Letter abstract

Nature Cell Biology 5, 224 - 230 (2003)
Published online: 24 February 2003 | doi:10.1038/ncb942

There is a Retraction (November 2014) associated with this Letter.

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

Miyuki Suzawa1, Ichiro Takada1, Junn Yanagisawa1, Fumiaki Ohtake1, Satoko Ogawa1,3, Toshimasa Yamauchi4, Takashi Kadowaki4, Yasuhiro Takeuchi5, Hiroshi Shibuya3, Yukiko Gotoh1, Kunihiro Matsumoto6 & Shigeaki Kato1,2


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-alpha (TNF-alpha) inhibit adipogenesis3, 4, the ligand-induced transcription factor peroxisome proliferator-activated receptor-gamma5 (PPAR-gamma), is a key inducer of adipogenesis. Therefore, regulatory coupling between cytokine- and PPAR-gamma-mediated signals might occur during adipogenesis. Here we show that the ligand-induced transactivation function of PPAR-gamma is suppressed by IL-1 and TNF-alpha, and that this suppression is mediated through NF-kappaB activated by the TAK1/TAB1/NF-kappaB-inducing kinase (NIK) cascade6, 7, 8, 9, a downstream cascade associated with IL-1 and TNF-alpha signalling. Unlike suppression of the PPAR-gamma transactivation function by mitogen-activated protein kinase-induced growth factor signalling through phosphorylation of the A/B domain10, NF-kappaB blocks PPAR-gamma binding to DNA by forming a complex with PPAR-gamma and its AF-1-specific co-activator PGC-2. Our results suggest that expression of IL-1 and TNF-alpha in bone marrow may alter the fate of pluripotent mesenchymal stem cells, directing cellular differentiation towards osteoblasts rather than adipocytes by suppressing PPAR-gamma function through NF-kappaB activated by the TAK1/TAB1/NIK cascade.

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
  2. CREST, Japan Science and Technology, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
  3. Division of Morphogenesis, Department of Developmental Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
  4. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
  5. Division of Endocrinology Department of Medicine University of Tokyo School of Medicine, Mejirodai, Bunkyo-ku, Tokyo 112-8688, Japan
  6. Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan

Correspondence to: Shigeaki Kato1,2 e-mail: uskato@mail.ecc.u-tokyo.ac.jp

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International Journal of Obesity Reviews (01 Feb 2003)

An adipogenic cofactor bound by the differentiation domain of PPARgamma
The EMBO Journal Article (01 Jul 1999)
Activation of peroxisome proliferator-activated receptor-gamma stimulates the growth arrest and DNA-damage inducible 153 gene in non-small cell lung carcinoma cells
Oncogene Original Article (27 Mar 2002)

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