Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice

Nature Medicine volume 10, pages 1208–1215 (2004)Cite this article

A Retraction to this article was published on 01 June 2005

Abstract

Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly generated Acdc promoter–driven Cre transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of Ppargc1a, the gene that encodes peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose Pten mRNA decreased with exposure to cold and increased with obesity, which were linked to the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose Pten could regulate insulin sensitivity and energy expenditure. Suppression of adipose Pten may become a beneficial strategy to treat type 2 diabetes and obesity.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of Acdc promoter–driven Cre transgenic mice and Acdc-Cre/Ptenflox/flox mice.
Figure 2: Characteristics of adipose-specific Pten-deficient mice.
Figure 3: Increased thermogenesis and energy expenditure with adipose mitochondrial hypergeneration in AdipoPten-KO mice.
Figure 4: Protein and mRNA analyses of Pten-deficient adipose tissues.
Figure 5: Suppression of Pten in 3T3-L1 adipocytes, and in vivo regulation of adipose Pten.
Figure 6

References

  1. Maehama, T. & Dixon, J.E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998).

    Article  CAS  Google Scholar 

  2. Jiang, G. & Zhang, B.B. Pi3-kinase and its up- and down-stream modulators as potential targets for the treatment of type II diabetes. Front. Biosci. 7, d903–d907 (2002).

    Article  CAS  Google Scholar 

  3. Whiteman, E.L., Cho, H. & Birnbaum, M.J. Role of Akt/protein kinase B in metabolism. Trends Endocrinol. Metab. 13, 444–451 (2002).

    Article  CAS  Google Scholar 

  4. Suzuki, A. et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. 22, 1169–78 (1998).

    Article  Google Scholar 

  5. Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    Article  CAS  Google Scholar 

  6. Horie, Y. et al. Hepatocyte-specific Pten results in steatohepatitis and hepatocellular carcinomas. J. Clin. Invest. 113, 1774–1783 (2004).

    Article  CAS  Google Scholar 

  7. Suzuki, A. et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J. Exp. Med. 90, 657–667 (2003).

    Article  Google Scholar 

  8. Kimura, T. et al. Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development 130, 1691–1700 (2003).

    Article  CAS  Google Scholar 

  9. Ono, H. et al. Regulation of phosphoinositide metabolism, AKT phosphorylation, and glucose transport by PTEN (phosphatase and tensin homolog deleted on chromosome 10) in 3T3-L1 adipocytes. Mol. Endocrinol. 15, 1411–1422 (2001).

    Article  CAS  Google Scholar 

  10. Nakashima, N. et al. The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J. Biol. Chem. 275, 12889–12895 (2000).

    Article  CAS  Google Scholar 

  11. Butler, M. et al. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 51, 1028–1034 (2002).

    Article  CAS  Google Scholar 

  12. Imai, T., Jiang, M., Chambon, P. & Metzger, D. Impaired adipogenesis and lipolysis in the mouse upon selective ablation of the retinoid X receptor α mediated by a tamoxifen-inducible chimeric Cre recombinase (Cre-ERT2) in adipocytes. Proc. Natl. Acad. Sci. USA 98, 224–228 (2001).

    CAS  Google Scholar 

  13. Bluher, M. et al. Adipose tissue selective insulin receptor knockout protects again obesity and obesity-related glucose intolerance. Dev. Cell. 3, 25–38 (2002).

    Article  CAS  Google Scholar 

  14. Barlow, C. et al. Targeted expression of Cre recombinase to adipose tissue of transgenic mice directs adipose-specific excision of loxP-flanked gene segments. Nucleic Acid Res. 25, 2543–2545 (1997).

    Article  CAS  Google Scholar 

  15. Fu, Y. et al. The adipocyte lipid binding protein (ALBP/aP2) gene facilitates foam cell formation in human THP-1 macrophages. Atherosclerosis 165, 259–269 (2002).

    Article  CAS  Google Scholar 

  16. Boord, J.B., Fazio, S. & Linton, M.F. Cytoplasmic fatty acid-binding proteins: emerging roles in metabolism and atherosclerosis. Curr. Opin. Lipidol. 13, 141–147 (2002).

    Article  CAS  Google Scholar 

  17. Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  Google Scholar 

  18. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  Google Scholar 

  19. Maeda, K. et al. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (Adipose Most abundant Gene transcript 1). Biochem. Biophys. Res. Commun. 221, 286–289 (1996).

    Article  CAS  Google Scholar 

  20. Okubo, K. et al. Large scale cDNA sequencing for analysis of quantitative and qualitative aspects of gene expression. Nat. Genet. 2, 173–179 (1992).

    Article  CAS  Google Scholar 

  21. Scherer, P.E., Williams, S., Fogliano, M., Baldini, G. & Lodish, H.F. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270, 26746–26749 (1995).

    Article  CAS  Google Scholar 

  22. Hu, E., Liang, P. & Spiegelman, B.M. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J. Biol. Chem. 271, 10697–10703 (1996).

    Article  CAS  Google Scholar 

  23. Hotta, K. et al. Circulating concentrations of the adipocyte protein, adiponectin, are decreased in parallel with reduced insulin sensitivity during the progression to type-2 diabetes in rhesus monkeys. Diabetes 50, 1126–1133 (2001).

    Article  CAS  Google Scholar 

  24. Kawamoto, S. et al. A novel reporter mouse that express enhanced green fluorescent protein upon Cre-mediated recombination. FEBS Lett. 470, 263–268 (2000).

    Article  CAS  Google Scholar 

  25. Hernandez, R., Teruel, T. & Lorenzo, M. Akt mediates insulin induction of glucose uptake and up-regulation of GLUT4 gene expression in brown adipocytes. FEBS Lett. 494, 225–231 (2001).

    Article  CAS  Google Scholar 

  26. Yap, D.B., Hsieh, J.K., Chan, F.S. & Lu, X. mdm2: a bridge over the two tumour suppressors, p53 and Rb. Oncogene 18, 7681–7689 (1999).

    Article  CAS  Google Scholar 

  27. Freeman, D.J. et al. PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3, 117–130 (2003).

    Article  CAS  Google Scholar 

  28. Hansen, J.B. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl. Acad. Sci. USA 101, 4112–4117 (2004).

    Article  CAS  Google Scholar 

  29. Shreiber, S.N. et al. The estrogen-related receptorα (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis. Proc. Natl. Acad. Sci. USA 101, 6472–6477 (2004).

    Article  Google Scholar 

  30. Stiles, B. et al. Liver-specific deletion of negative regulator PTEN results in fatty liver and insulin hypersensitivity. Proc. Natl. Acad. Sci. USA 101, 2082–2087 (2004).

    Article  CAS  Google Scholar 

  31. Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell 6, 77–86 (2000).

    Article  CAS  Google Scholar 

  32. Takahashi, M. et al. Genomic structure and mutations in adipose-specific gene, adiponectin. Int. J. Obes. Relat. Metab. Disord. 24, 861–868 (2000).

    Article  CAS  Google Scholar 

  33. Iwaki, M. et al. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 52, 1655–1663 (2003).

    Article  CAS  Google Scholar 

  34. Tarutani, et al. Tissue-specific knockout of the mouse Pig-a gene reveals important roles for GPI-anchored proteins in skin development. Proc. Natl. Acad. Sci. USA 94, 7400–7405 (1997).

    Article  CAS  Google Scholar 

  35. Miyawaki, K. et al. Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat. Med. 8, 738–742 (2002).

    Article  CAS  Google Scholar 

  36. Rossmeisl, M. et al. Expression of the uncoupling protein 1 from the aP2 gene promoter stimulates mitochondrial biogenesis in uniocular adipocytes in vivo. Eur. J. Biochem. 269, 19–28 (2002).

    Article  CAS  Google Scholar 

  37. Maeda, N. et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat. Med. 8, 731–737 (2002).

    Article  CAS  Google Scholar 

  38. Nishizawa, H. et al. Musclin, a novel skeletal muscle-derived secretory factor. J. Biol. Chem. 279, 19391–19395 (2004).

    Article  CAS  Google Scholar 

  39. Kashiwagi, A. et al. The regulation of glucose transport by cAMP stimulators via three different mechanisms in rat and human adipocytes. J. Biol. Chem. 258, 13685–13692 (1983).

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Matsuzawa and K. Sugihara for their encouragement, and K. Nishida, K. Oiki and S. Mizuno for technical assistance. This work was supported in part by grants from the Suzuken Memorial Foundation, The Nakajima Foundation, Kanae Foundation for Life and Socio-Medical Science, The Tokyo Biochemical Research Foundation, Takeda Medical Research Foundation, Uehara Memorial Foundation, Takeda Science Foundation, Novartis Foundation (Japan) for the Promotion of Science, The Cell Science Research Foundation, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, a Grant-in-Aid from the Japan Medical Association, The Naito Foundation, a grant from the Japan Heart Foundation Research, Kato Memorial Bioscience Foundation, Japan Research Foundation for Clinical Pharmacology, a grant from the Ministry of Health, Labor and Welfare, Japan, and Grants-in-Aid from COE Research and Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information

Authors and Affiliations

  1. Department of Social and Environmental Medicine, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Nobuyasu Komazawa, Gen Kondoh & Junji Takeda

  2. Department of Medicine and Pathophysiology, Graduate School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Morihiro Matsuda, Masanori Iwaki, Toshiyuki Takagi & Iichiro Shimomura

  3. Division of Food Science and Biotechnology, Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Sakyo-ku, 606-8502, Kyoto

    Wataru Mizunoya, Kazuo Inoue & Tohru Fushiki

  4. Department of Dermatology, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Yasuyuki Sumikawa

  5. Department of Biochemistry, Akita University, 1-1 Hondou, Akita, 010-8543, Akita, Japan

    Akira Suzuki

  6. Advanced Medical Discovery Institute, University of Toronto, Toronto, M5G 2Cl, Ontario, Canada

    Tak Wah Mak

  7. Department of Pathology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Toru Nakano

  8. Center for Advanced Science and Innovation, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Junji Takeda

  9. Department of Internal Medicine and Molecular Science, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka

    Iichiro Shimomura

  10. PREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Saitama, Japan

    Iichiro Shimomura

Authors
  1. Nobuyasu Komazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Morihiro Matsuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gen Kondoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wataru Mizunoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masanori Iwaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiyuki Takagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuyuki Sumikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuo Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akira Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tak Wah Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Toru Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tohru Fushiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Junji Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Iichiro Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iichiro Shimomura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Expression analyses of Cre in Adiponectin promoter-driven Cre transgenic mice. (PDF 34 kb)

Supplementary Fig. 2

Supplemental data of Fig. 4b, 5b, 5d and 5e. (PDF 286 kb)

Supplementary Table 1

Primers used in mRNA analyses (PDF 20 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Komazawa, N., Matsuda, M., Kondoh, G. et al. Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. Nat Med 10, 1208–1215 (2004). https://doi.org/10.1038/nm1117

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1117

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing