Klotho Protein Promotes Adipocyte Differentiation

Chihara, Yukana; Rakugi, Hiromi; Ishikawa, Kazuhiko; Ikushima, Masashi; Maekawa, Yoshihiro; Ohta, Junsuke; Kida, Iwao; Ogihara, Toshio

doi:10.1210/en.2005-1529

Cited by 74 publications

(80 citation statements)

References 24 publications

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“…Differentiation studies in 3T3-L1 cells have reported that the expression of mRNA for FABP4 is absent in undifferentiated cells, is detectable by day 3 of differentiation and then rapidly increases towards a steady state around day 8 (several 100-fold increase in gene expression), for up to 28 days. 20,22,27 Similar profiles of FABP4 gene expression have been observed during the differentiation of human marrow and adipose tissue stromal cells into adipocytes, 28,29 as well as during the differentiation of SGBS cells. 16 We specifically analysed the expression profile of FABP4 during the differentiation of SGBS cells to relate GIPR expression to a well-established molecular differentiation marker of adipogenesis.…”

Section: Discussionsupporting

confidence: 56%

“…15 A number of studies have established that the pattern and time-course of gene expression in SGBS cells during differentiation is comparable to the findings in human preadipocytes in primary culture and also resemble the characteristics of rodent preadipocyte cell lines such as 3T3-L1, 3T3-F442A and ob17. 15,16,[20][21][22][23][24] Differentiated SGBS cells also behave biochemically and functionally like human adipocytes differentiated in primary culture. 15,16,25 In this study, we used these cells to examine the regulation of GIPR expression in the context of the dynamic process of adipocyte differentiation.…”

Section: Discussionmentioning

confidence: 99%

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Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

et al. 2008

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Objective: To establish that human adipocytes express functional glucose-dependent insulinotropic peptide (GIP) receptors and in particular the regulation of GIP receptor (GIPR) expression in the context of the dynamic process of adipocyte differentiation. Design: A combination of semiquantitative real-time PCR and measurement of GIP-stimulated cAMP accumulation was used to establish the expression and functional coupling of GIPRs during in vitro differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes. Results: Semiquantitative real-time PCR revealed that GIPR expression was substantially increased by day 4 of differentiation, reaching a maximum around 6-8 days (B200-fold increase above undifferentiated cells, n ¼ 2). We also analysed the expression of the adipocyte fatty acid binding protein (FABP4) to relate GIPR expression to a molecular differentiation marker of adipogenesis. FABP4 expression was barely detectable in undifferentiated cells. However, following exposure to adipogenic medium, FABP4 expression gradually increased, with a maximal expression level around 10 days (B1 600 000-fold increase above undifferentiated cells, n ¼ 2). Thus, the increases in GIPR mRNA during adipogenesis occur earlier than FABP4, suggesting that it might represent a gene expressed early in terminal differentiation and thus plays a role in fat droplet formation. A unit of 1 mM GIP failed to raise intracellular cAMP levels above basal levels in undifferentiated cells (n ¼ 3). In stark contrast, the 9-day differentiated cells produced a robust concentration-dependent increase in cAMP accumulation following stimulation with GIP, with an EC 50 value of 2.3 nM (n ¼ 3). The maximal response represented a 9-34-fold increase in cAMP accumulation above basal levels. Conclusions: This study demonstrates that GIPRs are expressed by human adipocytes, both GIPR mRNA and functional receptor expression being present in differentiated adipocytes but not in preadipocytes. Further investigation into the functional effects of GIP on differentiated SGBS cells could help towards understanding exactly how GIP regulates fat accumulation in human adipocytes.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

et al. 2008

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“…It has tumor suppressor activities in breast cancer and is upregulated during klotho-induced adipocyte differentiation (Chihara et al, 2006). We analysed the effects of overexpression of klotho on C/EBPb protein ( Figure 5a) and mRNA (Figure 5b) levels and noticed significant upregulation of C/EBPb following overexpression of klotho in MCF-7 cells, compared with cells transfected with an empty vector.…”

Section: Klotho Inhibits Igf-1-induced Mcf-7 Proliferationmentioning

confidence: 99%

“…Interestingly, C/EBPb may serve as a link between klotho, the insulin/IGF-1 pathways and breast cancer growth inhibition. C/EBPb is involved in klotho signaling and is upregulated during klotho-induced adipocyte differentiation (Chihara et al, 2006). Moreover, the IGF-1 pathway can negatively regulate C/EBPb by phosphorylation of GSK3b, which leads to C/EBPb downregulation (Li et al, 2007).…”

Section: Klotho In Breast Cancer I Wolf Et Almentioning

confidence: 99%

“…The C/EBP family is involved in adipocyte differentiation, and klotho-deficient mice have barely detected amounts of white adipose tissue (Kuro-o et al, 1997). Indeed, klotho has been identified recently as an inducer of adipocyte differentiation, and this activity is mediated through upregulation of these transcription factors (Chihara et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

et al. 2008

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Klotho is an anti-aging gene, which has been shown to inhibit the insulin and insulin-like growth factor 1 (IGF-1) pathways in mice hepatocytes and myocytes. As IGF-1 and insulin regulate proliferation, survival and metastasis of breast cancer, we studied klotho expression and activities in human breast cancer. Immunohistochemistry analysis of klotho expression in breast tissue arrays revealed high klotho expression in normal breast samples, but very low expression in breast cancer. In cancer samples, high klotho expression was associated with smaller tumor size and reduced KI67 staining. Forced expression of klotho reduced proliferation of MCF-7 and MDA-MB-231 breast cancer cells, whereas klotho silencing in MCF-7 cells, which normally express klotho, enhanced proliferation. Moreover, forced expression of klotho in these cells, or treatment with soluble klotho, inhibited the activation of IGF-1 and insulin pathways, and induced upregulation of the transcription factor CCAAT/enhancer-binding protein b, a breast cancer growth inhibitor that is negatively regulated by the IGF-1-AKT axis. Co-immunoprecipitation revealed an interaction between klotho and the IGF-1 receptor. Klotho is also a known modulator of the fibroblast growth factor (FGF) pathway, a pathway that inhibits proliferation of breast cancer cells. Studies in breast cancer cells revealed increased activation of the FGF pathway by basic FGF following klotho overexpression. Klotho did not affect activation of the epidermal growth factor pathway in breast cancer cells. These data suggest klotho as a potential tumor suppressor and identify it as an inhibitor of the IGF-1 pathway and activator of the FGF pathway in human breast cancer.

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The interplay of Klotho with signaling pathway and microRNAs in cancers

Abolghasemi

Yousefi

Maniati

et al. 2019

J of Cellular Biochemistry

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Klotho (KL) gene has been accepted as an "aging suppressor" gene that encodes a single transmembrane protein in human known as Klotho which is commonly expressed in renal tubes. The interruption in the secretion of Klotho protein expedites aging whereas its high expression extends lifespan. The family of Klotho proteins has been reported to act as distinct receptors for endocrine fibroblast growth factors (FGFs), which manage multifarious metabolic processes. Further, the secreted Klotho is a hormonal factor that takes part in the ion channel organization. Numerous studies determined that this protein affects the function of a number of important signaling pathways, which may present an impact in tumorigenesis via the coordination of receptors located on them. This review article focuses on the effects of microRNAs on the performance of Klotho and how the interplay between Klotho and certain pathways like insulin‐like growth factor, FGF, Wnt, and transforming growth factor β contribute to the biogenesis of cancer. The present study is also pointed at defining the molecular mechanisms of these interactions.

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Klotho Protein Promotes Adipocyte Differentiation

Cited by 74 publications

References 24 publications

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

Functional expression of glucose-dependent insulinotropic polypeptide receptors is coupled to differentiation in a human adipocyte model

Klotho: a tumor suppressor and a modulator of the IGF-1 and FGF pathways in human breast cancer

The interplay of Klotho with signaling pathway and microRNAs in cancers

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