Forkhead transcription factor FoxO1 in adipose tissues regulates energy storage and expenditure

  1. Jun Nakae (nakaej{at}med.kobe-u.ac.jp)1,
  2. Yongheng Cao1,
  3. Miyo Oki1,
  4. Yasuko Orba2,
  5. Hirofumi Sawa3,
  6. Hiroshi Kiyonari4,
  7. Kristy Iskandar5,
  8. Koji Suga1,
  9. Marc Lombes6 and
  10. Yoshitake Hayashi5
  1. 1 21st Century COE Program for Signal Transduction Disease: Diabetes Mellitus as Model, Department of Clinical Molecular Medicine, Division of Diabetes, Digestive and Kidney Disease, Kobe University Graduate school of Medicine, Kobe 650-0017, Japan
  2. 2 Laboratory of Molecular & Cellular Pathology, Hokkaido University Graduate School of Medicine, N15, W7, Kita-ku, Sapporo 060-8638, Japan
  3. 3 21st Century COE Program for Zoonosis Control, Department of Molecular Pathobiology, Hokkaido University Research Center for Zoonosis Control, N18, W9, Kita-ku, Sapporo 060-0818, Japan
  4. 4 Laboratory for Animal Resources and Genetics Engineering Team, RIKEN Center for Developmental Biology (CDB), 2-2-3 Minatojima-minami-cho, Chuou-ku Kobe, Hyogo 650-0047, Japan
  5. 5 Division of Molecular Medicine and Medical Genetics, International Center for Medical Research and Treatment (ICMRT), Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
  6. 6 INSERM U 693, Faculte de Medecine Paris-Sud, 63, rue Gabriel Peri, 94276 Le Kremlin Bicêtre Cedex, France

    Abstract

    Objective: Adipose tissues serve as integrators of various physiological pathways, energy balance and glucose homeostasis. Forkhead transcription factor FoxO (Forkhead bOX-containing protein O subfamily) 1 mediates insulin action at transcriptional level. However, physiological roles of FoxO1 in adipose tissues remain unclear.

    Research Design and Methods: In the present study, we generated adipose tissue-specific FoxO1 transgenic mice (aP2-FLAG-Δ256) using adipose-specific adipocyte protein 2 (aP2) promoter/enhancer and a mutant FoxO1 (FLAGΔ256) in which the carboxyl terminal transactivation domain was deleted. Using these mice, we analyzed effects of overexpression of the FLAGΔ256 on glucose metabolism and energy homeostasis.

    Results: The aP2-FLAG-Δ256 showed improved glucose tolerance and insulin sensitivity accompanied with smaller size of adipocytes and increased Adiponectin (Adipoq) and Glut 4 (Slc2a4) and decreased Tnfα (Tnf) and Ccr2 (Ccr2) gene expression levels in white adipose tissue (WAT) under high fat diet. Furthermore, the aP2-FLAG-Δ256 had increased oxygen consumption accompanied with increased expression of PGC-1α protein and Ucp-1 (Ucp1), Ucp-2 (Ucp2), and β3-AR (Adrb3) in brown adipose tissue (BAT). Overexpression of the FLAGΔ256 in T37i cells, which are derived from hibernoma of SV40 large T antigen transgenic mice, increased expression of PGC-1α protein and Ucp1. Furthermore, knockdown of endogenous FoxO1 in T37i cells increased Pgc1α (Ppargc1a), Pgc1β (Ppargc1b), Ucp1 and Adrb3 gene expression.

    Conclusions: These data suggest that FoxO1 modulates energy homeostasis in WAT and BAT through regulation of adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake.

    Footnotes

      • Received May 26, 2007.
      • Accepted December 12, 2007.

    This Article

    1. Published online before print December 27, 2007, doi: 10.2337/db07-0698
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