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DNA/Histone Methylation and Adipocyte Differentiation: Applications to Obesity

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Handbook of Nutrition, Diet, and Epigenetics

Abstract

The adipose tissue has attracted great attention lately; in addition to be known as an energy store organ, it has also been shown as an endocrine organ. Dysfunction of adipose tissue plays critical roles in the pathogenesis of many metabolic diseases including obesity, type 2 diabetes, cancer cachexia, and lipodystrophies. The increased mass of adipose tissue in obese individuals is due to hypertrophy and hyperplasia. The transcriptional cascade during adipocyte differentiation has been well defined during the past two decades, while recent studies suggest epigenetic regulation plays an important part in adipocyte differentiation. In this chapter, we focus on the regulation of DNA methylation and histone methylation in adipocyte differentiation, as well as major enzymes involved in these processes. Targeting the methylation profiles of DNA and histone to reduce adipocyte differentiation may be a potential therapeutic approach to obesity.

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Abbreviations

αKG:

α-Ketoglutarate

5azadC:

5-aza-2′-Deoxycytidine

ASC-2:

Activating signal cointegrator 2

ASCOM:

ASC-2 complex

BAT:

Brown adipose tissue

BMP4:

Bone morphogenic protein 4

C/EBP:

CCAAT-enhancer-binding protein

Dnmts:

DNA methyltransferases

eWAT:

Epididymal white adipose tissue

HFD:

High fat diet

MBDs:

Methyl-CpG binding proteins

MCE:

Mitotic clonal expansion

MECP2:

Methyl-CpG binding protein-2

MEF:

Mouse embryonic fibroblast

NAFLD:

Nonalcohol fatty liver disease

MSCs:

Mesenchymal stem cells

PGC-1α:

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha

PPARγ:

Peroxisome proliferator-activated receptors γ

PRC2:

Polycomb repressive complex 2

PRDM16:

PR domain containing 16 protein

PTIP:

Pax transactivation domain-interacting protein

TETs:

Ten-eleven translocation methylcytosine dioxygenases

UCP1:

Uncoupling protein1

WAT:

White adipose tissue

Zfp423:

Zinc finger protein 423

References

  • Abumrad NA, Forest C et al (1991) Metabolism of oleic acid in differentiating BFC-1 preadipose cells. Am J Phys 261(1 Pt 1):E76–E86

    CAS  Google Scholar 

  • Agger K, Cloos PA et al (2007) UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449(7163):731–734

    Article  CAS  PubMed  Google Scholar 

  • Bertolini F (2013) Adipose tissue and breast cancer progression: a link between metabolism and cancer. Breast 22(Suppl 2):S48–S49

    Article  PubMed  Google Scholar 

  • Bird A (2002) DNA methylation patterns and epigenetic memory. Genes Dev 16(1):6–21

    Article  CAS  PubMed  Google Scholar 

  • Borengasser SJ, Zhong Y et al (2013) Maternal obesity enhances white adipose tissue differentiation and alters genome-scale DNA methylation in male rat offspring. Endocrinology 154(11):4113–4125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowers RR, Kim JW et al (2006) Stable stem cell commitment to the adipocyte lineage by inhibition of DNA methylation: role of the BMP-4 gene. Proc Natl Acad Sci U S A 103(35):13022–13027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cervantes-Rodriguez M, Martinez-Gomez M et al (2014) Sugared water consumption by adult offspring of mothers fed a protein-restricted diet during pregnancy results in increased offspring adiposity: the second hit effect. Br J Nutr 111(4):616–624

    Article  CAS  PubMed  Google Scholar 

  • Cho YW, Hong T et al (2007) PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex. J Biol Chem 282(28):20395–20406

    Article  CAS  PubMed  Google Scholar 

  • Cho YW, Hong SH et al (2009) Histone methylation regulator PTIP is required for PPAR gamma and C/EBP alpha expression and adipogenesis. Cell Metab 10(1):27–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cinti S (2009) Transdifferentiation properties of adipocytes in the adipose organ. Am J Physiol Endocrinol Metab 297(5):E977–E986

    Article  CAS  PubMed  Google Scholar 

  • Cuaranta-Monroy I, Simandi Z et al (2014) Highly efficient differentiation of embryonic stem cells into adipocytes by ascorbic acid. Stem Cell Res 13(1):88–97

    Article  CAS  PubMed  Google Scholar 

  • Ding Y, Li J et al (2014) DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding. Int J Obes 38(2):198–204

    Article  CAS  Google Scholar 

  • Farmer SR (2006) Transcriptional control of adipocyte formation. Cell Metab 4(4):263–273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farmer SR (2008) Brown fat and skeletal muscle: unlikely cousins? Cell 134(5):726–727

    Article  CAS  PubMed  Google Scholar 

  • de Franca SA, dos Santos MP et al (2016) A low-protein, high-carbohydrate diet stimulates thermogenesis in the brown adipose tissue of rats via ATF-2. Lipids 51(3):303–310

    Article  PubMed  Google Scholar 

  • Fujiki K, Shinoda A et al (2013) PPARgamma-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine. Nat Commun 4:2262

    Article  PubMed  Google Scholar 

  • Galic S, Oakhill JS et al (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316(2):129–139

    Article  CAS  PubMed  Google Scholar 

  • Garcia-Diaz DF, Lopez-Legarrea P et al (2014) Vitamin C in the treatment and/or prevention of obesity. J Nutr Sci Vitaminol (Tokyo) 60(6):367–379

    Article  CAS  Google Scholar 

  • Guo W, Chen J et al (2016) Epigenetic programming of Dnmt3a mediated by AP2alpha is required for granting preadipocyte the ability to differentiate. Cell Death Dis 7(12):e2496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu XM, Zhou YF et al (2016) Identification of zinc finger protein Bcl6 as a novel regulator of early adipose commitment. Open Biology 6(6):160065

    Article  PubMed  PubMed Central  Google Scholar 

  • Juan AH, Wang S et al (2017) Roles of H3K27me2 and H3K27me3 examined during fate specification of embryonic stem cells. Cell Rep 18(1):297

    Article  CAS  PubMed  Google Scholar 

  • Kamei Y, Suganami T et al (2010) Increased expression of DNA methyltransferase 3a in obese adipose tissue: studies with transgenic mice. Obesity (Silver Spring) 18(2):314–321

    Article  CAS  Google Scholar 

  • Kazantzis M, Takahashi V et al (2012) PAZ6 cells constitute a representative model for human brown pre-adipocytes. Front Endocrinol (Lausanne) 3:13

    Article  Google Scholar 

  • Kim H, Park J et al (2010) DNA methyltransferase 3-like affects promoter methylation of thymine DNA glycosylase independently of DNMT1 and DNMT3B in cancer cells. Int J Oncol 36(6):1563–1572

    Article  CAS  PubMed  Google Scholar 

  • Kim AY, Park YJ et al (2015) Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance. Nat Commun 6:7585

    Article  PubMed  Google Scholar 

  • Krishnan S, Horowitz S et al (2011) Structure and function of histone H3 lysine 9 methyltransferases and demethylases. Chembiochem 12(2):254–263

    Article  CAS  PubMed  Google Scholar 

  • Lee J, Saha PK et al (2008) Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis. Proc Natl Acad Sci U S A 105(49):19229–19234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee KH, Ju UI et al (2014) The histone demethylase PHF2 promotes fat cell differentiation as an epigenetic activator of both C/EBP alpha and C/EBP delta. Mol Cells 37(10):734–741

    Article  PubMed  PubMed Central  Google Scholar 

  • Lelliott CJ, Medina-Gomez G et al (2006) Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. PLoS Biol 4(11):e369

    Article  PubMed  PubMed Central  Google Scholar 

  • Lewandowska E, Zielinski A (2016) White adipose tissue dysfunction observed in obesity. Pol Merkur Lekarski 40(239):333–336

    PubMed  Google Scholar 

  • Li E, Bestor TH et al (1992) Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69(6):915–926

    Article  CAS  PubMed  Google Scholar 

  • Li HX, Xiao L et al (2010) Review: epigenetic regulation of adipocyte differentiation and adipogenesis. J Zhejiang Univ Sci B 11(10):784–791

    Article  PubMed  PubMed Central  Google Scholar 

  • Li J, Zhang N et al (2013) Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation. Cell Death Dis 4:e832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lidell ME, Betz MJ et al (2013) Evidence for two types of brown adipose tissue in humans. Nat Med 19(5):631–634

    Article  CAS  PubMed  Google Scholar 

  • Lizcano F, Romero C et al (2011) Regulation of adipogenesis by nuclear receptor PPARgamma is modulated by the histone demethylase JMJD2C. Genet Mol Biol 34(1):19–24

    CAS  PubMed  PubMed Central  Google Scholar 

  • Londono Gentile T, Lu C et al (2013) DNMT1 is regulated by ATP-citrate lyase and maintains methylation patterns during adipocyte differentiation. Mol Cell Biol 33(19):3864–3878

    Article  PubMed  PubMed Central  Google Scholar 

  • Luo Y, Burrington CM et al (2016) Metabolic phenotype and adipose and liver features in a high-fat western diet-induced mouse model of obesity-linked NAFLD. Am J Physiol Endocrinol Metab 310(6):E418–E439

    Article  PubMed  Google Scholar 

  • Matsumura Y, Nakaki R et al (2015) H3K4/H3K9me3 bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Mol Cell 60(4):584–596

    Article  CAS  PubMed  Google Scholar 

  • Milite C, Feoli A et al (2016) The emerging role of lysine methyltransferase SETD8 in human diseases. Clin Epigenetics 8:102

    Article  PubMed  PubMed Central  Google Scholar 

  • Musri MM, Corominola H et al (2006) Histone H3 lysine 4 dimethylation signals the transcriptional competence of the adiponectin promoter in preadipocytes. J Biol Chem 281(25):17180–17188

    Article  CAS  PubMed  Google Scholar 

  • Musri MM, Carmona MC et al (2010) Histone demethylase LSD1 regulates adipogenesis. J Biol Chem 285(39):30034–30041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okano M, Bell DW et al (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99(3):247–257

    Article  CAS  PubMed  Google Scholar 

  • Okuno Y, Ohtake F et al (2013) Epigenetic regulation of adipogenesis by PHF2 histone demethylase. Diabetes 62(5):1426–1434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parrillo L, Costa V et al (2016) Hoxa5 undergoes dynamic DNA methylation and transcriptional repression in the adipose tissue of mice exposed to high-fat diet. Int J Obes 40(6):929–937

    Article  CAS  Google Scholar 

  • Roganovic J, Petrovic N et al (2014) Effect of neuropeptide Y on norepinephrine-induced constriction in the rabbit facial artery after carotid artery occlusion. Vojnosanit Pregl 71(6):571–575

    Article  PubMed  Google Scholar 

  • Rosen ED, MacDougald OA (2006) Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 7(12):885–896

    Article  CAS  PubMed  Google Scholar 

  • Ruthenburg AJ, Allis CD et al (2007) Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark. Mol Cell 25(1):15–30

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto H, Kogo Y et al (2008) Sequential changes in genome-wide DNA methylation status during adipocyte differentiation. Biochem Biophys Res Commun 366(2):360–366

    Article  CAS  PubMed  Google Scholar 

  • Seale P, Bjork B et al (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454(7207):961–967

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shao ML, Ishibashi J et al (2016) Zfp423 maintains white adipocyte identity through suppression of the beige cell thermogenic gene program. Cell Metab 23(6):1167–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sharma NK, Varma V et al (2015) Obesity associated modulation of miRNA and co-regulated target transcripts in human adipose tissue of non-diabetic subjects. Microrna 4(3):194–204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stine RR, Shapira SN et al (2016) EBF2 promotes the recruitment of beige adipocytes in white adipose tissue. Mol Metab 5(1):57–65

    Article  CAS  PubMed  Google Scholar 

  • Takada I, Mihara M et al (2007) A histone lysine methyltransferase activated by non-canonical Wnt signalling suppresses PPAR-gamma transactivation. Nat Cell Biol 9(11):1273–1285

    Article  CAS  PubMed  Google Scholar 

  • Tang QQ, Otto TC et al (2004) Commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage. Proc Natl Acad Sci U S A 101(26):9607–9611

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tateishi K, Okada Y et al (2009) Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458(7239):757–761

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Torres-Andrade R, Moldenhauer R et al (2014) The increase in body weight induced by lack of methyl CpG binding protein-2 is associated with altered leptin signalling in the hypothalamus. Exp Physiol 99(9):1229–1240

    Article  CAS  PubMed  Google Scholar 

  • Ussar S, Lee KY et al (2014) ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med 6(247):247ra103

    Article  PubMed  PubMed Central  Google Scholar 

  • Wakabayashi K, Okamura M et al (2009) The peroxisome proliferator-activated receptor gamma/retinoid X receptor alpha heterodimer targets the histone modification enzyme PR-Set7/Setd8 gene and regulates adipogenesis through a positive feedback loop. Mol Cell Biol 29(13):3544–3555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Jin Q et al (2010) Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proc Natl Acad Sci U S A 107(16):7317–7322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Xu S et al (2013) Histone H3K9 methyltransferase G9a represses PPARgamma expression and adipogenesis. EMBO J 32(1):45–59

    Article  PubMed  Google Scholar 

  • Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286(5439):481–486

    Article  CAS  PubMed  Google Scholar 

  • Wu H, Zhang Y (2014) Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156(1–2):45–68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xia L, Wang C et al (2014) Time-specific changes in DNA methyltransferases associated with the leptin promoter during the development of obesity. Nutr Hosp 30(6):1248–1255

    PubMed  Google Scholar 

  • Yang Q, Liang X et al (2016a) AMPK/alpha-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metab 24(4):542–554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang XS, Wu R et al (2016b) DNA methylation biphasically regulates 3T3-L1 preadipocyte differentiation. Mol Endocrinol 30(6):677–687

    Article  PubMed  PubMed Central  Google Scholar 

  • Zha L, Li F et al (2015) The histone demethylase UTX promotes brown adipocyte thermogenic program via coordinated regulation of H3K27 demethylation and acetylation. J Biol Chem 290(41):25151–25163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zych J, Stimamiglio MA et al (2013) The epigenetic modifiers 5-aza-2′-deoxycytidine and trichostatin A influence adipocyte differentiation in human mesenchymal stem cells. Braz J Med Biol Res 46(5):405–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. College of Life Sciences, Wuhan University, Wuhan, China

    Yangmian Yuan, Danyang Wan & Ling Zheng

  2. Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China

    Chengyu Liu & Kun Huang

Authors
  1. Yangmian Yuan
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  2. Chengyu Liu
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  3. Danyang Wan
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  4. Kun Huang
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  5. Ling Zheng
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Corresponding authors

Correspondence to Kun Huang or Ling Zheng .

Editor information

Editors and Affiliations

  1. School of Life Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Diabetes and Nutritional Sciences Research Division, Faculty of Life Sciences and Medicine, King’s College London, London, UK

    Victor R. Preedy

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Yuan, Y., Liu, C., Wan, D., Huang, K., Zheng, L. (2019). DNA/Histone Methylation and Adipocyte Differentiation: Applications to Obesity. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-55530-0_96

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  • DOI: https://doi.org/10.1007/978-3-319-55530-0_96

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  • Publisher Name: Springer, Cham

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  • Online ISBN: 978-3-319-55530-0

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