MINIREVIEW Mechanisms of obesity and related pathologies: Transcriptional control of adipose tissue development Cecile Vernochet, Sidney B. Peres and Stephen R. Farmer Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA Introduction Obesity is a worldwide epidemic and a major contribu- tor to the development of a group of potentially life-threatening conditions referred to as the metabolic syndrome. This syndrome groups together several pathologies that can coexist, including insulin resis- tance, type II diabetes, dyslipidemia, cardiovascular disease, inflammation and some cancers, and all have a strong association with intra-abdominal adipose tissue mass [1]. Consequently, obesity has a significant cost on the well being of society because the incidence of these diseases is expected to double by the year 2030 and the associated healthcare expenditure will be > $100 billion in the USA alone [2,3]. The increased incidence of obesity, particularly in Western society, is considered to be the result of a change in lifestyle (i.e. less exercise) and eating habits (i.e. quantity and quality of food), which leads directly to an increase in adipose tissue mass and a disturbance of metabolism. A principal function of the adipose tissue is to store consumed dietary energy in the form of triglycerides within specialized organelles referred to as lipid drop- lets in adipocytes. This stored energy can be mobilized by activating lipolysis in response to the needs of the organism to supply fuels and nutrients to other organs. Adipose tissue also contributes to whole-body homeo- stasis as an endocrine organ secreting a multitude of Keywords brown adipose tissue; obesity; progenitors; PPAR gamma; white adipose tissue Correspondence S. R. Farmer, Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA Fax: +1 617 638 5339 Tel: +1 617 638 4186 E-mail: farmer@biochem.bumc.bu.edu (Received 25 March 2009, revised 5 August 2009, accepted 13 August 2009) doi:10.1111/j.1742-4658.2009.07302.x Obesity and its associated disorders, including diabetes and cardiovascular disease, have now reached epidemic proportions in the Western world, resulting in dramatic increases in healthcare costs. Understanding the pro- cesses and metabolic perturbations that contribute to the expansion of adi- pose depots accompanying obesity is central to the development of appropriate therapeutic strategies. This minireview focuses on a discussion of the recent identification of molecular mechanisms controlling the devel- opment and function of adipose tissues, as well as how these mechanisms contribute to the regulation of energy balance in mammals. Abbreviations BAT, brown adipose tissue; BMPs, bone morphogenetic proteins; C ⁄ EBP, CCAAT-enhancer-binding proteins; CtBP, C-terminal-binding protein; FACS, fluorescence-activated cell sorting; GFP, green fluorescent protein; PGC1, PPARc coactivator-1; PPAR, peroxisome proliferator-activated receptor; PRDM16, PR domain containing 16; SRC-1, steroid receptor coactivator-1; SVF, stromal vascular fraction; TZD, thiazolidinedione; UCP-1, uncoupling protein-1; WAT, white adipose tissue. FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5729 cytokines and hormones. An excess of food intake can increase fat mass and disrupt energy balance. Recent studies suggest that enlarged adipose tissue suffers from a variety of stresses, most likely as a result of lipotoxicity, hypoxia and low-grade chronic inflamma- tion [4]. The fat tissue responds to stress by repro- gramming its normal functions, comprising a change in the level and nature of the secreted adipokines and mobilization of stored lipids that are released into the circulation as free fatty acids, leading to lipotoxicity within other metabolic tissues. These responses are further exacerbated by the proliferation and differenti- ation of preadipocytes and possibly progenitor cells within adipose depots providing more adipocytes for hypertrophic expansion. This review discusses the mechanisms controlling the formation and function of adipose tissue and how these processes might be altered by various therapeutic interventions to correct the energy imbalances resulting from obesity. Location and function of the white and brown depots Adipose tissue is the most abundant tissue in humans, representing approximately 10–29% of body weight. It is found in a multitude of locations and consists of two major forms: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT is the main site for the storage of energy in the form of triglycerides located in large lipid droplets that occupy most of intracellular space of the many adipocytes distributed throughout the tissue. BAT, on the other hand, usually consumes energy to produce heat by catabolizing lip- ids; consequently, brown adipocytes store fewer trigly- cerides within small lipid droplets. WAT is mainly divided into two groups with distinct functions: sub- cutaneous (buttocks, thighs and abdomen) and intra-abdominal ⁄ visceral fat (omentum, intestines and perirenal areas) [5]. Each of these depots express important differences in their function stemming from a different pattern of gene expression [6]. Such func- tional differences appear to contribute to their particu- lar involvement in the development of the various pathologies associated with obesity. Specifically, lipid turnover in visceral WAT is faster than that in subcu- taneous compartments, thereby allowing a constant release of non-esterified fatty acids into the circulation. This turnover results from a high catecholamine-stimu- lated lipolysis and a reduction in the response to the anti-lipolytic activity of insulin. Additionally, visceral and subcutaneous adipose tissues secrete different patterns of adipokines and inflammatory cytokines in which the visceral depot tends to be significantly more inflammatory than the subcutaneous depot [7]. It is likely that the expansion of a particular WAT depot will predict the metabolic outcome of an individual as they become obese. Indeed, it is well known that not all obese individuals with the same body mass index become insulin resistant or develop type 2 diabetes or cardiovascular disease. Obese (i.e. metabolically healthy obese) subjects who usually accumulate the excess fat subcutaneously in the lower body (gynoid type of obesity) are metabolically healthy. However, other individuals (i.e. metabolically obese normal weight) with near normal body mass index are meta- bolically obese because they express many of the abnormalities associated with the metabolic syndrome. In some less common cases, individuals with lipodys- trophy, which results in a partial to almost complete loss of body fat, are highly prone to developing insulin resistance and associated diseases. There is a dearth of knowledge concerning the genetics and associated molecular mechanisms giving rise to such extremes of fat deposition within the population. Consequently, attempts to understand these processes will undoubt- edly contribute to strategies aiming to combat obesity and related dislipidemias. Much of our understanding of the involvement of adipose tissue in the metabolic syndrome has focused on white depots, as outlined above. Recent observa- tions of patients undergoing screening for various cancers have identified BAT in adult humans [8] that also likely influences energy balance and therefore contributes to the development of metabolic diseases. BAT is significantly more vascularized than WAT, and brown adipocytes contain abundant mitochon- dria to facilitate the catabolism of lipids through mitochondria-based b-oxidation; these features contribute to the red–brown color of the depot [5]. In rodents, BAT is mainly concentrated within the interscapular regions throughout adult life, whereas, in humans, it exists within these regions during fetal and neonatal periods of development. Indeed, until the recent discovery of BAT in adult humans, it was assumed that the absence of interscapular BAT meant that adults lack brown fat. However, the use of [ 18 F]-2-fluoro-d-deoxy-d-glucose positron emission tomography for metastatic cancer screening has iden- tified metabolically active BAT depots in the cervical, supraclavicular, axillary and paravertebral regions of adult humans [8–11]. BAT appears to be more fre- quent in women than in men, is inversely correlated with the body mass index, and can be activated by cold exposure. Even though the contribution of BAT to adult physiology is still unclear, the recent discovery that BAT exists in a significant amount in Control of adipose tissue development C. Vernochet et al. 5730 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS humans should stimulate renewed interest in under- standing its formation and function. Differentiation of white and brown preadipocytes Changes in adipose tissue mass as a result of genetic and environmental factors involve both hyperplasia (i.e. an increase in adipocyte number) and hypertrophy (i.e. an expansion of adipocyte volume as a result of the accumulation of lipids). Consequently, knowledge of the origin and molecular control of adipocyte progenitor commitment is important for our under- standing of what controls the expansion of fat mass in different individuals. Moreover, it is also important to understand the origins of each of the different white and brown depots because it appears that not all depots are equal as far as their involvement in the metabolic syndrome. White and brown adipocytes form during the differ- entiation of white or brown preadipocytes arising from mesenchymal stem cells located at different sites in the developing organism. Preadipocyte differentiation (adi- pogenesis) is regulated by a plethora of extracellular and intracellular signaling molecules and transcription factors that are common to both white and brown lineages, as well as specific to a particular type of prea- dipocyte [12]. Both white and brown adipogenesis is initiated by the activation of a cascade of transcription factors whose principal function is to induce the expression of peroxisome proliferator-activated recep- tor (PPAR)c and CCAAT-enhancer-binding protein (C ⁄ EBP)a, which are the master regulators of genes coding for the shared functions of white and brown adipocytes, including lipid and glucose metabolism, mitochondrial biogenesis and the production of adipo- kines [13–15]. PPARc is a member of the nuclear hormone receptor superfamily whose transcriptional activity is regulated by binding to appropriate ligands, which includes derivatives of fatty acids and synthetic lipophilic molecules employed as potent therapeutics for the treatment of insulin resistance, most notably the thiazolidinediones (TZDs), rosiglitazone and piog- litazone [16]. CEBPa cooperates with PPARc to elicit a positive-feedback loop that maintains the expression of both genes in the mature adipocyte and facilitates the expression of multiple proteins regulating insulin sensitivity, including the insulin-dependent glucose transporter GLUT4 and the insulin-sensitizing hor- mone, adiponectin [13]. Indeed, two recent studies demonstrate that the mechanisms by which PPARc and C ⁄ EBPs (C ⁄ EBPb and C ⁄ EBPa) cooperatively orchestrate adipocyte formation and function involve the binding to a large (> 3000) overlapping set of target genes [17,18]. The formation of brown adipocytes requires the expression of an additional set of transcriptional regu- lators that are absent or expressed at very low levels in white preadipocytes ⁄ adipocytes. These include two coregulators of transcription factors, a zinc finger pro- tein, PR domain containing 16 (PRDM16) and PPARc coactivator-1 (PGC-1)a [19,20]. Another member of the PGC-1 family, PGC-1b, is also expressed in white adipocytes, but appears to provide a function in asso- ciation with PGC-1a that is required for brown cell formation. The PGC1 transcriptional coactivators are major regulators of many aspects of oxidative metabo- lism, including mitochondrial biogenesis and respira- tion in oxidative tissues, such as cardiac and skeletal muscle and the liver, as well as brown adipocytes [21]. Mice deficient for PGC-1a expression are cold sensitive partly because of absence of uncoupling protein-1 (UCP-1), a proton transporter in brown adipocyte mitochondria that uncouples electron transport from ATP production, allowing the energy to dissipate as heat. Brown preadipocytes that lack PGC-1a are capa- ble of differentiating into brown fat cells as defined by enhanced mitochondrial biogenesis and the production of brown cell markers (i.e UCP-1), but they cannot induce thermogenesis in response to cAMP. Brown preadipocytes lacking both PGC-1a and PGC-1b are capable of forming adipocytes based on the accumula- tion of lipid droplets and the expression of genes com- mon to both white and brown fat function. They do not, however, produce brown-selective genes involved in mitochondrial biogenesis and function [22]. PGC-1b is expressed in white adipocytes and its absence might prevent the expression of some unknown function of white adipocytes. PGC-1 coactivators appear to regu- late the expression of genes involved in mitochondrial biogenesis and thermogenesis by coactivating several different transcription factors, including nuclear respi- ratory factors 1 and 2, PPARc and estrogen-related receptora. PRDM16 is highly expressed in brown adipocytes and absent from white adipocytes. It is required for brown adipocyte differentiation but is also expressed in other tissues [19]. Ectopic expression of PRDM16 in white adipocytes in culture or white depots in mice induces a program of gene expression, as well as mito- chondrial biogenesis and lipid metabolism consistent with the brown phenotype. Similarly, its knockdown in brown fat cells ablates their brown characteristics. PRDM16 appears to function by directing the PGC-1 coactivators to their target transcription factors docked on promoters ⁄ enhancers of genes controlling C. Vernochet et al. Control of adipose tissue development FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5731 the brown phenotype. Additionally, other studies sug- gest that PRDM16 also functions to repress select white adipocyte genes that are produced at very low levels in brown adipocytes [23]. Earlier studies have also suggested a role for the p160 family of coactiva- tors [steroid receptor coactivator-1 (SRC-1) and tran- scriptional intermediary factor-2 (TIF-2)] in regulating brown versus white adipocyte formation [24]. The data obtained in these studies are consistent with a role for SRC-1 in coactivating PPARc ⁄ PGC-1a to enhance the expression of brown target genes most notably UCP-1. Transcriptional intermediary factor-2 appears to atten- uate the activity of SRC-1 and thereby favors a white phenotype. It is therefore likely that mechanisms directing the differentiation of white or brown prea- dipocytes will produce the appropriate levels of these two coactivators in accordance with the eventual phenotype. It appears that the maintenance of the white pheno- type involves an active repression of brown genes in addition to the lack of the coactivators PGC-1a and PRDM16. Most notably, RIP140 (a ligand-dependent repressor of nuclear receptors), comprising a global negative regulator of genes controlling mitochondrial biogenesis, is highly expressed in WAT compared to BAT [25]. Knockout of RIP140 in mice leads to a lean phenotype as a result of a 70% reduction in total body fat present in the white depots but with the same num- ber of smaller adipocytes relative to controls and no change in food consumption [26]. The mice are also resistant to diet-induced obesity and appear to oxidize the consumed fat rather than storing it. Indeed, the suppression of RIP140 in white adipocytes by small interfering RNAs leads to a significantly enhanced expression of genes coding for mitochondrial functions such as thermogenesis and the b-oxidation of lipids [27,28]. The gene silencing activity of RIP140 involves an association with additional corepressors, including the NADH-dependent C-terminal-binding proteins (CtBPs) [25], which have recently been shown to facili- tate the repressive activity of PRDM16 [23] in brown adipocytes as well as that of C ⁄ EBPa in white adipo- cytes [29]. The precise role of CtBPs in regulating brown versus white adipocyte formation, however, remains unclear. Other regulators of white versus brown adipogenesis include the retinoblastoma protein Rb and its pocket protein family member p107 [30,31]. The suggestion that pocket proteins might negatively regulate brown adipocyte formation came from the fact that SV40 large T antigen, which binds to Rb, promotes the formation of brown adipocytes subsequent to its expression in white preadipocytes. Indeed, the disrup- tion of the Rb gene in white preadipocytes facilitates their differentiation into brown adipocytes, in part by enhancing PGC-1a expression and activity. Addition- ally, p107 ) ⁄ ) mice contain a significantly reduced white fat mass with no change in the mass of the interscapu- lar brown depot. The adipocytes present in the p107 ) ⁄ ) WAT contain smaller lipid droplets and more mitochondria, and express higher levels of UCP-1 and PGC-1a and lower levels of Rb. The role of these various transcription factors and nuclear factors is highlighted in Fig. 1. Developmental origin of WAT and BAT Fat depots are composed principally of two compart- ments, the stromal vascular fraction (SVF) and adipo- cytes filled with lipids. The SVF contains adipocyte precursors, preadipocytes, vascular cells such as endo- thelial and pericytes, as well as immune cells. The SVF is considered to be a source of adipocyte precursors because of the presence of cells within this fraction with the capacity to differentiate into adipocytes in vitro. Until recently, white and brown adipocytes were believed to arise from a common mesodermal progenitor, although recent studies employing lineage tracer techniques have started to identify progenitors specific for white versus brown depots. Some white adipocytes come from the neural crest, which derive from the neuroectoderm and can migrate to different regions during embryonic development. In vivo,it appears that only adipocytes in the cephalic region derive from the cranial neural crest [32] and that the other major depots have a separate developmental origin. It is very likely that the subcutaneous versus visceral white depots have distinct origins because they each express a unique pattern of developmental genes. Specifically, subcutaneous fat in both rodents and humans displays higher levels of En1 (engrailed 1), Shox2 and sfrp2, whereas intra-abdominal adipocytes express higher levels of Nr2f1 (COUP-TFI), HoxA5 and HoxC8 [6]. Recent studies have also highlighted the role of pericytes as progenitors of white adipocytes. Pericytes derived from the sclerotome (mesodermal origin) are an integral part of the microvasculature and are involved in a number of different processes, including angiogenesis and vasculogenesis [33]. Their source as potential stem cells for adipocytes in vitro and in vivo, as well as chondrocytes, osteoblasts and smooth muscle cells, has already been reported [34,35]. A recent study by Graff and colleagues [36] employing the upstream region of the PPARc gene to direct the expression of reporter genes in a series of elegant in vivo fate mapping investigations demonstrated that Control of adipose tissue development C. Vernochet et al. 5732 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS some white adipocytes arise from the mural compart- ment of blood vessels supplying adipose depots. Specif- ically, Graff and colleagues [36] generated a transgenic mouse in which the upstream region of the PPARc gene containing the promoters for both PPARc1 and PPARc2 was used to direct the expression of a doxicy- cline-repressible transactivator (Tet-off tTA). Using this mouse (PPARc-tTA), two further strains of trans- genics were generated. In one case (LacZ mouse), two additional alleles corresponding to a tTA-responsive Cre recombinase (TRE-Cre) and an allele (ROSA26- flox-stop-flox-lacZ) that indelibly expresses LacZ (b-galactosidase) in response to Cre activity were intro- duced. The generation of the other mouse [green fluorescent protein (GFP) mouse] involved the intro- duction of a TRE-H2B-GFP allele into the PPARc- tTA background to create a proliferation sensitive GFP reporter of PPAR c promoter activity. Conse- quently, the activation of the adipogenic-specific PPARc promoters during the development of adipo- cyte progenitor cells in the LacZ-mouse produced Cre that indelibly marked the cells with LacZ. LacZ expression can be repressed by doxicycline. If doxicy- cline was given to the mice after the expression of the PPARc-Cre gene, then the marked cells continued to produce LacZ because of the indelible nature of the system (ROSA26-flox-stop-flox-lacZ). In the other GFP mouse, activation of the PPARc promoters induced tTA, leading to production of GFP. Exposure to doxicycline after the initial developmental activation of the transgenic PPARc gene blocked GFP expression and the cells lost their GFP through dilution accompa- nying proliferation. If the marked cells became quies- cent, they continued to produce GFP and remained marked. To analyze the rapid and extensive expansion of the adipose lineage during the first postnatal 30 days (P30), Graff and colleagues [36] treated the LacZ-mice with doxicycline at different days during this developmental period. They observed homoge- neous lacZ expression in P30 white adipose depots that was not significantly diminished even when doxicycline was given to the mice during the first few postnatal days. These data suggest strongly that the majority of P30 adipocytes arise from a pre-existing, perinatal pool of PPARc-expressing cells (either adipocytes or prolif- erating progenitors). To determine whether these pre- existing cells were proliferating progenitors, the GFP mice were exposed to doxicycline between days P2 and P30 or allowed to mature to day p30 without any exposure. The adipose depots of the untreated mice expressed GFP, whereas those mice that were treated with doxicycline as early as P2 showed a marked reduction in GFP expression in both adipose depots and adipocytes. Taken together, the data obtained by Graff and colleagues [36] show that a pool of white adipocyte precursors is established perinatally and can proliferate. Additional studies also revealed that a progenitor pool continues to exist into adulthood for self-renewal during growth. Furthermore, fluorescence- activated cell sorting (FACS) isolation of the GFP-expressing progenitor cells from the stromal vas- cular fraction of adipose depots showed an adipogenic White Brown PRDM16 pR b C/EB P β C/EB P δ Ligands PGC1 α α TIF2 p107 RX R PP AR γ γ PRDM16 C/EBP α α PGC1 β β SRC1 RIP140 TIF2 RX R α PP AR PRDM16 CtBP1/ 2 CtBP1/ 2 C/EBP α α C/EBP α α TZD Mitochondria bi i Mitochondria bi TZD « White » « White » Lipogenesi s Insulin sensitivity Adipokine s ogene s i s Thermogenesis (UCP1) Lipids β−oxidation biiogenesis Thermogenesis (UCP1) Lipids β−oxidation gene s gene s Fig. 1. Transcription factors and nuclear reg- ulators controlling the expression of genes responsible for white versus brown adipo- cytes. White and brown adipocyte differenti- ation shares a common transcription cascade that leads to a lipogenic ⁄ lipolysis function and insulin sensitivity (central cas- cade). PRDM16, PGC1a and PGC1b induce the brown phenotype (mitochondria biogen- esis and thermogenic function) within brown adipocytes (right), whereas these functions are repressed by RIP140 and Rb within white adipocytes (left). On the other hand, CtBP1 ⁄ 2 represses a set of genes expressed at a higher level in white adipo- cytes (called ‘white’ genes) by interacting with PRDM16 in brown adipocytes (right) and with C ⁄ EBPa in white adipocytes upon TZD treatment (left). C. Vernochet et al. Control of adipose tissue development FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5733 potential in vitro. This same pool expressed a set of markers consistent with them belonging to the mural cell compartment including Sca-1, CD34, smooth mus- cle actin and platelet-derived growth factor b. These progenitors only existed in the vasculature of adipose tissue, and not in other organs, demonstrating that this population of mural cells is specifically committed to adipocyte lineage. A complementary series of studies performed by Friedman and colleagues [37] identified a subpopula- tion of early adipocyte progenitor cells (Lin): CD29+:CD34+:Sca-1+:CD24+) resident in the SVF of adult WAT with a significantly enhanced adi- pogenic potential over other cells isolated from the SVF. Engraftment of CD24+ cells is sufficient to restore a functional white depot in lipodystrophic mice and, in doing so, is sufficient to restore blood glucose levels to those of wild-type mice. These inves- tigators also isolated CD24+ cells from a transgenic mouse expressing a luciferase cDNA under the control of the adipocyte-specific leptin promoter. By visualiz- ing luciferase activity, they could monitor the develop- ment of newly-formed adipose tissue without invasive surgery. These CD24+ precursors failed to differenti- ate when engrafted into WAT pad of wild-type mice fed a normal diet. By contrast, when recipient wild- type mice were fed a high fat diet, luciferase activity was detected in three out of eight mice, suggesting that the local environment facilitates the recruitment and differentiation of the newly forming CD24+ adipocyte population. Interestingly, Friedman and colleagues. [37] have identified two populations of cells by FACS within the SVF depot that express dif- ferent levels of adipogenic potential based on the in vitro and in vivo expression of different adipocyte genes. The presence of at least two different popula- tions of adipocyte precursors within a white depot has also been reported in others studies, including those conducted in young donors in which the populations within the same SFV were dissociated from each other by their different adhesion properties. Even though the fast- and slow-adherent cells showed adipocyte differentiation capacity ex vivo, the fast- adherent one showed higher proliferation properties and potential therapeutic values [38,39]. Identifying precursors by FACS, giving them an identity card, and subsequently sorting them out, provides a power- ful tool for studying their function and properties with respect to therapeutic purposes. In the case of brown adipose development, Timmons et al. [40] reported that brown adipocyte precursors express a pattern of gene expression that overlaps with cells of myogenic origin. Recent fate mapping studies using the myogenic-specific promoter myf5 as the line- age tracer demonstrated that brown adipocytes and skeletal muscle share a common myf5 + progenitor that originates from dermomyotome [41]. Additionally, studies by Atit et al. [42] showed that some interscapu- lar brown fat bundles originate from cells of the dermomyotome that express En1. This close relation- ship between the myocyte and the brown adipocyte is consistent with both cell types expressing a common set of phenotypic characteristics, including specializa- tion for lipid catabolism requiring abundant mitochon- dria. Moreover, the dermomyotomal origins of brown adipocytes clearly reveal that they have a distinct developmental origin that is separate from the scle- rotomal (pericytes) origin of white adipocytes. It is also interesting that brown adipocytes found within white depots do not appear to arise from myf5-con- taining progenitors [41]. These brown adipocytes might develop by some unknown reprogramming of the white progenitors or transdifferentiation of white prea- dipocytes into brown adipocytes. The various lineages that give rise to the different adipose tissues are shown in Fig. 2. As descriptive as these fate mapping studies may be, they have the potential to provide powerful tools for identifying the genes and signaling pathways responsi- ble for the acquisition of different phenotypes in sub- cutaneous versus visceral depots. For example, the expansion of the visceral fat depot appears to be a more potent trigger for development of the metabolic syndrome than expansion of the subcutaneous depot. Understanding the mechanisms by which visceral adipocytes can express a more subcutaneous or brown phenotype should aid in the development of anti- obesity therapeutics. Recent lineage tracing studies suggest that both white and brown adipocytes originate from mesenchymal stem cells arising at a very early stage of development of the epithelial somite. A critical event within the somite is an epithelial–mesenchymal transition that facilitates forma- tion of the sclerotome and the dermomyotome ⁄ myotome. Brown adipocytes likely arise from myf5 + progenitor cells of the dermomyotome that also produce skeletal muscle, whereas white adipocytes arise from mural cells (pericytes) that originate in the sclerotome. The development of mesodermal tissues is controlled by a conserved set of embryonic signaling pathways, including bone morphogenetic proteins (BMPs), wing- less (Wnt), and nodal and fibroblast growth factors [6]. Recent studies suggest that these pathways might have a role in directing the formation of WAT and BAT during development. The most notable of these adipogenic effectors are members of the BMP family of transform- Control of adipose tissue development C. Vernochet et al. 5734 FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS ing growth factors. Many mouse models lacking either ligands, receptors or components of BMP signaling have been developed that show defects in mesodermal forma- tion [43]. Certains BMPs, in particular BMP2 and BMP4, enhance white adipogenesis in the presence of select hormones [44], whereas BMP7 appears to play a key role in the determination of BAT [45]. BMP7 knock- out embryos show a reduced brown fat pad mass and almost no UCP-1 expression. The adenoviral-mediated expression of BMP7 in mice results in a specific increase in brown but not white fat, leading to weight loss and an increase in energy expenditure [45]. Adipose tissue remodeling and the redistribution of lipids between the different white and brown depots A potential strategy for combating the negative health consequences of too much stored lipid in the visceral adipose depots is to redirect storage to the subcutane- ous compartment. Additionally, reprogramming vis- ceral depot gene expression to resemble the subcutaneous depot might also reduce pathologies associated with the enlarged visceral fat mass, without necessarily needing to mobilize the stored lipid. Indeed, the activation of PPARc in vivo by treatment of humans or mice with the TZD family of PPARc ligands causes a redistribution of lipid from visceral to subcutaneous fat [46]. A preferential increase in glu- cose uptake and intracellular metabolism in subcutane- ous fat contributes to the redistribution of triglycerides from visceral to subcutaneous in response to PPARc ligands [47]. A recent study in rats treated with the non-TZD PPARc agonist demonstrated that the tri- glyceride-derived lipid uptake and lipoprotein lipase activity in interscapular brown and subcutaneous inguinal fat depots are higher than those rates deter- mined in visceral tissues [48]. Thus, the activation of PPARc increases the metabolic activity of subcutane- ous depots. Another anti-obesity therapy would be to enhance the contribution of BAT to overall lipid metabolism. This could involve the redirection of consumed energy such as glucose and lipids to already existing BAT for catabolism rather than anabolism in white depots. This might require the selective activation of glucose and lipid metabolism in brown adipocytes. In this regard, recent studies have demonstrated that rosiglitazone enhances rat BAT lipogenesis from glucose without altering glucose uptake [49]. The most beneficial strat- egy, however, would be to increase the amount of BAT relative to WAT. It is well known that brown adipocytes can emerge within white depots in response to a variety of stimuli, including catecholamines, cold exposure, diet and PPARc ligands [14,50], although whether this adaptive response is sufficient to signifi- cantly alter energy balance in obese individuals is unclear. The recent discovery of BAT in adult humans presents investigators with the new challenge of how to increase its mass and ⁄ or activity as a part of an anti-obesity therapy. Additional knowledge of the molecular mechanisms controlling the formation of all adipose depots will contribute to the goal of combat- ing obesity and its associated disorders. Sclerotome PPARγ + Neural crest sox10 + Other MSC? Dermomyotome Myf 5 + Other MSC? ? White progenitors Brown progenitors Pericyte PDFβ +, CD34 + Myoblast Nr2f1, HoxA5, HoxC8 En1, Shox2, sfrp2 ? Subcutaneous WAT Visceral WAT Facial WAT BAT Muscle Brown-like adipocyte ? Myf 5 - Myf 5 + Fig. 2. Putative stem cell lineages that give rise to white and brown adipose depots, highlighting the complexity of the origins of adipose tissues. A common precursor cell expressing myf5 + gives rise to both brown adipocytes and skeletal muscle. Brown adipocytes that can arise within white adi- pose depots are myf5 ) , demonstrating that a bridge between the white and brown line- age is possible either during the progenitor phase or at the differentiated phase. On the other hand, different white depot progeni- tors (visceral and subcutaneous) express dif- ferent developmental genes and some facial WAT can originate from the neural crest. C. Vernochet et al. Control of adipose tissue development FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5735 References 1 Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, Van Pelt RE, Wang H & Eckel RH (2008) The metabolic syndrome. Endocr Rev 29, 777–822. 2 Alberti KG (1997) The costs of non-insulin-dependent diabetes mellitus. Diabet Med 14, 7–9. 3 Hogan P, Dall T & Nikolov P (2003) Economic costs of diabetes in the US in 2002. Diabetes Care 26, 917–932. 4 Gregor MG & Hotamisligil GS (2007) Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48, 1905–1914. 5 Cinti S (2005) The adipose organ. 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Control of adipose tissue development FEBS Journal 276 (2009) 5729–5737 ª 2009 The Authors Journal compilation ª 2009 FEBS 5737 . MINIREVIEW Mechanisms of obesity and related pathologies: Transcriptional control of adipose tissue development Cecile Vernochet, Sidney B. Peres and Stephen R. Farmer Department of Biochemistry,. directing the formation of WAT and BAT during development. The most notable of these adipogenic effectors are members of the BMP family of transform- Control of adipose tissue development C. Vernochet. to understand these processes will undoubt- edly contribute to strategies aiming to combat obesity and related dislipidemias. Much of our understanding of the involvement of adipose tissue in