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Review
, 17 (8), 480-95

Transcriptional and Epigenetic Control of Brown and Beige Adipose Cell Fate and Function

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Review

Transcriptional and Epigenetic Control of Brown and Beige Adipose Cell Fate and Function

Takeshi Inagaki et al. Nat Rev Mol Cell Biol.

Erratum in

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.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Cell type-specific chromatin states
a | In stem cells, transcription of adipocyte lineage-specific genes, such as peroxisome proliferator-activated receptor-γ (Pparg), is paused by the presence of bivalent histone H3 Lys4 and Lys27 trimethyl marks (H3K4me3 and H3K27me3; top left). The bivalent H3K4me3 and H3K9me3 marks are observed in lineage-specified 3T3-L1 pre-adipocytes (top right). During adipocyte differentiation, the bivalent H3K4me3 and H3K9me3 marks are gradually resolved to a monovalent H3K4me3 mark, followed by recruitment of phosphorylated CCAAT/enhancer-binding protein-β (C/EBPβ) and other transcription regulators (for example, signal transducer and activator of transcription 5A (STAT5A), glucocorticoid receptor (GR) and Mediator complexes) to the transcriptional ‘hotspot’, leading to PPARγ and C/EBPα expression. Subsequently, PPARγ and its co-regulators, such as retinoid X receptor (RXR), induce adipocyte-specific gene expression (bottom). PPARγ-induced gene transcription occurs at active chromatin, as characterized by acetylated H2K27 (H3K27ac) marks at the enhancer regions and H3K4me3 marks at the promoter regions of adipocyte-specific genes. b | The chromatin landscape of cell type-selective gene loci in differentiated brown adipocytes (top) and white adipocytes (bottom). In brown adipocytes, recruitment of the PPARγ-containing transcriptional complex is associated with high levels of H3K27ac and abundant H3K4me3 marks at the enhancer and promoter regions of the brown adipose tissue (BAT)-selective genes, respectively. By contrast, white adipose tissue (WAT)-selective genes are in the heterochromatin state, as marked by H3K9me3 and H3K27me3. In white adipocytes, enhancer protein complexes at WAT-selective genes are associated with active histone marks, whereas BAT-selective genes are in the heterochromatin state. Pol II, RNA polymerase II.
Figure 2
Figure 2. Transcriptional regulation of brown and beige adipocyte development
a | During prenatal development, classical brown pre-adipocytes arise primarily from cells residing in the dermomyotome that express engrailed 1 (EN1), myogenic factor 5 (MYF5) and paired-box protein 7 (PAX7). MYOD (myoblast determination protein) and myogenin drive myogenesis in the dermomyotome, whereas a number of transcriptional regulators, together with their regulatory factors and regulatory signals, control brown pre-adipocyte fate commitment (see main text for details). b | Beige adipocytes emerge postnatally from a pre-adipocyte population that is positive for platelet-derived growth factor receptor-α (PDGFRα+) and stem cells antigen 1 (SCA1+), or from smooth muscle-like precursors positive for myosin heavy chain 11 (MYH11+). This cell population can give rise to both beige and white adipocytes. Various internal or external stimuli, such as chronic cold exposure, PPARγ agonists, cancer, exercise and several endocrine hormones are known to promote beige adipocyte differentiation. On a molecular level, beige adipogenesis, similarly to brown adipogenesis, is under the control of a plethora of transcriptional regulators and signalling pathways (see main text for details). BMP7, bone morphogenetic protein 7; C/EBPβ, CCAAT-enhancer-binding protein β; CtBP, carboxy-terminal binding protein; EBF2, early B cell factor 2; EWS, Ewing sarcoma; FOXC2, forkhead box protein; HDAC3, histone deacetylase 3; HOXC8, homeobox C8; KLF11, Krüppel-like factor 11; miR, microRNA; MLL4, myeloid/lymphoid or mixed-lineage leukaemia 4; MRTFA, myocardin-related transcription factor A; PCAF, P300/CBP-associated factor; PKA, protein kinase A; PLAC8, placenta-specific gene 8 protein; PPARγ, peroxisome proliferator-activated receptor-γ; PRDM, PR domain zinc-finger protein; SRF, serum response factor; TAF7L, TATA-binding protein associated factor 7L; TGFβ transforming growth factor-β; TLE3, transducin-like enhancer protein 3; WAT, white adipose tissue; YBX1, Y-box binding protein 1; ZFP, zinc-finger protein 16. Grey, double-headed arrows indicate protein interaction and complex formation, whereas black arrow-headed and bar-headed lines show stimulatory and inhibitory effects, respectively.
Figure 3
Figure 3. Molecular mechanisms governing thermogenesis and the role of external cues in beige adipocyte biogenesis and function
a | Thermogenesis in differentiated brown and beige adipocytes is highly induced by cold exposure and β-adrenergic receptor (β-AR) signalling. Various transcriptional regulators are involved in this process (see main text for details) and, collectively, these molecules control the brown- and beige-selective thermogenic gene programme, including glucose and fatty acid (FA) uptake, Ucp1 gene expression and uncoupled cellular respiration. Grey, double-headed arrows indicate protein interaction and complex formation, whereas black arrow-headed and bar-headed lines show stimulatory and inhibitory effects, respectively. b | Cold and natriuretic peptides (NP) induce expression of thermogenic genes. In response to cold stimuli, catecholamine is released from the sympathetic nerve endings. Released catecholamine binds to β-AR and activates adenylyl cyclase (AC), leading to an increase in cAMP levels and activation of protein kinase A (PKA). Activated PKA phosphorylates JMJD1A and p38 MAPK. p38 MAPK is also phosphorylated through activating guanylyl cyclase (GC)–cGMP–protein kinase G (PKG) signalling when atrial NP (ANP) or ventricular NP (VNP) bind to the cardiac NP receptor. Activated p38 MAPK phosphorylates peroxisome proliferator-activated receptor-γ (PPARγ) co-activator 1α (PGC1α) and transcription factor ATF2. ATF2 then binds to CRE elements on the Pgc1a gene promoter region and promotes Pgc1a transcription. Phosphorylated PGC1α functions as a co-activator for PPARγ. Phosphorylated JMJD1A forms a transcriptional complex with the SWI/SNF chromatin remodeller and PPARγ. The phosphorylated JMJD1A SWI/SNF PPARγ complex induces enhancer–promoter proximity through forming a three-dimensional long-range chromatin loop and activates the transcription of thermogenic genes (for example, Ucp1 and Adrb1 (adrenoceptor-β1)). c | Chronic treatment of subcutaneous white adipose tissue (WAT)-derived pre-adipocytes with PPARγ agonists (such as thiazolinedione (TZD)) promotes beige adipocyte differentiation. This is achieved partly through PR domain zinc-finger protein 16 (PRDM16) stabilization and enhanced formation of the PRDM16–PPARγ complex. Chronic TZD treatment probably exerts its effects through reducing PRDM16 protein ubiquitylation and inhibiting its degradation by the proteasome. In addition, TZD can induce sirtuin 1 (Sirt1), which induces deacetylation of PPARγ and enhances the formation of the PRDM16–PPARγ complex. Finally, TZD treatment induces Krüppel-like factor 11 (KLF11), which then maintains the association of PPARγ with superenhancers of beige-selective genes. This collectively promotes activation of the beige-selective gene programme. C/EBPβ, CCAAT-enhancer-binding protein-β; CK2, casein kinase 2; CREB, cAMP-responsive element-binding; FOXC2, forkhead box protein C2; Gsα, stimulatory G protein subunit-α; H3K27, histone H3, Lys27; HDAC, histone deacetylase; IRF4, interferon regulatory factor 4; LXR, liver X receptor; RIP140, receptor-interacting protein 140; RXR, retinoid X receptor; T3, triiodothyronine; TR, thyroid hormone receptor; TWIST1, Twist-related protein 1; Ucp1, uncoupling protein 1; ZFP, zinc-finger protein.
Figure 4
Figure 4. Regulation of epigenetic factors by metabolites
a | Various metabolites can affect chromatin states by acting as cofactors for epigenetic regulators involved in adipogenesis. Acetyl-CoA and S-adenosyl methionine (SAM) are donors for histone acetyltransferases (HATs) and histone and DNA methyltransferases (HMTs and DNMTs), respectively. NAD+ and ATP regulate sirtuin demethylases (SIRTs) and kinases, respectively. α-ketoglutarate (αKG) is a cofactor of JMJD histone demethylases (JMJDs) and 5-methylcytosine hydroxylases (also known as TETs). b | Metabolites and changes in metabolic pathways can affect adipogenesis. Isocitrate dehydrogenase (IDH) catalyses isocitrate to produce αKG in the tricarboxylic acid (TCA) cycle. However, mutations in the IDH gene lead to the production of 2-hydroxyglutarate (2HG) from αKG, which in turn inhibits enzymatic activities of the αKG-dependent histone and DNA demethylases, such as JMJD and TETs, thereby inhibiting adipogenesis.

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