Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes

  1. Eun Hee Koh1,
  2. Joong-Yeol Park1,
  3. Hye-Sun Park2,
  4. Min Jae Jeon2,
  5. Je Won Ryu2,
  6. Mina Kim2,
  7. Sun Young Kim2,
  8. Min-Seon Kim1,
  9. Seung-Whan Kim3,
  10. In Sun Park4,
  11. Jang Hyun Youn5 and
  12. Ki-Up Lee1
  1. 1Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
  2. 2Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
  3. 3Department of Pharmacology, University of Ulsan College of Medicine, Seoul, Korea
  4. 4Department of Anatomy, College of Medicine, Inha University, Incheon, Korea
  5. 5Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, Los Angeles, California
  1. Address correspondence and reprint requests to Ki-Up Lee, MD, Department of Internal Medicine, University of Ulsan College of Medicine, Poongnap-dong, Songpa-ku, Seoul 138-736, Korea. E-mail: kulee{at}amc.seoul.kr

Abstract

OBJECTIVE—Adiponectin is an important adipocytokine that improves insulin action and reduces atherosclerotic processes. The plasma adiponectin level is paradoxically reduced in obese individuals, but the underlying mechanism is unknown. This study was undertaken to test the hypothesis that mitochondrial function is linked to adiponectin synthesis in adipocytes.

RESEARCH DESIGN AND METHODS—We examined the effects of rosiglitazone and the measures that increase or decrease mitochondrial function on adiponectin synthesis. We also examined the molecular mechanism by which changes in mitochondrial function affect adiponectin synthesis.

RESULTS—Adiponectin expression and mitochondrial content in adipose tissue were reduced in obese db/db mice, and these changes were reversed by the administration of rosiglitazone. In cultured adipocytes, induction of increased mitochondrial biogenesis (via adenoviral overexpression of nuclear respiratory factor-1) increased adiponectin synthesis, whereas impairment in mitochondrial function decreased it. Impaired mitochondrial function increased endoplasmic reticulum (ER) stress, and agents causing mitochondrial or ER stress reduced adiponectin transcription via activation of c-Jun NH2-terminal kinase (JNK) and consequent induction of activating transcription factor (ATF)3. Increased mitochondrial biogenesis reversed all of these changes.

CONCLUSIONS—Mitochondrial function is linked to adiponectin synthesis in adipocytes, and mitochondrial dysfunction in adipose tissue may explain decreased plasma adiponectin levels in obesity. Impaired mitochondrial function activates a series of mechanisms involving ER stress, JNK, and ATF3 to decrease adiponectin synthesis.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 7 September 2007. DOI: 10.2337/db07-0510.

    E.H.K., J.-Y.P., and H.-S.P. contributed equally to this work.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0510.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted August 28, 2007.
    • Received April 12, 2007.
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  1. Published online before print September 7, 2007, doi: 10.2337/db07-0510 Diabetes December 2007 vol. 56 no. 12 2973-2981
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