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.

  • Letter
  • Published:

Role of Jhdm2a in regulating metabolic gene expression and obesity resistance

Nature volume 458, pages 757–761 (2009)Cite this article

Abstract

Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases1,2. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development3,4. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts β-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by β-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor α (Ppara) and Ucp1 expression. Furthermore, we demonstrate that β-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Pparγ and Rxrα and their co-activators Pgc1α (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Jhdm2a -deficient mice exhibit obesity phenotypes.
Figure 2: Jhdm2a deficiency affects the expression of metabolic genes and impairs β-oxidation and glycerol release in skeletal muscle.
Figure 3: Jhdm2a deficiency results in functional defects in BAT.
Figure 4: Jhdm2a is induced by β-adrenergic receptor activation and functions as a co-activator of Ucp1.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The primary microarray data is accessible from the NCBI Gene Expression Omnibus repository under the accession number GSE13552.

References

  1. Klose, R. J. & Zhang, Y. Regulation of histone methylation by demethylimination and demethylation. Nature Rev. Mol. Cell Biol. 8, 307–318 (2007)

    Article  CAS  Google Scholar 

  2. Martin, C. & Zhang, Y. The diverse functions of histone lysine methylation. Nature Rev. Mol. Cell Biol. 6, 838–849 (2005)

    Article  CAS  Google Scholar 

  3. Okada, Y., Scott, G., Ray, M. K., Mishina, Y. & Zhang, Y. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature 450, 119–123 (2007)

    Article  ADS  CAS  Google Scholar 

  4. Yamane, K. et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell 125, 483–495 (2006)

    Article  CAS  Google Scholar 

  5. Spiegelman, B. M. & Flier, J. S. Obesity and the regulation of energy balance. Cell 104, 531–543 (2001)

    Article  CAS  Google Scholar 

  6. Evans, R. M., Barish, G. D. & Wang, Y. X. PPARs and the complex journey to obesity. Nature Med. 10, 355–361 (2004)

    Article  CAS  Google Scholar 

  7. Reddy, J. K. & Hashimoto, T. Peroxisomal β-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu. Rev. Nutr. 21, 193–230 (2001)

    Article  CAS  Google Scholar 

  8. Bedu, E., Desplanches, D., Pequignot, J., Bordier, B. & Desvergne, B. Double gene deletion reveals the lack of cooperation between PPARα and PPARβ in skeletal muscle. Biochem. Biophys. Res. Commun. 357, 877–881 (2007)

    Article  CAS  Google Scholar 

  9. Finck, B. N. et al. A potential link between muscle peroxisome proliferator- activated receptor-α signaling and obesity-related diabetes. Cell Metab. 1, 133–144 (2005)

    Article  CAS  Google Scholar 

  10. Hibuse, T. et al. Aquaporin 7 deficiency is associated with development of obesity through activation of adipose glycerol kinase. Proc. Natl Acad. Sci. USA 102, 10993–10998 (2005)

    Article  ADS  CAS  Google Scholar 

  11. Gulick, T., Cresci, S., Caira, T., Moore, D. D. & Kelly, D. P. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc. Natl Acad. Sci. USA 91, 11012–11016 (1994)

    Article  ADS  CAS  Google Scholar 

  12. Lopez, D., Irby, R. B. & McLean, M. P. Peroxisome proliferator-activated receptor α induces rat sterol carrier protein x promoter activity through two peroxisome proliferator-response elements. Mol. Cell. Endocrinol. 205, 169–184 (2003)

    Article  CAS  Google Scholar 

  13. Pineda Torra, I., Jamshidi, Y., Flavell, D. M., Fruchart, J. C. & Staels, B. Characterization of the human PPARα promoter: identification of a functional nuclear receptor response element. Mol. Endocrinol. 16, 1013–1028 (2002)

    PubMed  Google Scholar 

  14. Tugwood, J. D. et al. The mouse peroxisome proliferator activated receptor recognizes a response element in the 5′ flanking sequence of the rat acyl CoA oxidase gene. EMBO J. 11, 433–439 (1992)

    Article  CAS  Google Scholar 

  15. Bachman, E. S. et al. βAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297, 843–845 (2002)

    Article  ADS  CAS  Google Scholar 

  16. Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000)

    Article  CAS  Google Scholar 

  17. Enerback, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997)

    Article  ADS  CAS  Google Scholar 

  18. Kersten, S. et al. Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting. J. Clin. Invest. 103, 1489–1498 (1999)

    Article  CAS  Google Scholar 

  19. Cassard-Doulcier, A. M. et al. Tissue-specific and β-adrenergic regulation of the mitochondrial uncoupling protein gene: control by cis-acting elements in the 5′-flanking region. Mol. Endocrinol. 7, 497–506 (1993)

    CAS  PubMed  Google Scholar 

  20. Wang, Z. et al. Critical roles of the p160 transcriptional coactivators p/CIP and SRC-1 in energy balance. Cell Metab. 3, 111–122 (2006)

    Article  ADS  CAS  Google Scholar 

  21. Lomax, M. A. et al. Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine. Endocrinology 148, 461–468 (2007)

    Article  CAS  Google Scholar 

  22. Rando, T. A. & Blau, H. M. Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy. J. Cell Biol. 125, 1275–1287 (1994)

    Article  CAS  Google Scholar 

  23. Ross, S. R. et al. Hibernoma formation in transgenic mice and isolation of a brown adipocyte cell line expressing the uncoupling protein gene. Proc. Natl Acad. Sci. USA 89, 7561–7565 (1992)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. M. Spiegelman for the HIB1B cells, L. Xia for construction of the targeting vector, K. E. Gardner for critical reading of the manuscript, D. Pump and K. Hua (UNC Clinical Nutrition Research Unit, DK56350) for calorimetry and MRI, and N. Takahashi for helpful comments. Y.Z. is an investigator of the Howard Hughes Medical Institute.

Author Contributions K.T. and Y.Z. designed the experiments and prepared the manuscript. K.T. performed most of the experiments. Y.O. provided the data for Supplementary Fig. 3. E.K. analysed microarray data and generated Supplementary Figs 6 and 7.

Author information

Author notes

  1. Keisuke Tateishi

    Present address: Present address: Department of Gastroenterology, University of Tokyo Hospital, Japan.,

Authors and Affiliations

  1. Howard Hughes Medical Institute,,

    Keisuke Tateishi, Yuki Okada, Eric M. Kallin & Yi Zhang

  2. Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA,

    Keisuke Tateishi, Yuki Okada, Eric M. Kallin & Yi Zhang

Authors
  1. Keisuke Tateishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuki Okada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric M. Kallin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary References, Supplementary Figures S1-S12 and Supplementary Table 1. (PDF 5889 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tateishi, K., Okada, Y., Kallin, E. et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458, 757–761 (2009). https://doi.org/10.1038/nature07777

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07777

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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