Adipose Mitochondrial Biogenesis Is Suppressed in db/db and High-Fat Diet–Fed Mice and Improved by Rosiglitazone

  1. James X. Rong1,
  2. Yang Qiu23,
  3. Michael K. Hansen3,
  4. Lei Zhu34,
  5. Vivian Zhang3,
  6. Mi Xie1,
  7. Yuji Okamoto5,
  8. Michael D. Mattie6,
  9. Hiroyuki Higashiyama5,
  10. Satoshi Asano5,
  11. Jay C. Strum6 and
  12. Terence E. Ryan3
  1. 1High Throughput Biology, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina
  2. 2Cheminformatics, Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina
  3. 3Integrative Biology, High Throughput Biology, Discovery Research, GlaxoSmithKline, King of Prussia, Pennsylvania
  4. 4Biomedical Data Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina
  5. 5Tsukuba Research Laboratories, High Throughput Biology, Discovery Research, GlaxoSmithKline, Ibaraki, Japan
  6. 6Department of Quantitative Expression, Genetics Research, GlaxoSmithKline, Research Triangle Park, North Carolina
  1. Address correspondence and reprint requests to James X. Rong, High Throughput Biology, Discovery Research, GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC. E-mail: james.x.rong{at}gsk.com

Abstract

The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator–activated receptor (PPAR) γ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet–fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/+ and standard-fat diet–fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1β, PGC-1α, estrogen-related receptor α, and PPARα, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db06-1135.

  • Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1135.

  • 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 April 11, 2007.
    • Received August 14, 2006.
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  1. Diabetes vol. 56 no. 7 1751-1760
  1. Online-Only Appendix
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