Induction of Adiponectin, a Fat-Derived Antidiabetic and Antiatherogenic Factor, by Nuclear Receptors

  1. Masanori Iwaki1,
  2. Morihiro Matsuda1,
  3. Norikazu Maeda2,
  4. Tohru Funahashi2,
  5. Yuji Matsuzawa2,
  6. Makoto Makishima1 and
  7. Iichiro Shimomura13
  1. 1Department of Medicine and Pathophysiology, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, Osaka, Japan
  2. 2Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan
  3. 3PRESTO, Japan Science and Technology Corporation (JST), Saitama, Japan
  1. Address correspondence and reprint requests to Iichiro Shimomura, Department of Medicine and Pathophysiology, Graduate School of Frontier Biosciences, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, H2, Suita, Osaka 565-0871, Japan. E-mail: ichi{at}fbs.osaka-u.ac.jp

Abstract

Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-γ/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-γ-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-γ and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.

Footnotes

    • Accepted March 10, 2003.
    • Received January 20, 2003.
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