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Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice

Nature Genetics volume 30, pages 221–226 (2002)Cite this article

Abstract

The CBP protein (cAMP response element binding protein (CREB) binding protein)1 is a co-activator2 for several transcription factors with a wide range of important biological functions, such as sterol regulatory element binding proteins (SREBPs)3, CCAAT/enhancer-binding proteins (C/EBPs)4, nuclear receptors5,6 (including peroxisome proliferator–activated receptors, PPARs)7, and signal transducers and activators of transcription (STATs)8. In contrast to these individual transcription factors, the biological roles of CBP are poorly understood. CBP enhances transcriptional activities via histone acetylation and the recruitment of additional co-activators such as SRC (steroid coactivator)−1 (ref. 9). To identify its physiological functions using a loss-of-function mutant, we analyzed CBP-deficient mice10,11,12. As Crebbp null mice (Crebbp−/−) died during embryogenesis10,11,12, we used Crebbp+/− mice12. Unexpectedly, Crebbp+/− mice showed markedly reduced weight of white adipose tissue (WAT) but not of other tissues. Despite this lipodystrophy, Crebbp+/− mice showed increased insulin sensitivity and glucose tolerance and were completely protected from body weight gain induced by a high-fat (HF) diet. We observed increased leptin sensitivity and increased serum adiponectin levels in Crebbp+/− mice. These increased effects of insulin-sensitizing hormones secreted from WAT may explain, at least in part, the phenotypes of Crebbp+/− mice. This study demonstrates that CBP may function as a 'master-switch' between energy storage and expenditure.

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Figure 1: Heterozygous Crebbp deficiency significantly reduces transcriptional activity of SREBPs, C/EBPs and PPARs in EF cells. a,b,c, Transactivation analysis of SREBP1 (a), C/EBPβ (b) and PPARγ/RXR (c).
Figure 2: Crebbp+/− mice show markedly reduced weight of WAT, but not of other tissues. Tissue weight (in g, upper) and tissue weight/body weight (in g/g body weight, bottom) of wildtype (WT, left) and Crebbp+/− mice (+/−, right) under a high carbohydrate diet at 8 mo post natum.
Figure 3: Markedly reduced WAT mass in Crebbp+/− mice is due to the inhibition of TG accumulation in WAT in vivo.
Figure 4: Crebbp+/− mice show increased insulin sensitivity and glucose tolerance and were protected from HF diet–induced body weight gain.
Figure 5: Heterozygous Crebbp deficiency decreases molecules causing insulin resistance and markedly increases the effects of insulin-sensitizing hormones.
Figure 6: Alterations in gene expression associated with decreased tissue triglyceride content in Crebbp+/− mice.

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Acknowledgements

We are grateful to S. Uchida, K. Kirii, S. Sakata and T. Nagano for their excellent technical assistance. This work was supported by a grant from the Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (to T.Y.), a grant from the Human Science Foundation (to T.K.), a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology (to T. K.), a Grant-in Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (to T. K.), and by Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare (to T. K.).

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Author notes

  1. Yuichi Oike and Junji Kamon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Toshimasa Yamauchi, Junji Kamon, Hironori Waki, Hiroshi Miki, Ryozo Nagai, Satoshi Kimura & Takashi Kadowaki

  2. CREST of Japan Science and Technology Corporation, Japan

    Toshimasa Yamauchi, Hironori Waki, Yasuo Akanuma & Takashi Kadowaki

  3. Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, 860-0811, Japan

    Yuichi Oike

  4. Biological Research Laboratories, Nissan Chemical Industries, Saitama, 349-0294, Japan

    Junji Kamon & Takeshi Naitoh

  5. Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo, 160-8402, Japan

    Kajuro Komeda & Atsuko Tsuchida

  6. Third Department of Internal Medicine, Miyazaki Medical College, Miyazaki, 889-1692, Japan

    Yukari Date & Masamitsu Nakazato

  7. Department of Biochemistry, Faculty of Medicine, Kagoshima University, Kagoshima, 890-8520, Japan

    Meng-Xian Li & Takeyori Saheki

  8. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, 100-0005, Japan

    Yasuo Akanuma

  9. Department of Developmental Genetics, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, 862-0976, Japan

    Kenichi Yamamura

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  1. Toshimasa Yamauchi
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Correspondence to Takashi Kadowaki.

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Yamauchi, T., Oike, Y., Kamon, J. et al. Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nat Genet 30, 221–226 (2002). https://doi.org/10.1038/ng829

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