increased in cells that either overexpressed RARγ or in which tsRNA-16902 had been knocked down. We also assessed the adipogenic differentiation of hMSCs in which tsRNA-16902 was knocked down and at the same time a Smad2/3 inhibitor was added to disrupt Smad2/3 phosphorylation. The adipogenic differentiation of hMSCs in which tsRNA-16902 was knocked down was further enhanced upon the addition of a Smad2/3 signaling inhibitor relative to tsRNA-16902 knockdown alone. Conclusions: Through a comprehensive profiling analysis of tsRNAs that were differentially expressed in the context of hMSC adipogenic differentiation, we were able to identify tsRNA-16902 as a previously uncharacterized regulator of adipogenesis. tsRNA-16902 is able to regulate hMSC adipogenic differentiation by targeting RARγ via the Smad2/3 signaling pathway. Together, our results may thus highlight novel strategies of value for treating obesity.

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Growth differentiation factor 11 inhibits adipogenic differentiation by activating TGF‐beta/Smad signalling pathway

Cited by 42 publications

References 30 publications

TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment

TGF-β/SMAD signaling regulation of mesenchymal stem cells in adipocyte commitment

TGF-Β Family Inhibitors Blunt Adipogenesis Via Non-Canonical Regulation Of SMAD Pathways

A novel tsRNA-16902 regulating the adipogenic differentiation of human bone marrow mesenchymal stem cells

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