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Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade

Nature Cell Biology volume 5, pages 224–230 (2003)Cite this article

A Retraction to this article was published on 31 October 2014

Abstract

Pluripotent mesenchymal stem cells in bone marrow differentiate into adipocytes, osteoblasts and other cells1,2. Balanced cytodifferentiation of stem cells is essential for the formation and maintenance of bone marrow; however, the mechanisms that control this balance remain largely unknown. Whereas cytokines such as interleukin-1 (IL-1) and tumour-necrosis factor-α (TNF-α) inhibit adipogenesis3,4, the ligand-induced transcription factor peroxisome proliferator-activated receptor-γ5 (PPAR-γ), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-γ-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-γ is suppressed by IL-1 and TNF-α, and that this suppression is mediated through NF-κB activated by the TAK1/TAB1/NF-κB-inducing kinase (NIK) cascade6,7,8,9, a downstream cascade associated with IL-1 and TNF-α signalling. Unlike suppression of the PPAR-γ transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain10, NF-κB blocks PPAR-γ binding to DNA by forming a complex with PPAR-γ and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-α in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-γ function through NF-κB activated by the TAK1/TAB1/NIK cascade.

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Figure 1: IL-1 and TNF-α inhibit troglitazone-induced adipogenesis.
Figure 2: TAK1/TAB1/NIK mediates suppression of PPAR-γ function.
Figure 3: NF-κB prevents DNA binding by the PPAR-γ/RXR-α heterodimer.
Figure 4: Cytokine-induced association of PPAR-γ, NF-κB and PGC-2.
Figure 5: Blocking PPAR-γ function inhibits adipogenesis through the NIK cascade.

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Acknowledgements

We thank S. Tanaka for discussions; R. Nakamura and H. Higuchi for manuscript preparation; Sankyo Pharmaceuticals for troglitazone; P. Chambon for the mouse RXR-α cDNA; and D. Turner for the RNAi vector. This work was supported in part by a Grant-in-Aid for Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan (to S.K.).

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    Miyuki Suzawa, Ichiro Takada, Junn Yanagisawa, Fumiaki Ohtake, Satoko Ogawa, Yukiko Gotoh & Shigeaki Kato

  2. CREST, Japan Science and Technology, 4-1-8 Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Shigeaki Kato

  3. Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, 444-8585, Okazaki, Japan

    Satoko Ogawa & Hiroshi Shibuya

  4. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 113-8655, Tokyo, Japan

    Toshimasa Yamauchi & Takashi Kadowaki

  5. Division of Endocrinology Department of Medicine University of Tokyo School of Medicine, Mejirodai, Bunkyo-ku, 112-8688, Tokyo, Japan

    Yasuhiro Takeuchi

  6. Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, 464-8602, Nagoya, Japan

    Kunihiro Matsumoto

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Correspondence to Shigeaki Kato.

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Suzawa, M., Takada, I., Yanagisawa, J. et al. Cytokines suppress adipogenesis and PPAR-γ function through the TAK1/TAB1/NIK cascade. Nat Cell Biol 5, 224–230 (2003). https://doi.org/10.1038/ncb942

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