Regulatory Small and Long Noncoding RNAs in Brite/Brown Adipose Tissue

  • Marcel ScheidelerEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 251)


Brite/brown adipose tissue (BAT) is a thermogenic tissue able to dissipate energy via non-shivering thermogenesis. It is naturally activated by cold and has been demonstrated to increase thermogenic capacity, elevate energy expenditure, and to ultimately contribute to fat mass reduction. Thus, it emerges as novel therapeutic concept for pharmacological intervention in obesity and other metabolic disorders. Therefore, the comprehensive understanding of the regulatory network in thermogenic adipocytes is in demand.

The surprising findings that (1) all human protein-coding genes make up not more than 2% of our genome, (2) organismal complexity goes well along with the percentage of nonprotein-coding sequences, and that (3) three quarters of our genome are pervasively transcribed, provide evidence that noncoding RNAs (ncRNAs) are not junk, but a significant and even predominant part of our transcriptome representing a treasure chest worth retrieving regulatory determinants in biological processes and diseases.

In this chapter, the impact of regulatory small and long ncRNAs (lncRNAs) in particular microRNAs and lncRNAs on BAT formation and metabolic function and their involvement in physiological and pathological conditions has been reviewed.


Brite/brown thermogenic adipocyte Brown adipose tissue Long noncoding RNA Metabolism microRNA Noncoding RNA Obesity Regulatory RNA 


  1. Ailhaud G (2000) Adipose tissue as an endocrine organ. Int J Obes Relat Metab Disord 24(Suppl 2):S1–S3CrossRefGoogle Scholar
  2. Alvarez-Dominguez JR, Bai Z, Xu D et al (2015) De Novo reconstruction of adipose tissue transcriptomes reveals long non-coding RNA regulators of brown adipocyte development. Cell Metab 21:764–776. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Babak T, Blencowe BJ, Hughes TR (2005) A systematic search for new mammalian noncoding RNAs indicates little conserved intergenic transcription. BMC Genomics 6:104. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bai Z, Chai X-R, Yoon MJ et al (2017) Dynamic transcriptome changes during adipose tissue energy expenditure reveal critical roles for long noncoding RNA regulators. PLoS Biol 15:e2002176. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Birney E, Stamatoyannopoulos JA, Dutta A et al (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816. CrossRefPubMedGoogle Scholar
  6. Brannan CI, Dees EC, Ingram RS, Tilghman SM (1990) The product of the H19 gene may function as an RNA. Mol Cell Biol 10:28–36CrossRefGoogle Scholar
  7. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359. CrossRefPubMedGoogle Scholar
  8. Cao W, Daniel KW, Robidoux J et al (2004) p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene. Mol Cell Biol 24:3057–3067CrossRefGoogle Scholar
  9. Chen Y, Siegel F, Kipschull S et al (2013) miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat Commun 4:1769. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chen Y, Buyel JJ, Hanssen MJW et al (2016) Exosomal microRNA miR-92a concentration in serum reflects human brown fat activity. Nat Commun 7:11420. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chou C-F, Lin Y-Y, Wang H-K et al (2014) KSRP ablation enhances brown fat gene program in white adipose tissue through reduced miR-150 expression. Diabetes 63:2949–2961. CrossRefPubMedPubMedCentralGoogle Scholar
  12. Christopher AF, Kaur RP, Kaur G et al (2016) MicroRNA therapeutics: discovering novel targets and developing specific therapy. Perspect Clin Res 7:68–74. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Cinti S (2012) The adipose organ at a glance. Dis Model Mech 5:588–594. CrossRefPubMedPubMedCentralGoogle Scholar
  14. Cohen P, Spiegelman BM (2016) Cell biology of fat storage. Mol Biol Cell 27:2523–2527. CrossRefPubMedPubMedCentralGoogle Scholar
  15. de Almeida RA, Fraczek MG, Parker S et al (2016) Non-coding RNAs and disease: the classical ncRNAs make a comeback. Biochem Soc Trans 44:1073–1078. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Derrien T, Johnson R, Bussotti G et al (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775–1789. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Djebali S, Davis CA, Merkel A et al (2012) Landscape of transcription in human cells. Nature 489:101–108. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Dogini DB, Pascoal VDB, Avansini SH et al (2014) The new world of RNAs. Genet Mol Biol 37:285–293CrossRefGoogle Scholar
  19. Feuermann Y, Kang K, Gavrilova O et al (2013) MiR-193b and miR-365-1 are not required for the development and function of brown fat in the mouse. RNA Biol 10:1807–1814. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114. CrossRefPubMedGoogle Scholar
  21. Fu T, Seok S, Choi S et al (2014) MicroRNA 34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte fibroblast growth factor 21 signaling and SIRT1 function. Mol Cell Biol 34:4130–4142. CrossRefPubMedPubMedCentralGoogle Scholar
  22. Fu X, Dong B, Tian Y et al (2015) MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids. J Clin Investig 125:2497–2509. CrossRefPubMedGoogle Scholar
  23. Gelling RW, Yan W, Al-Noori S et al (2008) Deficiency of TNFalpha converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice. Endocrinology 149:6053–6064. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Giroud M, Karbiener M, Pisani DF et al (2016a) Let-7i-5p represses brite adipocyte function in mice and humans. Sci Rep 6:28613. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Giroud M, Pisani DF, Karbiener M et al (2016b) miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formation and function. Mol Metab 5:615–625. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Guttman M, Amit I, Garber M et al (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458:223–227. CrossRefPubMedPubMedCentralGoogle Scholar
  27. Herrera BM, Lockstone HE, Taylor JM et al (2010) Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes. Diabetologia 53:1099–1109. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Hu F, Wang M, Xiao T et al (2015) miR-30 promotes thermogenesis and the development of beige fat by targeting RIP140. Diabetes 64:2056–2068. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Hydbring P, Badalian-Very G (2013) Clinical applications of microRNAs. F1000Res 2:136. CrossRefPubMedPubMedCentralGoogle Scholar
  30. Iyer MK, Niknafs YS, Malik R et al (2015) The landscape of long noncoding RNAs in the human transcriptome. Nat Genet 47:199–208. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Jimenez-Preitner M, Berney X, Uldry M et al (2011) Plac8 is an inducer of C/EBPβ required for brown fat differentiation, thermoregulation, and control of body weight. Cell Metab 14:658–670. CrossRefPubMedGoogle Scholar
  32. Jones M, Tontonoz P (2014) Enhanced thermogenesis in the blinc of an eye. Mol Cell 55:343–344. CrossRefPubMedGoogle Scholar
  33. Kajimura S, Seale P, Kubota K et al (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460:1154–1158. CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kajimura S, Seale P, Spiegelman BM (2010) Transcriptional control of brown fat development. Cell Metab 11:257–262. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Karbiener M, Fischer C, Nowitsch S et al (2009) microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma. Biochem Biophys Res Commun 390:247–251. CrossRefPubMedGoogle Scholar
  36. Karbiener M, Pisani DF, Frontini A et al (2014) MicroRNA-26 family is required for human adipogenesis and drives characteristics of brown adipocytes. Stem Cells 32:1578–1590. CrossRefPubMedGoogle Scholar
  37. Kim SY, Kim AY, Lee HW et al (2010) miR-27a is a negative regulator of adipocyte differentiation via suppressing PPARgamma expression. Biochem Biophys Res Commun 392:323–328. CrossRefPubMedGoogle Scholar
  38. Kim Y-J, Sano T, Nabetani T et al (2012) GPRC5B activates obesity-associated inflammatory signaling in adipocytes. Sci Signal 5:ra85. CrossRefPubMedGoogle Scholar
  39. Kim H-J, Cho H, Alexander R et al (2014) MicroRNAs are required for the feature maintenance and differentiation of brown adipocytes. Diabetes 63:4045–4056. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kim J, Okla M, Erickson A et al (2016) Eicosapentaenoic acid potentiates brown thermogenesis through FFAR4-dependent up-regulation of miR-30b and miR-378. J Biol Chem 291:20551–20562. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kiskinis E, Chatzeli L, Curry E et al (2014) RIP140 represses the “brown-in-white” adipocyte program including a futile cycle of triacylglycerol breakdown and synthesis. Mol Endocrinol 28:344–356. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleotides. Nat Rev Drug Discov 11:125–140. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kong X, Yu J, Bi J et al (2015) Glucocorticoids transcriptionally regulate miR-27b expression promoting body fat accumulation via suppressing the browning of white adipose tissue. Diabetes 64:393–404. CrossRefPubMedGoogle Scholar
  44. Lander ES, Linton LM, Birren B et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921. CrossRefPubMedGoogle Scholar
  45. Lavery CA, Kurowska-Stolarska M, Holmes WM et al (2016) miR-34a(-/-) mice are susceptible to diet-induced obesity. Obesity (Silver Spring) 24:1741–1751. CrossRefGoogle Scholar
  46. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefGoogle Scholar
  47. Leonardsson G, Steel JH, Christian M et al (2004) Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc Natl Acad Sci U S A 101:8437–8442. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Li S, Mi L, Yu L et al (2017) Zbtb7b engages the long noncoding RNA Blnc1 to drive brown and beige fat development and thermogenesis. Proc Natl Acad Sci U S A 114:E7111–E7120. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Lv Y-F, Yu J, Sheng Y-L et al (2018) Glucocorticoids suppress the browning of adipose tissue via miR-19b in male mice. Endocrinology 159:310–322. CrossRefPubMedGoogle Scholar
  50. Meakin PJ, Harper AJ, Hamilton DL et al (2012) Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice. Biochem J 441:285–296. CrossRefPubMedGoogle Scholar
  51. Mercer TR, Dinger ME, Sunkin SM et al (2008) Specific expression of long noncoding RNAs in the mouse brain. Proc Natl Acad Sci U S A 105:716–721. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Mi L, Zhao X-Y, Li S et al (2017) Conserved function of the long noncoding RNA Blnc1 in brown adipocyte differentiation. Mol Metab 6:101–110. CrossRefPubMedGoogle Scholar
  53. Mori M, Nakagami H, Rodriguez-Araujo G et al (2012) Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol 10:e1001314. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Mori MA, Thomou T, Boucher J et al (2014) Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J Clin Invest 124:3339–3351. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Mudhasani R, Imbalzano AN, Jones SN (2010) An essential role for Dicer in adipocyte differentiation. J Cell Biochem 110:812–816. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Mudhasani R, Puri V, Hoover K et al (2011) Dicer is required for the formation of white but not brown adipose tissue. J Cell Physiol 226:1399–1406. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Nedergaard J, Cannon B (2010) The changed metabolic world with human brown adipose tissue: therapeutic visions. Cell Metab 11:268–272. CrossRefPubMedGoogle Scholar
  58. Nedergaard J, Bengtsson T, Cannon B (2011) New powers of brown fat: fighting the metabolic syndrome. Cell Metab 13(3):238–240. CrossRefPubMedGoogle Scholar
  59. Ng R, Hussain NA, Zhang Q et al (2017) miRNA-32 drives brown fat thermogenesis and trans-activates subcutaneous white fat browning in mice. Cell Rep 19:1229–1246. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Oliverio M, Schmidt E, Mauer J et al (2016) Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nat Cell Biol 18:328–336. CrossRefPubMedGoogle Scholar
  61. Pan D, Mao C, Quattrochi B et al (2014) MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat Commun 5:4725. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Petrovic N, Walden TB, Shabalina IG et al (2010) Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 285:7153–7164. CrossRefPubMedGoogle Scholar
  63. Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136:629–641. CrossRefPubMedGoogle Scholar
  64. Prasanth KV, Spector DL (2007) Eukaryotic regulatory RNAs: an answer to the “genome complexity” conundrum. Genes Dev 21:11–42. CrossRefPubMedGoogle Scholar
  65. Puigserver P, Wu Z, Park CW et al (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839CrossRefGoogle Scholar
  66. Ramsköld D, Wang ET, Burge CB, Sandberg R (2009) An abundance of ubiquitously expressed genes revealed by tissue transcriptome sequence data. PLoS Comput Biol 5:e1000598. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Robidoux J, Cao W, Quan H et al (2005) Selective activation of mitogen-activated protein (MAP) kinase kinase 3 and p38alpha MAP kinase is essential for cyclic AMP-dependent UCP1 expression in adipocytes. Mol Cell Biol 25:5466–5479. CrossRefPubMedPubMedCentralGoogle Scholar
  68. Rochford JJ, Semple RK, Laudes M et al (2004) ETO/MTG8 is an inhibitor of C/EBPbeta activity and a regulator of early adipogenesis. Mol Cell Biol 24:9863–9872. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Rohas LM, St-Pierre J, Uldry M et al (2007) A fundamental system of cellular energy homeostasis regulated by PGC-1alpha. Proc Natl Acad Sci U S A 104:7933–7938. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Rosen ED, Hsu C-H, Wang X et al (2002) C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev 16:22–26. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Seale P, Bjork B, Yang W et al (2008) PRDM16 controls a brown fat/skeletal muscle switch. Nature 454:961–967. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Seale P, Conroe HM, Estall J et al (2011) Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 121:96–105. CrossRefPubMedGoogle Scholar
  73. Slaby O, Laga R, Sedlacek O (2017) Therapeutic targeting of non-coding RNAs in cancer. Biochem J 474:4219–4251. CrossRefPubMedGoogle Scholar
  74. Sun M, Kraus WL (2015) From discovery to function: the expanding roles of long noncoding RNAs in physiology and disease. Endocr Rev 36:25–64. CrossRefPubMedGoogle Scholar
  75. Sun L, Trajkovski M (2014) MiR-27 orchestrates the transcriptional regulation of brown adipogenesis. Metab Clin Exp 63:272–282. CrossRefPubMedGoogle Scholar
  76. Sun L, Xie H, Mori MA et al (2011) Mir193b-365 is essential for brown fat differentiation. Nat Cell Biol 13:958–965. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Sun K-K, Zhong N, Yang Y et al (2013) Enhanced radiosensitivity of NSCLC cells by transducer of erbB2.1 (TOB1) through modulation of the MAPK/ERK pathway. Oncol Rep 29:2385–2391. CrossRefPubMedGoogle Scholar
  78. Sun J, Ruan Y, Wang M et al (2016) Differentially expressed circulating LncRNAs and mRNA identified by microarray analysis in obese patients. Sci Rep 6:35421. CrossRefPubMedPubMedCentralGoogle Scholar
  79. Taft RJ, Pheasant M, Mattick JS (2007) The relationship between non-protein-coding DNA and eukaryotic complexity. BioEssays 29:288–299. CrossRefPubMedGoogle Scholar
  80. Tanaka T, Yoshida N, Kishimoto T, Akira S (1997) Defective adipocyte differentiation in mice lacking the C/EBPbeta and/or C/EBPdelta gene. EMBO J 16:7432–7443. CrossRefPubMedPubMedCentralGoogle Scholar
  81. Trajkovski M, Ahmed K, Esau CC, Stoffel M (2012) MyomiR-133 regulates brown fat differentiation through Prdm16. Nat Cell Biol 14:1330–1335. CrossRefPubMedGoogle Scholar
  82. van Rooij E, Purcell AL, Levin AA (2012) Developing microRNA therapeutics. Circ Res 110:496–507. CrossRefPubMedGoogle Scholar
  83. Vance KW, Ponting CP (2014) Transcriptional regulatory functions of nuclear long noncoding RNAs. Trends Genet 30:348–355. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Venter JC, Adams MD, Myers EW et al (2001) The sequence of the human genome. Science 291:1304–1351. CrossRefPubMedGoogle Scholar
  85. Villarroya F, Cereijo R, Villarroya J, Giralt M (2017) Brown adipose tissue as a secretory organ. Nat Rev Endocrinol 13:26–35. CrossRefPubMedGoogle Scholar
  86. Villena JA (2015) New insights into PGC-1 coactivators: redefining their role in the regulation of mitochondrial function and beyond. FEBS J 282:647–672. CrossRefPubMedGoogle Scholar
  87. Wahid F, Shehzad A, Khan T, Kim YY (2010) MicroRNAs: synthesis, mechanism, function, and recent clinical trials. Biochim Biophys Acta 1803:1231–1243. CrossRefPubMedGoogle Scholar
  88. Wahid F, Khan T, Kim YY (2014) MicroRNA and diseases: therapeutic potential as new generation of drugs. Biochimie 104:12–26. CrossRefPubMedGoogle Scholar
  89. Wilusz JE, Sunwoo H, Spector DL (2009) Long noncoding RNAs: functional surprises from the RNA world. Genes Dev 23:1494–1504. CrossRefPubMedPubMedCentralGoogle Scholar
  90. Wu J, Boström P, Sparks LM et al (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–376. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Wu Y, Zuo J, Zhang Y et al (2013) Identification of miR-106b-93 as a negative regulator of brown adipocyte differentiation. Biochem Biophys Res Commun 438:575–580. CrossRefPubMedGoogle Scholar
  92. Wu D, Zhou W, Wang S et al (2015) Tob1 enhances radiosensitivity of breast cancer cells involving the JNK and p38 pathways. Cell Biol Int 39:1425–1430. CrossRefPubMedGoogle Scholar
  93. Xu G, Ji C, Song G et al (2015) MiR-26b modulates insulin sensitivity in adipocytes by interrupting the PTEN/PI3K/AKT pathway. Int J Obes 39:1523–1530. CrossRefGoogle Scholar
  94. Xue B, Coulter A, Rim JS et al (2005) Transcriptional synergy and the regulation of Ucp1 during brown adipocyte induction in white fat depots. Mol Cell Biol 25:8311–8322. CrossRefPubMedPubMedCentralGoogle Scholar
  95. Zhang K, Shi Z-M, Chang Y-N et al (2014) The ways of action of long non-coding RNAs in cytoplasm and nucleus. Gene 547:1–9. CrossRefPubMedGoogle Scholar
  96. Zhang H, Guan M, Townsend KL et al (2015) MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1α signaling network. EMBO Rep 16:1378–1393. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Zhao X-Y, Li S, Wang G-X et al (2014) A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol Cell 55:372–382. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Zhu Y, Zhang X, Ding X et al (2014) miR-27 inhibits adipocyte differentiation via suppressing CREB expression. Acta Biochim Biophys Sin Shanghai 46:590–596. CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German Research Center for Environmental HealthNeuherbergGermany
  2. 2.Joint Heidelberg-IDC Translational Diabetes ProgramHeidelberg University HospitalHeidelbergGermany
  3. 3.German Center for Diabetes Research (DZD)NeuherbergGermany

Personalised recommendations