Key Points
-
Brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function is coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators.
-
Histone modification, DNA methylation and chromatin conformational changes have crucial roles in the determination and maintenance of brown and beige adipocyte fate.
-
Currently, more than 50 transcriptional regulators are known to control brown or beige adipocyte differentiation. A large proportion of the regulators, if not all of them, function through master regulators such as peroxisome proliferator-activated receptor-γ (PPARγ) and their partners CCAAT/enhancer-binding protein-ß (C/EBPβ), PR domain zinc-finger protein 16 (PRDM16) and PPARγ co-activator-1α (PGC1α).
-
Various external stimuli, such as chronic cold exposure and synthetic PPARγ ligands, promote beige adipocyte biogenesis in adipocyte precursors. These cues are sensed by cell surface receptors (such as the β-adrenergic receptor) and nuclear receptors (such as PPARγ), leading to dynamic changes in chromatin structures, as well as changes in expression and activity of the key transcriptional regulators.
Abstract
White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Change history
12 July 2017
Two errors in Table 1 of the HTML and PDF versions of this article have been corrected. In addition, corrections to a number of protein definitions have been made.
References
Sidossis, L. & Kajimura, S. Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. J. Clin. Invest. 125, 478–486 (2015).
Cypess, A. M. et al. Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360, 1509–1517 (2009).
Ouellet, V. et al. Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J. Clin. Endocrinol. Metab. 96, 192–199 (2011).
van Marken Lichtenbelt, W. D. et al. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360, 1500–1508 (2009).
Saito, M. et al. High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58, 1526–1531 (2009).
Yoneshiro, T. et al. Recruited brown adipose tissue as an antiobesity agent in humans. J. Clin. Invest. 123, 3404–3408 (2013).
van der Lans, A. A. et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J. Clin. Invest. 123, 3395–3403 (2013).
Lee, P. et al. Temperature-acclimated brown adipose tissue modulates insulin sensitivity in humans. Diabetes 63, 3686–3698 (2014).
Hanssen, M. J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).
Heaton, J. M. The distribution of brown adipose tissue in the human. J. Anat. 112, 35–39 (1972).
Lidell, M. E. et al. Evidence for two types of brown adipose tissue in humans. Nat. Med. 19, 631–634 (2013).
Kajimura, S., Spiegelman, B. M. & Seale, P. Brown and beige fat: physiological roles beyond heat generation. Cell Metab. 22, 546–559 (2015).
Wu, J. et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150, 366–376 (2012).
Sharp, L. Z. et al. Human BAT possesses molecular signatures that resemble beige/brite cells. PLoS ONE 7, e49452 (2012).
Shinoda, K. et al. Genetic and functional characterization of clonally derived adult human brown adipocytes. Nat. Med. 21, 389–394 (2015).
Min, S. Y. et al. Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice. Nat. Med. 22, 312–318 (2016).
Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154–1158 (2009). This paper reports the generation of thermogenic BAT from non-adipogenic cells in vivo.
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007). This paper reports the identification of PRDM16, the master regulator of brown adipocyte development.
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
Kajimura, S., Seale, P. & Spiegelman, B. M. Transcriptional control of brown fat development. Cell Metab. 11, 257–262 (2010).
Rosen, E. D. et al. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Mol. Cell 4, 611–617 (1999).
Barak, Y. et al. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).
Tontonoz, P., Hu, E. & Spiegelman, B. M. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79, 1147–1156 (1994).
Nishikata, I. et al. A novel EVI1 gene family, MEL1, lacking a PR domain (MEL1S) is expressed mainly in t(1;3)(p36;q21)-positive AML and blocks G-CSF-induced myeloid differentiation. Blood 102, 3323–3332 (2003).
Harms, M. J. et al. PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev. 29, 298–307 (2015).
Lefterova, M. I. et al. PPARγ and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes Dev. 22, 2941–2952 (2008). This is the first paper to report the genome-wide analysis of transcription factors during adipogenesis.
Mikkelsen, T. S. et al. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143, 156–169 (2010). This paper reports a comprehensive genome-wide epigenetic analysis in human and mouse adipocytes.
Lefterova, M. I. et al. Cell-specific determinants of peroxisome proliferator-activated receptor γ function in adipocytes and macrophages. Mol. Cell. Biol. 30, 2078–2089 (2010).
Matsumura, Y. et al. H3K4/H3K9me3 bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Mol. Cell 60, 584–596 (2015).
Siersbaek, R. et al. Extensive chromatin remodelling and establishment of transcription factor 'hotspots' during early adipogenesis. EMBO J. 30, 1459–1472 (2011).
Waki, H. et al. Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation. PLoS Genet. 7, e1002311 (2011).
Siersbaek, M. S. et al. Genome-wide profiling of peroxisome proliferator-activated receptor γ in primary epididymal, inguinal, and brown adipocytes reveals depot-selective binding correlated with gene expression. Mol. Cell. Biol. 32, 3452–3463 (2012).
Rajakumari, S. et al. EBF2 determines and maintains brown adipocyte identity. Cell Metab. 17, 562–574 (2013).
Pan, D. et al. Jmjd3-mediated H3K27me3 dynamics orchestrate brown fat development and regulate white fat plasticity. Dev. Cell 35, 568–583 (2015). This study reports the importance of repressive H3K27me3 marks in regulating BAT-selective gene expression.
Loft, A. et al. Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes Dev. 29, 7–22 (2015). This study describes genome-wide changes in chromatin structure and promoter–enhancers during the browning of white adipocytes.
Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371–375 (2014).
Claussnitzer, M. et al. FTO obesity variant circuitry and adipocyte browning in humans. N. Engl. J. Med. 373, 895–907 (2015). This paper describes the long-range functional interaction between non-coding sequences within the FTO locus and IRX3 to regulate beige fat thermogenesis and obesity.
Abe, Y. et al. JMJD1A is a signal-sensing scaffold that regulates acute chromatin dynamics via SWI/SNF association for thermogenesis. Nat. Commun. 6, 7052 (2015). This study describes a mechanism by which a conformational change in chromatin structure controls thermogenic gene expression through phosphorylation of histone demethylase JMJD1A.
Lepper, C. & Fan, C. M. Inducible lineage tracing of Pax7-descendant cells reveals embryonic origin of adult satellite cells. Genesis 48, 424–436 (2010).
Atit, R. et al. β-catenin activation is necessary and sufficient to specify the dorsal dermal fate in the mouse. Dev. Biol. 296, 164–176 (2006).
Wang, W. et al. Ebf2 is a selective marker of brown and beige adipogenic precursor cells. Proc. Natl Acad. Sci. USA 111, 14466–14471 (2014).
Ohno, H., Shinoda, K., Ohyama, K., Sharp, L. Z. & Kajimura, S. EHMT1 controls brown adipose cell fate and thermogenesis through the PRDM16 complex. Nature 504, 163–167 (2013). This paper reports the identification of EHMT1 as the key epigenetic regulator of BAT development and its role in whole-body energy metabolism.
Harms, M. J. et al. Prdm16 is required for the maintenance of brown adipocyte identity and function in adult mice. Cell Metab. 19, 593–604 (2014).
Ishibashi, J. et al. An Evi1-C/EBPβ complex controls peroxisome proliferator-activated receptor γ2 gene expression to initiate white fat cell differentiation. Mol. Cell. Biol. 32, 2289–2299 (2012).
Park, J. H. et al. A multifunctional protein, EWS, is essential for early brown fat lineage determination. Dev. Cell 26, 393–404 (2013).
Zhou, H., Wan, B., Grubisic, I., Kaplan, T. & Tjian, R. TAF7L modulates brown adipose tissue formation. eLife 3, e02811 (2014).
Karamitri, A., Shore, A. M., Docherty, K., Speakman, J. R. & Lomax, M. A. Combinatorial transcription factor regulation of the cyclic AMP-response element on the Pgc-1α promoter in white 3T3-L1 and brown HIB-1B preadipocytes. J. Biol. Chem. 284, 20738–20752 (2009).
Jimenez-Preitner, M. et al. Plac8 is an inducer of C/EBPβ required for brown fat differentiation, thermoregulation, and control of body weight. Cell Metab. 14, 658–670 (2011).
Chen, Y. et al. miR-155 regulates differentiation of brown and beige adipocytes via a bistable circuit. Nat. Commun. 4, 1769 (2013).
Mori, M., Nakagami, H., Rodriguez-Araujo, G., Nimura, K. & Kaneda, Y. Essential role for miR-196a in brown adipogenesis of white fat progenitor cells. PLoS Biol. 10, e1001314 (2012).
Jin, Q. et al. Gcn5 and PCAF regulate PPARγ and Prdm16 expression to facilitate brown adipogenesis. Mol. Cell. Biol. 34, 3746–3753 (2014).
Lee, J. E. et al. H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation. eLife 2, e01503 (2013).
Dempersmier, J. et al. Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol. Cell 57, 235–246 (2015).
Villanueva, C. J. et al. Adipose subtype-selective recruitment of TLE3 or Prdm16 by PPARγ specifies lipid storage versus thermogenic gene programs. Cell Metab. 17, 423–435 (2013).
Stine, R. R. et al. EBF2 promotes the recruitment of beige adipocytes in white adipose tissue. Mol. Metab. 5, 57–65 (2016).
Seale, P. et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J. Clin. Invest. 121, 96–105 (2011).
Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).
Cohen, P. et al. Ablation of PRDM16 and beige adipose causes metabolic dysfunction and a subcutaneous to visceral fat switch. Cell 156, 304–316 (2014).
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008).
Scime, A. et al. Rb and p107 regulate preadipocyte differentiation into white versus brown fat through repression of PGC-1α. Cell Metab. 2, 283–295 (2005).
Cederberg, A. et al. FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. Cell 106, 563–573 (2001). This paper reports the identification of FOXC2 as the first cell-autonomous transcriptional activator of beige adipocyte development and thermogenesis, and further demonstrates the importance of beige fat in whole-body energy homeostasis.
McDonald, M. E. et al. Myocardin-related transcription factor a regulates conversion of progenitors to beige adipocytes. Cell 160, 105–118 (2015).
Long, J. Z. et al. A smooth muscle-like origin for beige adipocytes. Cell Metab. 19, 810–820 (2014).
Yadav, H. et al. Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling. Cell Metab. 14, 67–79 (2011).
Koncarevic, A. et al. A novel therapeutic approach to treating obesity through modulation of TGFβ signaling. Endocrinology 153, 3133–3146 (2012).
Bi, P. et al. Inhibition of Notch signaling promotes browning of white adipose tissue and ameliorates obesity. Nat. Med. 20, 911–918 (2014).
Cinti, S. The Adipose Organ (Editrice Kurtis,1999).
Kozak, U. C. et al. An upstream enhancer regulating brown-fat-specific expression of the mitochondrial uncoupling protein gene. Mol. Cell. Biol. 14, 59–67 (1994).
Cao, W. et al. 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, 3057–3067 (2004). This paper provides a molecular mechanism by which β-AR signalling is integrated into the transcriptional activation of thermogenic genes through p38 MAPK-mediated phosphorylation.
Rim, J. S., Xue, B., Gawronska-Kozak, B. & Kozak, L. P. Sequestration of thermogenic transcription factors in the cytoplasm during development of brown adipose tissue. J. Biol. Chem. 279, 25916–25926 (2004).
Collins, S. β-adrenoceptor signaling networks in adipocytes for recruiting stored fat and energy expenditure. Front. Endocrinol. 2, 102 (2011).
Karamanlidis, G., Karamitri, A., Docherty, K., Hazlerigg, D. G. & Lomax, M. A. C/EBPβ reprograms white 3T3-L1 preadipocytes to a brown adipocyte pattern of gene expression. J. Biol. Chem. 282, 24660–24669 (2007).
Li, F. et al. Histone deacetylase 1 (HDAC1) negatively regulates thermogenic program in brown adipocytes via coordinated regulation of H3K27 deacetylation and methylation. J. Biol. Chem. 291, 4523–4536 (2016).
Shinoda, K. et al. Phosphoproteomics identifies CK2 as a negative regulator of beige adipocyte thermogenesis and energy expenditure. Cell Metab. 22, 997–1008 (2015).
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998). This paper reports the identification of PGC1α, the master regulator of mitochondrial biogenesis, and the thermogenic gene programme in BAT.
Tiraby, C. et al. Acquirement of brown fat cell features by human white adipocytes. J. Biol. Chem. 278, 33370–33376 (2003).
Iida, S., Chen, W., Nakadai, T., Ohkuma, Y. & Roeder, R. G. PRDM16 enhances nuclear receptor-dependent transcription of the brown fat-specific Ucp1 gene through interactions with Mediator subunit MED1. Genes Dev. 29, 308–321 (2015).
Chen, W., Yang, Q. & Roeder, R. G. Dynamic interactions and cooperative functions of PGC-1α and MED1 in TRα-mediated activation of the brown-fat-specific UCP-1 gene. Mol. Cell 35, 755–768 (2009).
Kong, X. et al. IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 158, 69–83 (2014).
Hallberg, M. et al. A functional interaction between RIP140 and PGC-1α regulates the expression of the lipid droplet protein CIDEA. Mol. Cell. Biol. 28, 6785–6795 (2008).
Wang, H. et al. Liver X receptor α is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype. Mol. Cell. Biol. 28, 2187–2200 (2008).
Picard, F. et al. SRC-1 and TIF2 control energy balance between white and brown adipose tissues. Cell 111, 931–941 (2002).
Pan, D., Fujimoto, M., Lopes, A. & Wang, Y. X. Twist-1 is a PPARδ-inducible, negative-feedback regulator of PGC-1α in brown fat metabolism. Cell 137, 73–86 (2009).
Hansen, J. B. et al. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation. Proc. Natl Acad. Sci. USA 101, 4112–4117 (2004).
Christian, M. et al. RIP140-targeted repression of gene expression in adipocytes. Mol. Cell. Biol. 25, 9383–9391 (2005).
Powelka, A. M. et al. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes. J. Clin. Invest. 116, 125–136 (2006).
Leonardsson, G. et al. Nuclear receptor corepressor RIP140 regulates fat accumulation. Proc. Natl Acad. Sci. USA 101, 8437–8442 (2004).
Uldry, M. et al. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab. 3, 333–341 (2006).
Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell 119, 121–135 (2004).
Bordicchia, M. et al. Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes. J. Clin. Invest. 122, 1022–1036 (2012).
Petrovic, N. et al. Chronic peroxisome proliferator-activated receptor γ (PPARγ) 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 (2009).
Rong, J. X. et al. Adipose mitochondrial biogenesis is suppressed in db/db and high-fat diet-fed mice and improved by rosiglitazone. Diabetes 56, 1751–1760 (2007).
Wilson-Fritch, L. et al. Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J. Clin. Invest. 114, 1281–1289 (2004).
Sell, H. et al. Peroxisome proliferator-activated receptor γ agonism increases the capacity for sympathetically mediated thermogenesis in lean and ob/ob mice. Endocrinology 145, 3925–3934 (2004).
Fukui, Y., Masui, S., Osada, S., Umesono, K. & Motojima, K. A new thiazolidinedione, NC-2100, which is a weak PPAR-γ activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice. Diabetes 49, 759–767 (2000).
Vernochet, C. et al. C/EBPα and the corepressors CtBP1 and CtBP2 regulate repression of select visceral white adipose genes during induction of the brown phenotype in white adipocytes by peroxisome proliferator-activated receptor γ agonists. Mol. Cell. Biol. 29, 4714–4728 (2009).
Tai, T. A. et al. Activation of the nuclear receptor peroxisome proliferator-activated receptor γ promotes brown adipocyte differentiation. J. Biol. Chem. 271, 29909–29914 (1996).
Sears, I. B., MacGinnitie, M. A., Kovacs, L. G. & Graves, R. A. Differentiation-dependent expression of the brown adipocyte uncoupling protein gene: regulation by peroxisome proliferator-activated receptor gamma. Mol. Cell. Biol. 16, 3410–3419 (1996).
Viswakarma, N. et al. Transcriptional regulation of Cidea, mitochondrial cell death-inducing DNA fragmentation factor α-like effector A, in mouse liver by peroxisome proliferator-activated receptor α and γ. J. Biol. Chem. 282, 18613–18624 (2007).
Sugii, S. et al. PPARγ activation in adipocytes is sufficient for systemic insulin sensitization. Proc. Natl Acad. Sci. USA 106, 22504–22509 (2009).
Step, S. E. et al. Anti-diabetic rosiglitazone remodels the adipocyte transcriptome by redistributing transcription to PPARγ-driven enhancers. Genes Dev. 28, 1018–1028 (2014).
Qiang, L. et al. Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ. Cell 150, 620–632 (2012).
Ohyama, K. et al. A synergistic anti-obesity effect by a combination of capsinoids and cold temperature through promoting beige adipocyte biogenesis. Diabetes 65, 1410–1423 (2016).
Schulz, T. J. et al. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proc. Natl Acad. Sci. USA 108, 143–148 (2011).
Tseng, Y. H. et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).
Bostrom, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).
Fisher, F. M. et al. FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis. Genes Dev. 26, 271–281 (2012).
Emanuelli, B. et al. Interplay between FGF21 and insulin action in the liver regulates metabolism. J. Clin. Invest. 124, 515–527 (2014).
Pascual, G. et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-γ. Nature 437, 759–763 (2005).
Ghisletti, S. et al. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARγ. Mol. Cell 25, 57–70 (2007).
Lu, C. & Thompson, C. B. Metabolic regulation of epigenetics. Cell Metab. 16, 9–17 (2012).
Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012). This study reports that a change in metabolite (2HG) levels caused by IDH mutations inhibits histone demethylation and affects lineage-specific gene expression, revealing a mechanism by which metabolites control adipocyte development.
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).
Moussaieff, A. et al. Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab. 21, 392–402 (2015).
Stelzer, Y., Shivalila, C. S., Soldner, F., Markoulaki, S. & Jaenisch, R. Tracing dynamic changes of DNA methylation at single-cell resolution. Cell 163, 218–229 (2015).
Guenther, M. G., Levine, S. S., Boyer, L. A., Jaenisch, R. & Young, R. A. A chromatin landmark and transcription initiation at most promoters in human cells. Cell 130, 77–88 (2007).
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).
Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).
Chen, T. & Dent, S. Y. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat. Rev. Genet. 15, 93–106 (2014).
Voigt, P. et al. Asymmetrically modified nucleosomes. Cell 151, 181–193 (2012).
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).
Mikkelsen, T. S. et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature 448, 553–560 (2007).
Zhao, X. Y., Li, S., Wang, G. X., Yu, Q. & Lin, J. D. A long noncoding RNA transcriptional regulatory circuit drives thermogenic adipocyte differentiation. Mol. Cell 55, 372–382 (2014).
Yadav, N. et al. CARM1 promotes adipocyte differentiation by coactivating PPARγ. EMBO Rep. 9, 193–198 (2008).
Dixen, K. et al. ERRγ enhances UCP1 expression and fatty acid oxidation in brown adipocytes. Obesity 21, 516–524 (2013).
Wang, L. et al. Histone H3K9 methyltransferase G9a represses PPARγ expression and adipogenesis. EMBO J. 32, 45–59 (2013).
Tateishi, K., Okada, Y., Kallin, E. M. & Zhang, Y. Role of Jhdm2a in regulating metabolic gene expression and obesity resistance. Nature 458, 757–761 (2009).
Liu, W. et al. miR-133a regulates adipocyte browning in vivo. PLoS Genet. 9, e1003626 (2013).
Trajkovski, M., Ahmed, K., Esau, C. C. & Stoffel, M. MyomiR-133 regulates brown fat differentiation through Prdm16. Nat. Cell Biol. 14, 1330–1335 (2012).
Yin, H. et al. MicroRNA-133 controls brown adipose determination in skeletal muscle satellite cells by targeting Prdm16. Cell Metab. 17, 210–224 (2013).
Sun, L. & Trajkovski, M. MiR-27 orchestrates the transcriptional regulation of brown adipogenesis. Metabolism 63, 272–282 (2014).
Feuermann, Y. et al. 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 (2013).
Sun, L. et al. Mir193b-365 is essential for brown fat differentiation. Nat. Cell Biol. 13, 958–965 (2011).
Hu, F. et al. miR-30 promotes thermogenesis and the development of beige fat by targeting RIP140. Diabetes 64, 2056–2068 (2015).
Fu, T. et al. 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 (2014).
Pan, D. et al. MicroRNA-378 controls classical brown fat expansion to counteract obesity. Nat. Commun. 5, 4725 (2014).
Zhang, H. et al. MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1α signaling network. EMBO Rep. 16, 1378–1393 (2015).
Kumar, N., Liu, D., Wang, H., Robidoux, J. & Collins, S. Orphan nuclear receptor NOR-1 enhances 3′,5′-cyclic adenosine 5′-monophosphate-dependent uncoupling protein-1 gene transcription. Mol. Endocrinol. 22, 1057–1064 (2008).
Molchadsky, A. et al. p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity. Cell Death Differ. 20, 774–783 (2013).
Hallenborg, P. et al. p53 regulates expression of uncoupling protein 1 through binding and repression of PPARγ coactivator-1α. Am. J. Physiol. Endocrinol. Metab. 310, E116–E128 (2016).
Calo, E. et al. Rb regulates fate choice and lineage commitment in vivo. Nature 466, 1110–1114 (2010).
Gerhart-Hines, Z. et al. The nuclear receptor Rev-erbα controls circadian thermogenic plasticity. Nature 503, 410–413 (2013).
Nam, D. et al. Novel function of Rev-erbα in promoting brown adipogenesis. Sci. Rep. 5, 11239 (2015).
Zha, L. et al. The histone demethylase UTX promotes brown adipocyte thermogenic program via coordinated regulation of H3K27 demethylation and acetylation. J. Biol. Chem. 290, 25151–25163 (2015).
Laurila, P. P. et al. USF1 deficiency activates brown adipose tissue and improves cardiometabolic health. Sci. Transl. Med. 8, 323ra13 (2016).
Gupta, R. K. et al. Transcriptional control of preadipocyte determination by Zfp423. Nature 464, 619–623 (2010).
Acknowledgements
The authors apologize for their inability to cite many papers that contributed to the advancement of this field, owing to a space limit. S.K. is supported by the US National Institutes of Health (NIH; DK97441 and DK108822), the Pew Charitable Trust and the Japan Science and Technology Agency. T.I. and J.S. are supported by grants-in-aid for scientific research (B, 25291002 and S, 22229009) and the translational systems biology and medicine initiative (TSBMI) from the Ministry of Education, Science, Sports and Culture (MEXT), Japan. The authors thank Yoshihiro Matsumura for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Interscapular BAT
-
Brown adipose tissue (BAT) is a specialized organ that produces heat. BAT is localized in the interscapular and perirenal regions of rodents and infants.
- Myoblasts
-
Myogenic progenitor cells that differentiate into myocytes (muscle cells).
- Transcriptional co-regulator
-
Transcriptional regulator that acts through forming a complex with DNA-binding transcriptional factors.
- Pioneer factors
-
Transcription factors that can access their target genomic sites in closed chromatin. Pioneer factors trigger enhancer competency and control cell fate determination.
- Retinoid X receptor
-
(RXR). A nuclear receptor that heterodimerizes with other nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). Endogenous ligands remain unknown.
- Epididymal WAT and inguinal WAT
-
Inguinal white adipose tissue (WAT) is a major subcutaneous WAT depot in rodents. Epididymal WAT is a visceral WAT.
- Human multipotent adipose-derived stem (hMADS) cells
-
Cells derived from the prepubic fat pad of a 4-month-old male donor. hMADS cells differentiate to white adipocytes using an adipogenic cocktail, and also to beige adipocytes as a result of chronic treatment with synthetic peroxisome proliferator-activated receptor (PPAR) agonists such as rosiglitazone.
- Superenhancers
-
Enhancer domains that are densely occupied with transcriptional regulators and mediator complexes. Superenhancers have key roles in regulating expression of genes essential for cell fate.
- Somitic mesoderm
-
Mesodermal tissue, which in vertebrate embryos forms in concert with the neural tube during neurulation. This area develops into somites that give rise to skeletal muscle, bone, connective tissues and skin.
- Cancer cachexia
-
A wasting syndrome that leads to body weight loss and atrophy of WAT and skeletal muscle in response to a malignant growth.
- Resistin
-
A Cys-rich secreted peptide from adipocytes that is associated with obesity and diabetes.
- Mediator complex subunit 1
-
(MED1). A core component of the Mediator complex that functions as a transcriptional co-activator. MED1 associates with general transcription factors and RNA polymerase II and has an essential role in activator-dependent transcription in all eukaryotes.
- Irisin
-
A secreted peptide from skeletal muscle (that is, a myokine) that regulates browning of WAT and thermogenesis.
- Nuclear receptor co-repressor
-
(NCoR). A transcriptional repressor that recruits histone deacetylases to the regulatory elements of its target genes and represses their transcription.
Rights and permissions
About this article
Cite this article
Inagaki, T., Sakai, J. & Kajimura, S. Transcriptional and epigenetic control of brown and beige adipose cell fate and function. Nat Rev Mol Cell Biol 17, 480–495 (2016). https://doi.org/10.1038/nrm.2016.62
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrm.2016.62
This article is cited by
-
Aging adipose tissue, insulin resistance, and type 2 diabetes
Biogerontology (2024)
-
Epitranscriptomics in metabolic disease
Nature Metabolism (2023)
-
Blockage of PPARγ T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions
Cell Death & Differentiation (2023)
-
Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation
Nature Communications (2023)
-
Integrated gene expression profiles reveal a transcriptomic network underlying the thermogenic response in adipose tissue
Scientific Reports (2023)
