Diabetology International

, Volume 9, Issue 4, pp 215–223 | Cite as

Histone demethylases regulate adipocyte thermogenesis

  • Takeshi InagakiEmail author
Review Article


Adipocytes play a pivotal role in the regulation of energy metabolism. While white adipocyte stores energy, brown adipocyte dissipates energy by producing heat. In addition, another type of heat-producing adipocyte, beige adipocyte, emerges in white adipose tissue in response to chronic coldness. This phenotypic adaptation to the cold environment is considered to be attributed to the epigenetic modifications. Histone methylation is a chemically stable epigenetic modification and thus a proper mechanism for long-lasting cellular memory. Several histone methyl-modifying enzymes such as EHMT1, JMJD1A, JMJD3, and LSD1 are reported to be involved in the beige adipose cell fate determination. Among these, a histone demethylase JMJD1A senses cold environment by being phosphorylated at S265 in response to β-adrenergic receptor stimulation. Phosphorylated JMJD1A regulates both acute and cold thermogenesis. Under acute coldness, phosphorylated JMJD1A forms a complex with chromatin remodeler SWI/SNF and DNA-bound PPARγ, which recruits JMJD1A to the target genomic regions in brown adipocyte. This complex formation, in turn, induces the expression of target genes by bringing the enhancer and the promoter into close proximity. During chronic coldness, phosphorylated JMJD1A regulates beige adipogenesis through a two-step mechanism. In the first step, phosphorylated JMJD1A is recruited to the regulatory regions of target genes by forming a complex with PRDM16, PGC1α, and DNA-bound PPARγ. In the second step, JMJD1A demethylates histone H3K9me2 and induces stable expression of beige-selective genes. The phenotypic analyses of Jmjd1a-null mice and non-phosphorylated mutant S265A Jmjd1a knock-in mice indicate that JMJD1A is a potential therapeutic target for the treatment of obesity-related diseases including metabolic syndrome and type 2 diabetes.


BAT Beige adiopocyte JMJD1A PPARγ Histone methylation Epigenetics 



A summary of this review was presented in the Lilly Award Lecture at the 61st Japan Diabetes Society 2018, Tokyo, Japan. The author would like to express sincere gratitude to Dr. Juro Sakai for his mentoring, his colleagues and collaborators for their helpful support during performing the projects, and Dr. Hiroshi Shibata for critical reading of the manuscript. The author is supported by JSPS KAKENHI (Grant Numbers 18H04796, 17H03631, 25291002), Astellas Foundation for Research on Metabolic Disorders, the Novartis Foundation (Japan) for the Promotion of Science, the Tokyo Biochemical Research Foundation, the Naito Foundation, the Ichiro Kanehara Foundation, Japan Diabetes Foundation, Suzuken Memorial Foundation, and Kao Research Council for the Study of Healthcare Science.

Compliance with ethical standards

Conflict of interest

The author declares no competing interests.

Ethics policy

This article does not contain any experimental studies with human or animal subjects.


  1. 1.
    Shi Y, Lan F, Matson C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;7:941–53.CrossRefGoogle Scholar
  2. 2.
    Bannister AJ, Schneider R, Kouzarides T. Histone methylation: dynamic or static? Cell. 2002;7:801–6.CrossRefGoogle Scholar
  3. 3.
    Bannister AJ, Kouzarides T. Reversing histone methylation. Nature. 2005;7054:1103–6.CrossRefGoogle Scholar
  4. 4.
    Inagaki T, Sakai J, Kajimura S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol. 2016;8:480–95.CrossRefGoogle Scholar
  5. 5.
    Seale P, Bjork B, Yang W, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature. 2008;7207:961–7.CrossRefGoogle Scholar
  6. 6.
    Kajimura S, Seale P, Kubota K, et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009;7259:1154–8.CrossRefGoogle Scholar
  7. 7.
    Ohno H, Shinoda K, Ohyama K, et al. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature. 2013;7478:163–7.CrossRefGoogle Scholar
  8. 8.
    Ogawa H, Ishiguro K, Gaubatz S, et al. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 2002;5570:1132–6.CrossRefGoogle Scholar
  9. 9.
    Kaukonen R, Mai A, Georgiadou M, et al. Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription. Nat Commun. 2016;7:12237.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Pan D, Huang L, Zhu LJ, et al. Jmjd3-mediated H3K27me3 dynamics orchestrate brown fat development and regulate white fat plasticity. Dev Cell. 2015;5:568–83.CrossRefGoogle Scholar
  11. 11.
    Bernstein BE, Mikkelsen TS, Xie X, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;2:315–26.CrossRefGoogle Scholar
  12. 12.
    Matsumura Y, Nakaki R, Inagaki T, et al. H3K4/H3K9me3 bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Mol Cell. 2015;4:584–96.CrossRefGoogle Scholar
  13. 13.
    Zeng X, Jedrychowski MP, Chen Y, et al. Lysine-specific demethylase 1 promotes brown adipose tissue thermogenesis via repressing glucocorticoid activation. Genes Dev. 2016;16:1822–36.CrossRefGoogle Scholar
  14. 14.
    Lin JZ, Farmer SR. LSD1-a pivotal epigenetic regulator of brown and beige fat differentiation and homeostasis. Genes Dev. 2016;16:1793–5.CrossRefGoogle Scholar
  15. 15.
    Duteil D, Tosic M, Willmann D, et al. Lsd1 prevents age-programed loss of beige adipocytes. Proc Natl Acad Sci USA. 2017;20:5265–70.CrossRefGoogle Scholar
  16. 16.
    Sambeat A, Gulyaeva O, Dempersmier J, et al. LSD1 interacts with Zfp516 to promote UCP1 transcription and brown fat program. Cell Rep. 2016;11:2536–49.CrossRefGoogle Scholar
  17. 17.
    Yamane K, Toumazou C, Tsukada Y, et al. JHDM2A, a JmjC-containing H3K9 demethylase, facilitates transcription activation by androgen receptor. Cell. 2006;3:483–95.CrossRefGoogle Scholar
  18. 18.
    Abe Y, Rozqie R, Matsumura Y, et al. JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat Commun. 2015;6:7052.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Abe Y, Fujiwara Y, Takahashi H, et al. Histone demethylase JMJD1A coordinates acute and chronic adaptation to cold stress via thermogenic phospho-switch. Nat Commun. 2018;9:1566.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Inagaki T, Tachibana M, Magoori K, et al. Obesity and metabolic syndrome in histone demethylase JHDM2a-deficient mice. Genes Cells. 2009;8:991–1001.CrossRefGoogle Scholar
  21. 21.
    Tateishi K, Okada Y, Kallin EM, et al. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature. 2009;7239:757–61.CrossRefGoogle Scholar
  22. 22.
    Okada Y, Scott G, Ray MK, et al. Histone demethylase JHDM2A is critical for Tnp1 and Prm1 transcription and spermatogenesis. Nature. 2007;7166:119–23.CrossRefGoogle Scholar
  23. 23.
    Kuroki S, Matoba S, Akiyoshi M, et al. Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science. 2013;6150:1106–9.CrossRefGoogle Scholar
  24. 24.
    Fan L, Peng G, Sahgal N, et al. Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival. Oncogene. 2016;19:2441–52.CrossRefGoogle Scholar
  25. 25.
    Loh YH, Zhang W, Chen X, et al. Jmjd1a and Jmjd2c histone H3 Lys 9 demethylases regulate self-renewal in embryonic stem cells. Genes Dev. 2007;20:2545–57.CrossRefGoogle Scholar
  26. 26.
    Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;1:277–359.CrossRefGoogle Scholar
  27. 27.
    Cannon B, Nedergaard J. Metabolic consequences of the presence or absence of the thermogenic capacity of brown adipose tissue in mice (and probably in humans). Int J Obes. 2010;34:S7–16.CrossRefGoogle Scholar
  28. 28.
    Mimura I, Nangaku M, Kanki Y, et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol Cell Biol. 2012;15:3018–32.CrossRefGoogle Scholar
  29. 29.
    Smemo S, Tena JJ, Kim KH, et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature. 2014;7492:371–5.CrossRefGoogle Scholar
  30. 30.
    Claussnitzer M, Dankel SN, Kim KH, et al. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med. 2015;10:895–907.CrossRefGoogle Scholar
  31. 31.
    Zou Y, Lu P, Shi J, et al. IRX3 promotes the browning of white adipocytes and its rare variants are associated with human obesity risk. EBioMedicine. 2017;24:64–75.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Inagaki T. Regulations of adipocyte phenotype and obesity by IRX3. positive or negative? EBioMedicine. 2017;24:7–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Japan Diabetes Society 2018

Authors and Affiliations

  1. 1.Laboratory of Epigenetics and Metabolism, Institute for Molecular and Cellular RegulationGunma UniversityMaebashiJapan

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