Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia

Yukari Kyumoto, Eiichi Hinoi, Takashi Iezaki, Saya Takada, Syota Hashizume, Yoshifumi Takahata, Emiko Tsuruta, Satoshi Takahashi, Yukio Yoneda

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Abstract

Although tetradecanoyl phorbol acetate induced sequence-7 (TIS7) has been identified as a co-activator/repressor of gene transcription in different eukaryotic cells, little attention has been paid to the functionality of TIS7 in adipocytes. Here, we evaluated the possible role of TIS7 in mechanisms underlying the regulation of adipogenesis. TIS7 expression was preferentially up-regulated in white adipose tissues (WAT) of obesity model mice as well as in pre-adipocytic 3T3-L1 cells cultured under hypoxic conditions. TIS7 promoter activity was selectively enhanced by activating transcription factor-6 (ATF6) among different transcription factors tested, while induction of TIS7 by hypoxic stress was markedly prevented by knockdown of ATF6 by shRNA in 3T3-L1 cells. Overexpression of TIS7 markedly inhibited Oil Red O staining and expression of particular adipogenic genes in 3T3-L1 cells. TIS7 synergistically promoted gene transactivation mediated by Wingless-type mouse mammary tumor virus integration site family (Wnt)/β-catenin, while blockade of the Wnt/β-catenin pathway by a dominant negative form of T-cell factor-4 (DN-TCF4) markedly prevented the inhibition of adipogenesis in 3T3-L1 cells with TIS7 overexpression. TIS7 predominantly interacted with β-catenin in the nucleus of WAT in the genetically obese ob/ob mice as well as in 3T3-L1 cells cultured under hypoxic conditions. Both knockdown of TIS7 by shRNA and introduction of DN-TCF4 similarly reversed the hypoxia-induced inhibition of adipogenic gene expression in 3T3-L1 cells. These findings suggest that TIS7 could play a pivotal role in adipogenesis through interacting with β-catenin to promote the canonical Wnt signaling in pre-adipocytes under hypoxic stress such as obesity.

Original languageEnglish
Pages (from-to)1117-1128
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1832
Issue number8
DOIs
Publication statusPublished - May 14 2013

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Catenins
Adipogenesis
Adipocytes
Acetates
3T3-L1 Cells
Transcription Factor 7-Like 2 Protein
Activating Transcription Factor 6
White Adipose Tissue
Small Interfering RNA
Hypoxia
phorbol
Obesity
Virus Integration
Genes
Mouse mammary tumor virus
Co-Repressor Proteins
Wnt Signaling Pathway
Eukaryotic Cells
Transcriptional Activation
Transcription Factors

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology

Cite this

Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia. / Kyumoto, Yukari; Hinoi, Eiichi; Iezaki, Takashi; Takada, Saya; Hashizume, Syota; Takahata, Yoshifumi; Tsuruta, Emiko; Takahashi, Satoshi; Yoneda, Yukio.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1832, No. 8, 14.05.2013, p. 1117-1128.

Research output: Contribution to journalArticle

Kyumoto, Yukari ; Hinoi, Eiichi ; Iezaki, Takashi ; Takada, Saya ; Hashizume, Syota ; Takahata, Yoshifumi ; Tsuruta, Emiko ; Takahashi, Satoshi ; Yoneda, Yukio. / Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2013 ; Vol. 1832, No. 8. pp. 1117-1128.
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