BBAMCB-57671; No. of pages: 6; 4C: 4, 5 Biochimica et Biophysica Acta xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
Review
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MicroRNAs are key regulators of brown adipogenesis
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Joseph Yi Zhou a, Lixin Li b,⁎
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Article history: Received 26 April 2014 Received in revised form 22 July 2014 Accepted 13 August 2014 Available online xxxx
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Keywords: Brown adipocytes White adipose tissue MicroRNA Beige fat Obesity Prdm16
Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0G4, Canada College of Health Professionals, Physician Assistant Program, Central Michigan University, Mount Pleasant, MI 48859, USA
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The recent discovery of microRNA, thousands of short, non-coding strands of RNA, that regulate gene expressions on the transcriptional level throughout the body, raises the possibility of their roles as therapeutic targets in the treatment of a diverse range of diseases including diabetes, cancer, cardiovascular disease, and obesity. Specifically, their potential as therapeutic targets in the treatment of obesity has been highlighted. Brown adipose tissue containing a large number of mitochondria and expressing Ucp-1 is metabolically active through dissipating energy as heat in cold temperatures. Brown adipose, which was previously thought to be present only in neonatal and infants, has been recently unexpectedly identified in various anatomical regions of the adult human body. Furthermore, brown adipocytes have been shown to originate from skeletal and cardiovascular myoblast progenitor cells. Several identified microRNAs participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-β program. These miRNAs are potential therapeutic targets in the induction of brown adipocyte lineage differentiation from myoblast and white adipose, through which the Ucp-1 expression is regulated to increase calorie expenditure and reduce body weight in obese individuals. This review focuses on the current understanding of miRNAs on the regulation of brown adipogenesis. © 2014 Published by Elsevier B.V.
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1. Introduction
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1.1. Obesity and type 2 diabetes
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Obesity is a major risk factor for a number of chronic diseases such as type II diabetes, stroke, and cardiovascular disease. Obesity has become a growing international concern with prevalence now doubled in the US compared to two decades ago [1]. Weight loss is known to improve or slow down the progression of type 2 diabetes and other chronic diseases associated with obesity [2,3]. Although medications for the treatment of obesity would be an ideal option for weight loss, the development of safe and effective drugs has been unsuccessful [4].
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1.2. Adipose tissue
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There are two types of adipose tissue in mammals, which are white adipose tissue (WAT) and brown adipose tissue (BAT). White adipocytes contain very few mitochondria and no Ucp-1 (uncoupling
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Abbreviations: BAT, brown adipose tissue; WAT, white adipose tissue; iBAT, intrascapular brown adipose tissue; SAT, subcutaneous fat; Mef-2, myocyte enhancer factor-2; PGC-1α, Ppar-Y co-activator; Prdm16, PR domain containing 16; C/ebpβ, CCAAT/enhancer-binding protein β; Ucp-1, uncoupling protein-1; Ppars, peroxisome proliferator-activated receptors; Rux1t1, runt-related transcription factor 1, translocate to 1; hMADS, human multipotent adipose-derived stem; Adam17, Adam metallopeptidase domain 17 ⁎ Corresponding author. Tel.: +1 989 774 3039; fax: +1 989 774 2433. E-mail address: [email protected] (L. Li).
protein-1) expression. Brown adipocytes consist of a relatively large number of mitochondria and abundant levels of Ucp-1. White adipose tissue is sub-categorized as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). VAT is associated with increased several metabolic risk factors, and thus identified as a pathogenic fat depot [5]. On the contrary, SAT is associated with improved metabolic profiles [5]. Brown adipocytes generate heat to maintain the core body temperature when stimulated by cold and a β-3 adrenergic agonist through a process assisted by the mitochondrial Ucp-1 [6]. Classic brown adipocytes, concentrated in BAT, identified as adipocytes expressing Ucp-1, are found specifically in interscapular, perirenal, and axillary depots. However, it was recently discovered that a small percentage of adipocytes that express Ucp-1 exist in SAT [7,8]. These clusters of Ucp-1 expressing adipocytes in SAT are defined as beige/brite adipocytes or ‘browning’ in white adipocytes [7,8]. However, the ultimate thermogenic function of the beige/brite adipocytes does not differ from that of classical brown adipocytes [8]. Importantly, functionally active regions of brown adipose tissue are present in adult males and females and are inversely associated with BMI, indicating its potential role in weight loss therapy [9–11].
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1.3. Differentiation and development of brown adipocyte and beige fat: 71 Prdm16 and C/ebp program 72 Classical brown fat is derived from Myf-5 positive progenitor cells, 73 which are muscle-like cellular lineage during embryonic development 74 [12]. Interestingly, various tissues such as skin fibroblasts, myoblasts, 75
http://dx.doi.org/10.1016/j.bbalip.2014.08.009 1388-1981/© 2014 Published by Elsevier B.V.
Please cite this article as: J.Y. Zhou, L. Li, MicroRNAs are key regulators of brown adipogenesis, Biochim. Biophys. Acta (2014), http://dx.doi.org/ 10.1016/j.bbalip.2014.08.009
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Table 1 MiRNAs and their roles in the brown adipogenesis program.
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MicroRNAs (miRNAs) are a family of short, non-coding, 19–23 base pair RNA molecules that mediate gene expression by inhibiting messenger RNA translations and destabilizing messenger RNA [25]. Expressed throughout the body in various types of tissue, miRNAs regulate more than 60% of the mammalian genome [25]. At least 1000 unique miRNAs were identified in the human genome until now [26]. MiRNA transcripts, which are transcribed by RNA Polymerase II, are located in various non-coding parts of the genome; some are found in introns and others in intergenic domains. The expression of miRNA is regulated either through several transcription factors or through processing precursors [27]; on the other hand, one individual miRNA can target and regulate hundreds of genes via interaction with partially complementary sites located at the 3′UTR of mRNAs to destabilize and inhibit mRNA translation, further reducing protein production [27,28]. MiRNAs are, therefore, very important post-transcriptional regulators of gene expression. Due to their special role in mediating gene expression in various tissues, miRNAs have been shown to regulate adipocyte differentiation, insulin secretion [29], insulin signaling and glucose homeostasis [30]. MiRNAs are also proven to be key regulators of tissue development and differentiation. Several miRNAs have been found to participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-β program [26]. The abundance of these conserved miRNAs in developing adipose tissues was also studied recently. A deep sequencing approach shows that the expression levels of these miRNAs have a large range, and vary from several counts for rare miRNAs to several million reads for most abundant miRNAs. Thirty-two miRNA families are classified as abundantly expressed [31]. Among those miRNAs expressed differently in brown and white adipocytes, the miR-27 family is one of the most abundant miRNAs [31]. MiR-193b–365 cluster is another miRNA that has been demonstrated to be enriched in brown fat [32]. MiR 133a, a muscle specific miRNA, was absent from white adipocytes but highly
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2.1. MicroRNAs
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Only in recent years, it is found that several microRNAs (miRNAs) associate with these transcription factors that play important regulator roles in the switching on and off of the brown adipogenic lineage
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2. Role of miRNAs: inducers of brown adipocytes and beige fat
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determination either as a ligand or an agonist. This review focuses on our current understanding of the role of specific miRNAs in the differentiation of various tissues to BAT, BAT development, and their potential as therapeutic targets for the treatment of obesity. Identified microRNAs that are known to regulate brown adipogenesis are listed in Table 1.
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and skeletal myoblast stem cells (satellites cell) were recently found to differentiate into BAT. These stem cells are derived from the Myf-5 positive lineage [6,13]. The “brown-like” cells or “beige” or “brite” cells within white adipose tissue are previously thought to arise from the Myf-5 negative lineage [12,14]. Using a new lineage-tracing approach optimal for adipocyte, recent findings suggest that beige fat is derived from Myf 5-Cre positive or Myf 5-negative lineage, depending on the depot [15,16]. Importantly, classic brown as well as beige adipocytes can be activated by cold (referred to as ‘browning’ of adipocytes) and share similar transcriptional cascades in adipogenic differentiation [17]. Two transcription factors, Prdm16 (PR domain containing 16), a zinc-finger transcriptional factor, and C/ebp-β (CCAAT/enhancerbinding protein-β), are highly expressed in brown adipocytes compared to white adipocytes and myocytes [12,18,19]. Their expressions determine the differentiation direction of brown fat precursors to myogenic or brown fat, and the differentiation direction of white fat precursors to brown adipocytes or white fat [12,20]. Inhibition of Prdm16 expression in brown fat precursors promotes muscle differentiation. In contrast, myoblasts can differentiate into brown fat cells induced by ectopic expression of Prdm16 [12]. Prdm16 thus acts as a key control factor in the brown fat program [12,21]. Ectopic expression of C/ebp-β in white adipocytes is associated with a significant increase in brown adipocyte-specific genes and inhibition of white adipocyte-specific genes [19,22,23]. Prdm16 together with the active form of C/ebp-β forms a transcriptional complex, which plays a critical role in controlling the cell switch from myoblastic precursors to brown fat cells [19,21], and drives a full functional brown fat program in non-adipogenic cells [19]. Brown fat differentiation also requires Ppar-ϒ [17], furthermore, activation of Ppar-γ agonist in white adipocytes by can induce brown adipose specific genes [18]. C/ebp-β activates transcription of C/ebp-α and Ppar-ϒ, and induces transcription of Ucp1 [24]. Ppar-ϒ and the C/ ebp peptide family function synergistically to stimulate adipogenesis and maintain the differentiated state of white and brown adipocytes by promoting cell-cycle re-entry and mitotic clonal expansion [18].
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MiRNA
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References
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Mir-26a/b MiR-27
Promote brown fat adipogenesis Promote white fat adipogenesis Suppress brown fat adipogenesis
[44]
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MiR-106b–93
Suppress brown fat adipogenesis
[43]
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MiR-133
MiR-155
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MiR-193b/365
Prdm16
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MiR-196a
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MiR-378
Forskolin Cold temperature Adrenergic MyoD Cold temperature
Promote myogenesis Suppress brown fat adipogenesis Suppress beige fat adipogenesis Suppress brown fat adipogenesis Promote beige fat adipogenesis Suppress myogenesis Promote brown fat adipogenesis Promote white fat adipogenesis Suppress WAT adipogenesis Promote beige fat adipogenesis
[13,35]
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Forskolin Cold temperature Mef2 Tgfβ-1
Ucp-1 Adam17 Ppar-α Pgc1-β Prdm16 Ucp-1 Prdm16 Pparα Pgc-1α Prdm16
[49]
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Rosiglitazone Cold temperature Cold temperature
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MiR-455
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C/ebp-β Pgc-1α Runxltl Ppar-Y C/ebp-α Hoxc8
MyoR C/ebp-β C/ebp-α Ucp-1
[36] [32]
[45]
Promote myogenesis Promote brown adipogenesis
[41,42]
Suppress myogenesis Promote brown fat adipogenesis
[33]
Please cite this article as: J.Y. Zhou, L. Li, MicroRNAs are key regulators of brown adipogenesis, Biochim. Biophys. Acta (2014), http://dx.doi.org/ 10.1016/j.bbalip.2014.08.009
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2.3. MiR155: miR-155 targets C/ebp-β
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MiR-155 is abundant in brown adipose tissue, particularly in proliferating brown preadipocytes, but declines after differentiation is induced, indicating an important role of miR-155 in BAT development [36]. The program regulating myoblast to adipocyte lineage differentiation is controlled by miRNA found in preadipocytes, specifically miR155, through targeting C/ebp-β. All three C/ebp-β isoforms have been shown to be suppressed in miR-155 overexpressing preadipocytes [36]. Furthermore, expression of Pgc-1α (Ppar-Y co-activator) which regulates respiration, and mitochondrial biogenesis was downregulated by miR-155, and upregulated when silencing of miR-155 in vitro [37,38]. Enhanced brown adipose tissue activity and increased beige fat tissue were found in miR-155 deficient mice [36]. In contrast, overexpression of miR-155 in mice exhibits a decrease of brown adipose tissue mass and impaired brown adipose tissue activity [36]. In addition, the function of BAT and expression of Ucp-1 and Pgc-1 are significantly increased after acute cold exposure in miR-155 knockout mice [36]. MiR-155 expression is also reported to be associated with obesity and dysfunction of adipose tissue in human [39]. All together, these findings suggest a reciprocal negative regulation between miR155 and C/ebp-β in controlling the development of brown and beige fat cells through the regulation of brown lineage commitment [36] (Figs. 1 and 2).
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2.5. MiR-455: miR-455 up-regulates Ucp-1
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MiR-455 is reported to be upregulated during brown preadipocyte differentiation, although the expression level is low in white preadipocytes and white mature adipocytes [33]. Similar to the effects of miR-193, upregulation of Ucp-1 during brown adipogenesis identified in skeletal myocytes was observed along with an increase in miR-455 expression [33]. This suggests a possible role for miR-455 in the skeletal myocyte lineage shift to brown adipocytes. Norepinephrine and rosiglitazone, both Ppar-Y agonists, are also reported to induce miR-455 expression [33]. These findings indicate that miRNA-455 promotes brown fat differentiation by directly targeting Ucp-1 (Fig. 1).
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2.6. MiR-378/378*: miR-378 up-regulates C/ebp-α and C/ebp-β
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MiR 378 is more abundant in brown adipose tissue compared to heart muscle and skeletal muscle. MiR-378 stimulates myogenesis and has a regulatory role in mediating adipogenesis [41,42] (Fig. 1). The presence of an adipocyte locus encoding miR-378 contained in the intron of the transcriptional activator Pgc1-β indicates that the expression of miR-378 is also induced in adipogenesis [41]. PGC-1 β is well known to involve in mitochondrial biogenesis, and elevated expression of Pgc1β was concordant with miR-378 expression. MiR-378 was also shown to upregulate the expression of C/ebp-α and C/ebp-β, both of which are adipogenic proliferating and differentiating factors [41]. C/ebp-β further
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MiR-133, is highly expressed in brown fat, SAT, and beige adipocyte, although less enriched compared to skeletal and cardiac muscles [13, 35]. It is one of the most down regulated miRNAs after exposure to low temperature. Cold exposure down regulates miR-133, through its temperature dependent transcriptional activator, Mef-2 [16,35]. Specifically, both isoforms of miR-133; miR-133a and miR-133b are decreased following induction of differentiation in SVF from BAT after cold exposure. Furthermore, inhibition of miR-133 both in vitro [35] and in vivo [21] produced an increase in Ucp-1 expression, constituting a program contributing to cold-mediated upregulation of Ucp-1 expression [35]. MiR-133 directly targets and inhibits Prdm16 expression via a miR133 target site located within 3′UTR in the Prdm-16 transcript in white as well as brown adipocytes [35]. Silencing of miR-133 in vitro through anti-miR-133 is associated with enhancement of Prdm16. In contrast, overexpression of miR-133 completely inhibits Prdm16 expression along with a significantly reduced expression in Ucp-1, Pparα and Ppar-γ levels and an increase in the myogenic regulatory factors including Myg and MyoD expression [35]. These findings imply a key role of miR-133 in brown adipocyte differentiation. Prdm16 and its downstream peptide Ucp-1 are highly expressed in SAT, while expression levels were much lower in VAT [18,19]. In addition, the pre-adipocyte isolated from the SAT contained more miR-133 when compared with VAT precursors, suggesting that the regulation of Prdm16 expression in SAT is primarily mediated by miR-133 [35]. In agreement with this finding, deletion of miR-133a gene results in browning of SAT in vivo, and associates with increased insulin sensitivity and glucose tolerance [21]. These findings suggest an inhibitory role of miR-133 in white fat browning and beige fat differentiation. Taken together, miR-133 plays a central role in regulating Prdm16 and brown adipogenesis after cold exposure in BAT and SAT (Figs. 1 and 2).
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2.2. MiR-133: miR-133 targets Prdm16
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MiR-193b and miR-365 are co-located on chromosome 16 as a cluster during transcription. Both miRNAs are highly expressed in iBAT relative to other tissues and showed significant upregulation during brown adipogenesis of SVF cells from interscapular brown fat. The expression of the miR-193 and miR-365 cluster was also increased in white adipogenesis [32]. Inhibition of either miRNA in preadipocytes from stromal vascular fraction (SVF) during adipocyte differentiation significantly reduced lipid accumulation and adipocyte specific genes, with a more marked reduction in brown fat specific genes such as Ucp-1, Pgc-1α, Prdm16, and Cidea (cell death-inducing DNA fragmentation factor, alpha subunit-like effector A), associated with increased expression of myogenic specific markers [32]. Conversely, forced expression of miR193 or miR-365 in C2C12 myoblast is associated with both white and brown adipogenesis as indicated by increased expression of white and brown marker genes and an inhibition of the entire myogenesis program [32]. Thus, the MiR-193b/365 cluster plays a key regulating role in directing the brown and myogenic lineages (Fig. 1). MiR193b–365 was targeted and upregulated by Prdm16 through direct regulation of another brown adipose enriched marker, Ppar-α. This is a program that controls the lineage determination shift from skeletal myogenesis to brown adipogenesis [35]. The cell signaling pathways through which the cluster regulates the brown fat differentiation are not clear. One possible pathway that miR193 regulates adipogenesis is through a direct inhibition of Runx1t1 (runt-related transcription factor 1; translocate to 1), which is known as a white and brown adipogenesis inhibitor. Blocking of miR-193 was associated with increased Runx1t1, implying that miR-193 induces Ucp-1 expression by inhibiting Runx1t1 [32]. Another possible pathway that miR-93 suppresses myogenesis is through the miR-193-induced down regulation of Cdon (cell adhesion associated, oncogene regulated). Cdon is known to be a cell surface receptor mediating the expression of myogenic proliferation factors and Igfb-5 (insulin-like growth factor-binding protein-5). Furthermore, C/ebp-α as well as Ppar-γ, both adipocyte growth factors, are transcriptionally upregulated by miR-193b. Despite this, controversial findings by Feuermann indicated that the development, differentiation, and function of BAT do not require the presence of miR-193b and miR-365-1 [40].
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2.4. MiR-193b and miR-365: Prdm16 up-regulates miR-193b and miR-365 213
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expressed in brown preadipocytes and brown adipocytes [32–34]. Due to very limited data available, it is still not clear whether the abundance of these miRNAs is crucial, and in line with their physiological role in brown fat or beige fat differentiation and development [34]. Particularly those rare miRNAs that are expressed at very low level, whether prompting or inhibiting of those miRNAs can actually change the cellular phenotype is undermined.
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Fig. 1. Overview of the miRNAs in the regulation of differentiation of Myf 5+ mesenchymal precursors into myoblast or brown adipocytes.
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2.7. MiR-106b–93: miR-106b–93 suppresses Ucp-1 expression
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induces Ucp-1 expression, leading to a brown adipogenic program shift [41]. This unique instance with miR-378 and miR-378*, which stimulates myogenic differentiation, suggests that the myogenesis and brown adipogenesis programs are simultaneously upregulated [42].
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MiR-106b and miR-93 form clusters and co-locate on chromo280 some 7 [43]. Expression of miR-106–93 was significantly increased 281 in mature brown adipocyte compared to brown preadipocyte [43]. 282 Silencing of miR-106b and miR-93 in differentiating brown adipo283 cytes significantly induced brown fat specific differentiation genes 284 including Ucp-1, Prdm16, Cidea (cell death inducing DNA fragmen285 tation factor), Ppar-α, and Pgc1-α along with brown adipocyte 286 lipid-droplet accumulation [43]. Conversely, Ucp-1 expression was 287 suppressed by ectopic expression of miR-106b and miR-93 in differ288 entiating brown adipocytes. In addition, in high fat diet-induced 289 obese mice, miR-106b and miR-93 expression levels are higher in 290 brown adipose tissues compared to control mice [43]. These data 291 Q13 imply that the miR-106b–93 cluster plays an inhibition role and are 292 negative regulators in brown adipocyte differentiation and energy 293 homeostasis [43] (Figs. 1 and 2). 294
2.8. MiR-27: miR-27 targets brown transcriptional program
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MiR-27 contains highly evolutionarily conserved heptamer or octamer seed motifs within the 3′ untranslated regions (3′UTRs) of Prdm16, Creb, Pparα, and Pparγ [44]. The abundance of miR 27a is enriched in brown fat and WAT, but expression is higher in preadipocyte (SVF) isolated from VAT than SAT. Cold temperature
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suppresses miR-27 expression in brown adipose tissue and white adipose tissue, whereas miR-27 inhibits brown adipogenesis in both cultured cells and primary SAT preadipocytes [44]. The inhibition effect of miR-27 on beige adipogenesis is fully prevented when Ppar-ϒ or Prdm16 is silenced by siRNAs in brown preadipocytes [44]. These findings suggest that the inhibition effect of miR-27 is through a direct suppression on Prdm16, Ppar-α, and Pgc1-β, and an indirect effect on Pgc1-α [44] (Fig. 2). MiR-27, therefore, plays a central role in cold stimulated beige and brown adipogenesis by targeting the downstream transcriptional network [44].
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2.9. MiR-196a: miR-196a suppresses Hoxc8
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The abundance of miR-196a is much lower in BAT compared with WAT [45]. This indicates an important role of miR-196a in promoting brite adipocyte differentiation, and its role on brown fat development is modest. The expression levels of miR-196a in the stromal vascular fraction (SVF) of WAT are elevated when stimulated by cold exposure as well as a β3-agonist. In addition, miR-196a targets and suppresses Hoxc 8 (human homeobox protein hoxc8) during brown adipogenesis in WAT progenitor cells [45] (Fig. 2). Hoxc8 is classified as a WAT gene, due to its high expression level in white adipocytes compared to brown adipocytes. It directly suppresses C/ebp-β, another cell fate switch in brown adipogenesis. Although the Hox family of homeobox genes (Hox genes) plays a major role in determining the BAT and WAT differentiations [46,47,45], only Hoxc 8 is known to suppress brown adipogenesis and functions as a gatekeeper during brown adipogenesis induction [47,48]. Suppression of miR-196a in progenitor cells obtained from mouse and human WAT was associated with a down regulation of brown adipocyte markers due to Hoxc 8 up-regulation.
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Fig. 2. Overview of the miRNAs in the regulation of the differentiation of Myf 5− mesenchymal precursors into white adipocytes or beige fat.
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2.10. MiR-26: miR-26 targets Ucp-1 through Adam17
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Conversely, forced expression of miR-196a in mouse adipose tissue increases both BAT mass and energy expenditure through inhibition of the Hoxc-8 expression. A recent study further indicates that C/ebp-β is suppressed by a complex of Hoxc8 and Hdac3 (histone deacetylase 3) via a 3′ regulatory sequence [45]. Thus, MiR-196a induces browning of white adipose tissue through the inhibition of Hoxc-8 [45].
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MiR-26a is the first miRNA studied in human adipocytes. It is highly expressed in BAT. Cold exposure significantly induces miR-26 in WAT 337 [49]. Overexpression of miR-26a or miR-26b in human multipotent 338 adipose-derived stem (hMADS) cells leads to a significant increase in 339 Ucp-1 and Pgc-1α gene expression [49]. hMADS, a very useful model 340 for studying human adipogenesis [49–51], was originally isolated from 341 human adipose tissue [50,52,53]. Treatment with a PPARγ agonist, 342 rosiglitazone, can direct the hMADs to differentiate toward the brown 343 Q16 fat [49]. Interestingly, miR-26a enhances rosiglitazone-induced ‘brow344 ning’ in hMADS, indicating that elevated Ucp-1 abundance induced by 345 miR-26a may result from other downstream target gene besides 346 PPARγ activation. Sheddase Adam metallopeptidase domain 17 347 (Adam17), a tumor necrosis factor-α (TNF-α)-converting enzyme 348 [54], was recently shown to regulate brown fat marker gene expres349 sion [49]. Overexpression of miR-26a in hMADs downregulates 350 Adam17 mRNA, and inhibition of miR-26a/b leads to a significant eleva351 tion of Adam17 at both protein and mRNA expression. In addition, 352 Adam17 knockdown is able to elevate Ucp-1 expression in brite adipo353 cytes and introduce a similar effect on adipogenesis mediated by miR335 336
26a/b. These findings suggest that Adam17 is a direct target of miR-26 introduced white and brite adipogenesis [49]. Ultimately, these findings strongly suggest a key role of the miR-26a/b on human adipocyte differentiation and brown adipogenesis [49]. MiR-26 targets Ucp-1 that is mediated through Adam17 (Fig. 2).
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3. Conclusion and future directions
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MicroRNAs are a class of short, non-coding RNAs that control the expression of various target genes in diverse tissue types throughout the body and are known to play important roles in regulating brown adipocyte adipogenesis. There are 91 miRNAs that have been identified to date to be potentially important for the development of brown adipose tissue [32]. However, the correlation between the abundance level of these identified miRNAs and their roles in regulating brown fat development is still unclear. The important roles of miRNAs in the regulation of brown adipocyte differentiation, development, or brown fat function were studied in only a very small number of miRNAs. Several miRNAs including miR-133, miR-155, miR-193b/365, and miR-455 are known to regulate the differentiation of Myf5 positive mesenchymal precursor cells into skeletal/cardio myoblasts, and further into brown adipocytes [15,36,32,33]. Other microRNAs, including miR-196a, play an important role in inducing functional brown adipocytes in WAT or the browning of white adipocytes [47]. C/ebp-β and Prdm16 act as the master regulator and lead to the upregulation of brown adipogenic genes and inhibition of mesenchymal precursor cells' differentiation into myoblasts. Together, miRNAs mediate counter regulatory programs of brown adipose and myofibril differentiation from the precursor cells through targeting or
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being regulated by these master regulators, suggesting their potential in thermogenesis. It is clear that maintaining elevated daily energy expenditures improves the long term effectiveness of weight loss in obese individuals. This strategy can be achieved by increasing beige or brown adipogenesis, increasing physiological active brown adipocyte numbers, and enhancing recruitment of beige fat cells. Thus, targeting miRNAs in preadipocytes to induce thermogenesis in BAT or WAT is a feasible strategy in treating obesity. Taken together, miRNAs and the related pathways that participated in brown adipogenesis represent important therapeutic targets for the treatment of obesity and type 2 diabetes. Future work should be focused on identifying miRNAs that participate in brown fat adipogenesis and further understanding miRNA-based regulation of brown and beige adipocyte adipogenesis.
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Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
Review
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MicroRNAs are key regulators of brown adipogenesis
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Joseph Yi Zhou a, Lixin Li b,⁎
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Article history: Received 26 April 2014 Received in revised form 22 July 2014 Accepted 13 August 2014 Available online xxxx
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Keywords: Brown adipocytes White adipose tissue MicroRNA Beige fat Obesity Prdm16
Department of Anatomy and Cell Biology, McGill University, Montreal, QC H3A 0G4, Canada College of Health Professionals, Physician Assistant Program, Central Michigan University, Mount Pleasant, MI 48859, USA
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The recent discovery of microRNA, thousands of short, non-coding strands of RNA, that regulate gene expressions on the transcriptional level throughout the body, raises the possibility of their roles as therapeutic targets in the treatment of a diverse range of diseases including diabetes, cancer, cardiovascular disease, and obesity. Specifically, their potential as therapeutic targets in the treatment of obesity has been highlighted. Brown adipose tissue containing a large number of mitochondria and expressing Ucp-1 is metabolically active through dissipating energy as heat in cold temperatures. Brown adipose, which was previously thought to be present only in neonatal and infants, has been recently unexpectedly identified in various anatomical regions of the adult human body. Furthermore, brown adipocytes have been shown to originate from skeletal and cardiovascular myoblast progenitor cells. Several identified microRNAs participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-β program. These miRNAs are potential therapeutic targets in the induction of brown adipocyte lineage differentiation from myoblast and white adipose, through which the Ucp-1 expression is regulated to increase calorie expenditure and reduce body weight in obese individuals. This review focuses on the current understanding of miRNAs on the regulation of brown adipogenesis. © 2014 Published by Elsevier B.V.
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1. Introduction
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1.1. Obesity and type 2 diabetes
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Obesity is a major risk factor for a number of chronic diseases such as type II diabetes, stroke, and cardiovascular disease. Obesity has become a growing international concern with prevalence now doubled in the US compared to two decades ago [1]. Weight loss is known to improve or slow down the progression of type 2 diabetes and other chronic diseases associated with obesity [2,3]. Although medications for the treatment of obesity would be an ideal option for weight loss, the development of safe and effective drugs has been unsuccessful [4].
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1.2. Adipose tissue
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There are two types of adipose tissue in mammals, which are white adipose tissue (WAT) and brown adipose tissue (BAT). White adipocytes contain very few mitochondria and no Ucp-1 (uncoupling
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Abbreviations: BAT, brown adipose tissue; WAT, white adipose tissue; iBAT, intrascapular brown adipose tissue; SAT, subcutaneous fat; Mef-2, myocyte enhancer factor-2; PGC-1α, Ppar-Y co-activator; Prdm16, PR domain containing 16; C/ebpβ, CCAAT/enhancer-binding protein β; Ucp-1, uncoupling protein-1; Ppars, peroxisome proliferator-activated receptors; Rux1t1, runt-related transcription factor 1, translocate to 1; hMADS, human multipotent adipose-derived stem; Adam17, Adam metallopeptidase domain 17 ⁎ Corresponding author. Tel.: +1 989 774 3039; fax: +1 989 774 2433. E-mail address: [email protected] (L. Li).
protein-1) expression. Brown adipocytes consist of a relatively large number of mitochondria and abundant levels of Ucp-1. White adipose tissue is sub-categorized as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). VAT is associated with increased several metabolic risk factors, and thus identified as a pathogenic fat depot [5]. On the contrary, SAT is associated with improved metabolic profiles [5]. Brown adipocytes generate heat to maintain the core body temperature when stimulated by cold and a β-3 adrenergic agonist through a process assisted by the mitochondrial Ucp-1 [6]. Classic brown adipocytes, concentrated in BAT, identified as adipocytes expressing Ucp-1, are found specifically in interscapular, perirenal, and axillary depots. However, it was recently discovered that a small percentage of adipocytes that express Ucp-1 exist in SAT [7,8]. These clusters of Ucp-1 expressing adipocytes in SAT are defined as beige/brite adipocytes or ‘browning’ in white adipocytes [7,8]. However, the ultimate thermogenic function of the beige/brite adipocytes does not differ from that of classical brown adipocytes [8]. Importantly, functionally active regions of brown adipose tissue are present in adult males and females and are inversely associated with BMI, indicating its potential role in weight loss therapy [9–11].
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1.3. Differentiation and development of brown adipocyte and beige fat: 71 Prdm16 and C/ebp program 72 Classical brown fat is derived from Myf-5 positive progenitor cells, 73 which are muscle-like cellular lineage during embryonic development 74 [12]. Interestingly, various tissues such as skin fibroblasts, myoblasts, 75
http://dx.doi.org/10.1016/j.bbalip.2014.08.009 1388-1981/© 2014 Published by Elsevier B.V.
Please cite this article as: J.Y. Zhou, L. Li, MicroRNAs are key regulators of brown adipogenesis, Biochim. Biophys. Acta (2014), http://dx.doi.org/ 10.1016/j.bbalip.2014.08.009
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Table 1 MiRNAs and their roles in the brown adipogenesis program.
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MicroRNAs (miRNAs) are a family of short, non-coding, 19–23 base pair RNA molecules that mediate gene expression by inhibiting messenger RNA translations and destabilizing messenger RNA [25]. Expressed throughout the body in various types of tissue, miRNAs regulate more than 60% of the mammalian genome [25]. At least 1000 unique miRNAs were identified in the human genome until now [26]. MiRNA transcripts, which are transcribed by RNA Polymerase II, are located in various non-coding parts of the genome; some are found in introns and others in intergenic domains. The expression of miRNA is regulated either through several transcription factors or through processing precursors [27]; on the other hand, one individual miRNA can target and regulate hundreds of genes via interaction with partially complementary sites located at the 3′UTR of mRNAs to destabilize and inhibit mRNA translation, further reducing protein production [27,28]. MiRNAs are, therefore, very important post-transcriptional regulators of gene expression. Due to their special role in mediating gene expression in various tissues, miRNAs have been shown to regulate adipocyte differentiation, insulin secretion [29], insulin signaling and glucose homeostasis [30]. MiRNAs are also proven to be key regulators of tissue development and differentiation. Several miRNAs have been found to participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-β program [26]. The abundance of these conserved miRNAs in developing adipose tissues was also studied recently. A deep sequencing approach shows that the expression levels of these miRNAs have a large range, and vary from several counts for rare miRNAs to several million reads for most abundant miRNAs. Thirty-two miRNA families are classified as abundantly expressed [31]. Among those miRNAs expressed differently in brown and white adipocytes, the miR-27 family is one of the most abundant miRNAs [31]. MiR-193b–365 cluster is another miRNA that has been demonstrated to be enriched in brown fat [32]. MiR 133a, a muscle specific miRNA, was absent from white adipocytes but highly
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2.1. MicroRNAs
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Only in recent years, it is found that several microRNAs (miRNAs) associate with these transcription factors that play important regulator roles in the switching on and off of the brown adipogenic lineage
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determination either as a ligand or an agonist. This review focuses on our current understanding of the role of specific miRNAs in the differentiation of various tissues to BAT, BAT development, and their potential as therapeutic targets for the treatment of obesity. Identified microRNAs that are known to regulate brown adipogenesis are listed in Table 1.
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and skeletal myoblast stem cells (satellites cell) were recently found to differentiate into BAT. These stem cells are derived from the Myf-5 positive lineage [6,13]. The “brown-like” cells or “beige” or “brite” cells within white adipose tissue are previously thought to arise from the Myf-5 negative lineage [12,14]. Using a new lineage-tracing approach optimal for adipocyte, recent findings suggest that beige fat is derived from Myf 5-Cre positive or Myf 5-negative lineage, depending on the depot [15,16]. Importantly, classic brown as well as beige adipocytes can be activated by cold (referred to as ‘browning’ of adipocytes) and share similar transcriptional cascades in adipogenic differentiation [17]. Two transcription factors, Prdm16 (PR domain containing 16), a zinc-finger transcriptional factor, and C/ebp-β (CCAAT/enhancerbinding protein-β), are highly expressed in brown adipocytes compared to white adipocytes and myocytes [12,18,19]. Their expressions determine the differentiation direction of brown fat precursors to myogenic or brown fat, and the differentiation direction of white fat precursors to brown adipocytes or white fat [12,20]. Inhibition of Prdm16 expression in brown fat precursors promotes muscle differentiation. In contrast, myoblasts can differentiate into brown fat cells induced by ectopic expression of Prdm16 [12]. Prdm16 thus acts as a key control factor in the brown fat program [12,21]. Ectopic expression of C/ebp-β in white adipocytes is associated with a significant increase in brown adipocyte-specific genes and inhibition of white adipocyte-specific genes [19,22,23]. Prdm16 together with the active form of C/ebp-β forms a transcriptional complex, which plays a critical role in controlling the cell switch from myoblastic precursors to brown fat cells [19,21], and drives a full functional brown fat program in non-adipogenic cells [19]. Brown fat differentiation also requires Ppar-ϒ [17], furthermore, activation of Ppar-γ agonist in white adipocytes by can induce brown adipose specific genes [18]. C/ebp-β activates transcription of C/ebp-α and Ppar-ϒ, and induces transcription of Ucp1 [24]. Ppar-ϒ and the C/ ebp peptide family function synergistically to stimulate adipogenesis and maintain the differentiated state of white and brown adipocytes by promoting cell-cycle re-entry and mitotic clonal expansion [18].
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References
t1:4
Mir-26a/b MiR-27
Promote brown fat adipogenesis Promote white fat adipogenesis Suppress brown fat adipogenesis
[44]
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MiR-106b–93
Suppress brown fat adipogenesis
[43]
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MiR-133
MiR-155
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MiR-193b/365
Prdm16
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MiR-196a
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MiR-378
Forskolin Cold temperature Adrenergic MyoD Cold temperature
Promote myogenesis Suppress brown fat adipogenesis Suppress beige fat adipogenesis Suppress brown fat adipogenesis Promote beige fat adipogenesis Suppress myogenesis Promote brown fat adipogenesis Promote white fat adipogenesis Suppress WAT adipogenesis Promote beige fat adipogenesis
[13,35]
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Forskolin Cold temperature Mef2 Tgfβ-1
Ucp-1 Adam17 Ppar-α Pgc1-β Prdm16 Ucp-1 Prdm16 Pparα Pgc-1α Prdm16
[49]
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Rosiglitazone Cold temperature Cold temperature
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MiR-455
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Norepinephrine Ppar-Y agonist
C/ebp-β Pgc-1α Runxltl Ppar-Y C/ebp-α Hoxc8
MyoR C/ebp-β C/ebp-α Ucp-1
[36] [32]
[45]
Promote myogenesis Promote brown adipogenesis
[41,42]
Suppress myogenesis Promote brown fat adipogenesis
[33]
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2.3. MiR155: miR-155 targets C/ebp-β
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MiR-155 is abundant in brown adipose tissue, particularly in proliferating brown preadipocytes, but declines after differentiation is induced, indicating an important role of miR-155 in BAT development [36]. The program regulating myoblast to adipocyte lineage differentiation is controlled by miRNA found in preadipocytes, specifically miR155, through targeting C/ebp-β. All three C/ebp-β isoforms have been shown to be suppressed in miR-155 overexpressing preadipocytes [36]. Furthermore, expression of Pgc-1α (Ppar-Y co-activator) which regulates respiration, and mitochondrial biogenesis was downregulated by miR-155, and upregulated when silencing of miR-155 in vitro [37,38]. Enhanced brown adipose tissue activity and increased beige fat tissue were found in miR-155 deficient mice [36]. In contrast, overexpression of miR-155 in mice exhibits a decrease of brown adipose tissue mass and impaired brown adipose tissue activity [36]. In addition, the function of BAT and expression of Ucp-1 and Pgc-1 are significantly increased after acute cold exposure in miR-155 knockout mice [36]. MiR-155 expression is also reported to be associated with obesity and dysfunction of adipose tissue in human [39]. All together, these findings suggest a reciprocal negative regulation between miR155 and C/ebp-β in controlling the development of brown and beige fat cells through the regulation of brown lineage commitment [36] (Figs. 1 and 2).
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2.5. MiR-455: miR-455 up-regulates Ucp-1
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MiR-455 is reported to be upregulated during brown preadipocyte differentiation, although the expression level is low in white preadipocytes and white mature adipocytes [33]. Similar to the effects of miR-193, upregulation of Ucp-1 during brown adipogenesis identified in skeletal myocytes was observed along with an increase in miR-455 expression [33]. This suggests a possible role for miR-455 in the skeletal myocyte lineage shift to brown adipocytes. Norepinephrine and rosiglitazone, both Ppar-Y agonists, are also reported to induce miR-455 expression [33]. These findings indicate that miRNA-455 promotes brown fat differentiation by directly targeting Ucp-1 (Fig. 1).
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2.6. MiR-378/378*: miR-378 up-regulates C/ebp-α and C/ebp-β
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MiR 378 is more abundant in brown adipose tissue compared to heart muscle and skeletal muscle. MiR-378 stimulates myogenesis and has a regulatory role in mediating adipogenesis [41,42] (Fig. 1). The presence of an adipocyte locus encoding miR-378 contained in the intron of the transcriptional activator Pgc1-β indicates that the expression of miR-378 is also induced in adipogenesis [41]. PGC-1 β is well known to involve in mitochondrial biogenesis, and elevated expression of Pgc1β was concordant with miR-378 expression. MiR-378 was also shown to upregulate the expression of C/ebp-α and C/ebp-β, both of which are adipogenic proliferating and differentiating factors [41]. C/ebp-β further
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MiR-133, is highly expressed in brown fat, SAT, and beige adipocyte, although less enriched compared to skeletal and cardiac muscles [13, 35]. It is one of the most down regulated miRNAs after exposure to low temperature. Cold exposure down regulates miR-133, through its temperature dependent transcriptional activator, Mef-2 [16,35]. Specifically, both isoforms of miR-133; miR-133a and miR-133b are decreased following induction of differentiation in SVF from BAT after cold exposure. Furthermore, inhibition of miR-133 both in vitro [35] and in vivo [21] produced an increase in Ucp-1 expression, constituting a program contributing to cold-mediated upregulation of Ucp-1 expression [35]. MiR-133 directly targets and inhibits Prdm16 expression via a miR133 target site located within 3′UTR in the Prdm-16 transcript in white as well as brown adipocytes [35]. Silencing of miR-133 in vitro through anti-miR-133 is associated with enhancement of Prdm16. In contrast, overexpression of miR-133 completely inhibits Prdm16 expression along with a significantly reduced expression in Ucp-1, Pparα and Ppar-γ levels and an increase in the myogenic regulatory factors including Myg and MyoD expression [35]. These findings imply a key role of miR-133 in brown adipocyte differentiation. Prdm16 and its downstream peptide Ucp-1 are highly expressed in SAT, while expression levels were much lower in VAT [18,19]. In addition, the pre-adipocyte isolated from the SAT contained more miR-133 when compared with VAT precursors, suggesting that the regulation of Prdm16 expression in SAT is primarily mediated by miR-133 [35]. In agreement with this finding, deletion of miR-133a gene results in browning of SAT in vivo, and associates with increased insulin sensitivity and glucose tolerance [21]. These findings suggest an inhibitory role of miR-133 in white fat browning and beige fat differentiation. Taken together, miR-133 plays a central role in regulating Prdm16 and brown adipogenesis after cold exposure in BAT and SAT (Figs. 1 and 2).
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MiR-193b and miR-365 are co-located on chromosome 16 as a cluster during transcription. Both miRNAs are highly expressed in iBAT relative to other tissues and showed significant upregulation during brown adipogenesis of SVF cells from interscapular brown fat. The expression of the miR-193 and miR-365 cluster was also increased in white adipogenesis [32]. Inhibition of either miRNA in preadipocytes from stromal vascular fraction (SVF) during adipocyte differentiation significantly reduced lipid accumulation and adipocyte specific genes, with a more marked reduction in brown fat specific genes such as Ucp-1, Pgc-1α, Prdm16, and Cidea (cell death-inducing DNA fragmentation factor, alpha subunit-like effector A), associated with increased expression of myogenic specific markers [32]. Conversely, forced expression of miR193 or miR-365 in C2C12 myoblast is associated with both white and brown adipogenesis as indicated by increased expression of white and brown marker genes and an inhibition of the entire myogenesis program [32]. Thus, the MiR-193b/365 cluster plays a key regulating role in directing the brown and myogenic lineages (Fig. 1). MiR193b–365 was targeted and upregulated by Prdm16 through direct regulation of another brown adipose enriched marker, Ppar-α. This is a program that controls the lineage determination shift from skeletal myogenesis to brown adipogenesis [35]. The cell signaling pathways through which the cluster regulates the brown fat differentiation are not clear. One possible pathway that miR193 regulates adipogenesis is through a direct inhibition of Runx1t1 (runt-related transcription factor 1; translocate to 1), which is known as a white and brown adipogenesis inhibitor. Blocking of miR-193 was associated with increased Runx1t1, implying that miR-193 induces Ucp-1 expression by inhibiting Runx1t1 [32]. Another possible pathway that miR-93 suppresses myogenesis is through the miR-193-induced down regulation of Cdon (cell adhesion associated, oncogene regulated). Cdon is known to be a cell surface receptor mediating the expression of myogenic proliferation factors and Igfb-5 (insulin-like growth factor-binding protein-5). Furthermore, C/ebp-α as well as Ppar-γ, both adipocyte growth factors, are transcriptionally upregulated by miR-193b. Despite this, controversial findings by Feuermann indicated that the development, differentiation, and function of BAT do not require the presence of miR-193b and miR-365-1 [40].
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expressed in brown preadipocytes and brown adipocytes [32–34]. Due to very limited data available, it is still not clear whether the abundance of these miRNAs is crucial, and in line with their physiological role in brown fat or beige fat differentiation and development [34]. Particularly those rare miRNAs that are expressed at very low level, whether prompting or inhibiting of those miRNAs can actually change the cellular phenotype is undermined.
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induces Ucp-1 expression, leading to a brown adipogenic program shift [41]. This unique instance with miR-378 and miR-378*, which stimulates myogenic differentiation, suggests that the myogenesis and brown adipogenesis programs are simultaneously upregulated [42].
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MiR-106b and miR-93 form clusters and co-locate on chromo280 some 7 [43]. Expression of miR-106–93 was significantly increased 281 in mature brown adipocyte compared to brown preadipocyte [43]. 282 Silencing of miR-106b and miR-93 in differentiating brown adipo283 cytes significantly induced brown fat specific differentiation genes 284 including Ucp-1, Prdm16, Cidea (cell death inducing DNA fragmen285 tation factor), Ppar-α, and Pgc1-α along with brown adipocyte 286 lipid-droplet accumulation [43]. Conversely, Ucp-1 expression was 287 suppressed by ectopic expression of miR-106b and miR-93 in differ288 entiating brown adipocytes. In addition, in high fat diet-induced 289 obese mice, miR-106b and miR-93 expression levels are higher in 290 brown adipose tissues compared to control mice [43]. These data 291 Q13 imply that the miR-106b–93 cluster plays an inhibition role and are 292 negative regulators in brown adipocyte differentiation and energy 293 homeostasis [43] (Figs. 1 and 2). 294
2.8. MiR-27: miR-27 targets brown transcriptional program
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MiR-27 contains highly evolutionarily conserved heptamer or octamer seed motifs within the 3′ untranslated regions (3′UTRs) of Prdm16, Creb, Pparα, and Pparγ [44]. The abundance of miR 27a is enriched in brown fat and WAT, but expression is higher in preadipocyte (SVF) isolated from VAT than SAT. Cold temperature
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suppresses miR-27 expression in brown adipose tissue and white adipose tissue, whereas miR-27 inhibits brown adipogenesis in both cultured cells and primary SAT preadipocytes [44]. The inhibition effect of miR-27 on beige adipogenesis is fully prevented when Ppar-ϒ or Prdm16 is silenced by siRNAs in brown preadipocytes [44]. These findings suggest that the inhibition effect of miR-27 is through a direct suppression on Prdm16, Ppar-α, and Pgc1-β, and an indirect effect on Pgc1-α [44] (Fig. 2). MiR-27, therefore, plays a central role in cold stimulated beige and brown adipogenesis by targeting the downstream transcriptional network [44].
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The abundance of miR-196a is much lower in BAT compared with WAT [45]. This indicates an important role of miR-196a in promoting brite adipocyte differentiation, and its role on brown fat development is modest. The expression levels of miR-196a in the stromal vascular fraction (SVF) of WAT are elevated when stimulated by cold exposure as well as a β3-agonist. In addition, miR-196a targets and suppresses Hoxc 8 (human homeobox protein hoxc8) during brown adipogenesis in WAT progenitor cells [45] (Fig. 2). Hoxc8 is classified as a WAT gene, due to its high expression level in white adipocytes compared to brown adipocytes. It directly suppresses C/ebp-β, another cell fate switch in brown adipogenesis. Although the Hox family of homeobox genes (Hox genes) plays a major role in determining the BAT and WAT differentiations [46,47,45], only Hoxc 8 is known to suppress brown adipogenesis and functions as a gatekeeper during brown adipogenesis induction [47,48]. Suppression of miR-196a in progenitor cells obtained from mouse and human WAT was associated with a down regulation of brown adipocyte markers due to Hoxc 8 up-regulation.
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Conversely, forced expression of miR-196a in mouse adipose tissue increases both BAT mass and energy expenditure through inhibition of the Hoxc-8 expression. A recent study further indicates that C/ebp-β is suppressed by a complex of Hoxc8 and Hdac3 (histone deacetylase 3) via a 3′ regulatory sequence [45]. Thus, MiR-196a induces browning of white adipose tissue through the inhibition of Hoxc-8 [45].
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MiR-26a is the first miRNA studied in human adipocytes. It is highly expressed in BAT. Cold exposure significantly induces miR-26 in WAT 337 [49]. Overexpression of miR-26a or miR-26b in human multipotent 338 adipose-derived stem (hMADS) cells leads to a significant increase in 339 Ucp-1 and Pgc-1α gene expression [49]. hMADS, a very useful model 340 for studying human adipogenesis [49–51], was originally isolated from 341 human adipose tissue [50,52,53]. Treatment with a PPARγ agonist, 342 rosiglitazone, can direct the hMADs to differentiate toward the brown 343 Q16 fat [49]. Interestingly, miR-26a enhances rosiglitazone-induced ‘brow344 ning’ in hMADS, indicating that elevated Ucp-1 abundance induced by 345 miR-26a may result from other downstream target gene besides 346 PPARγ activation. Sheddase Adam metallopeptidase domain 17 347 (Adam17), a tumor necrosis factor-α (TNF-α)-converting enzyme 348 [54], was recently shown to regulate brown fat marker gene expres349 sion [49]. Overexpression of miR-26a in hMADs downregulates 350 Adam17 mRNA, and inhibition of miR-26a/b leads to a significant eleva351 tion of Adam17 at both protein and mRNA expression. In addition, 352 Adam17 knockdown is able to elevate Ucp-1 expression in brite adipo353 cytes and introduce a similar effect on adipogenesis mediated by miR335 336
26a/b. These findings suggest that Adam17 is a direct target of miR-26 introduced white and brite adipogenesis [49]. Ultimately, these findings strongly suggest a key role of the miR-26a/b on human adipocyte differentiation and brown adipogenesis [49]. MiR-26 targets Ucp-1 that is mediated through Adam17 (Fig. 2).
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3. Conclusion and future directions
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MicroRNAs are a class of short, non-coding RNAs that control the expression of various target genes in diverse tissue types throughout the body and are known to play important roles in regulating brown adipocyte adipogenesis. There are 91 miRNAs that have been identified to date to be potentially important for the development of brown adipose tissue [32]. However, the correlation between the abundance level of these identified miRNAs and their roles in regulating brown fat development is still unclear. The important roles of miRNAs in the regulation of brown adipocyte differentiation, development, or brown fat function were studied in only a very small number of miRNAs. Several miRNAs including miR-133, miR-155, miR-193b/365, and miR-455 are known to regulate the differentiation of Myf5 positive mesenchymal precursor cells into skeletal/cardio myoblasts, and further into brown adipocytes [15,36,32,33]. Other microRNAs, including miR-196a, play an important role in inducing functional brown adipocytes in WAT or the browning of white adipocytes [47]. C/ebp-β and Prdm16 act as the master regulator and lead to the upregulation of brown adipogenic genes and inhibition of mesenchymal precursor cells' differentiation into myoblasts. Together, miRNAs mediate counter regulatory programs of brown adipose and myofibril differentiation from the precursor cells through targeting or
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395 Q17 This work is supported by a Central Michigan University starting 396 fund to L.L.
References
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being regulated by these master regulators, suggesting their potential in thermogenesis. It is clear that maintaining elevated daily energy expenditures improves the long term effectiveness of weight loss in obese individuals. This strategy can be achieved by increasing beige or brown adipogenesis, increasing physiological active brown adipocyte numbers, and enhancing recruitment of beige fat cells. Thus, targeting miRNAs in preadipocytes to induce thermogenesis in BAT or WAT is a feasible strategy in treating obesity. Taken together, miRNAs and the related pathways that participated in brown adipogenesis represent important therapeutic targets for the treatment of obesity and type 2 diabetes. Future work should be focused on identifying miRNAs that participate in brown fat adipogenesis and further understanding miRNA-based regulation of brown and beige adipocyte adipogenesis.
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