title: Repression of adipogenesis through promotion of Wnt/β-catenin signaling by TIS7 up-regulated in adipocytes under hypoxia.
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.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Yukari
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Takashi
authors.initials: T
authors.lastname: Iezaki
authors.forename: Saya
authors.initials: S
authors.lastname: Takada
authors.forename: Syota
authors.initials: S
authors.lastname: Hashizume
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takahata
authors.forename: Emiko
authors.initials: E
authors.lastname: Tsuruta
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
mesh_terms: D041721:3T3-L1 Cells; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; C490044:Ifrd1 protein, mouse; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin