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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.

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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

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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.

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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

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  1. Nobuyasu Komazawa
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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)

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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

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