regulation of adipocyte differentiation

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+ SPECIAL SECTION: MOLECULAR MECHANISMS IN OBESITY AND VISCERAL OBESITY +

Regulation of adipocyte differentiation Hana Koutnikova and Johan Auwerx

Once multipotent mesechymal cells become committed t o the adipoblast lineage, adipogenesis, the process o f preadipocytes differentiation into adipocytes is initiated. This process starts with a phase o f exponential growth o f adipoblasts. Following confluence o f these adipoblasts, the cells enter into a cell cycle arrest, they re-enter the cell cycle and pass through a limited number o f cell divisions, and finally differentiate into ful ly mature adipocytes. Adipogenesis is controlled by a complex cross-talk between positive and negative regulators, such as hormonal and nutritional stimuli, that change the activity o f a selected set o f transcription factors. Regulation o f adipogenesis is crucial t o keep the body energy balance because a limited amount o f adipose tissue, lipodystrophy, or an excess o f adipose tissue, such as occurs in obesity, lead t o profound metabolic dysfunctions and disease.

Keywords: adipocyte; differentiation; regulation; transcription.

Ann Med 2001; 33: 556-561.

Introduction

Mesenchymal stem cells are the precursors for three distinct cell lineages: adipocytes, myocytes and chondrocytes. The process in which such pluripotent mesenchymal cells give rise to adipoblasts is known as lineage determination, while the process of transition from preadipocytes to adipocytes is referred to as adipocyte differentiation. Following exponential growth of precursors, and at the moment of confluence, preadipocytes enter into a cell cycle arrest. To start the terminal phase of adipocyte differentiation, cells re-enter the cell cycle and undergo a limited number of cell divisions known as the clonal expansion of preadipocytes. Terminal differentiation is then

~~

From the lnstitut de Genetique et de Biologie Molkculaire et Cellulaire (IGBMC), CNRSIINSERM, Universite Louis Pasteur, Illkirch, CU de Strasbourg, France.

Correspondence: Johan Auwerx, MD, IGBMC, PO Box 163, 67404 Illkirch, France. E-mail: [email protected], Fax: +33 388 653201.

characterized by rounding up of the fibroblast-like preadipocytes and accumulation of lipid vacuoles.

Our current understanding of transcriptional regulation of adipogenesis is primarily based on in vitro studies with different white preadipocyte cell lines such as the mouse cell lines 3T3-L1, 3T3-F442A and Ob17. These preadipocytes, when cultured in the presence of methylisobutylxanthine, dexamethasone, insulin and fetal serum, differentiate into mature adipocytes. These cell lines induced to differentiate in vitro do not, however, recapitulate the complexity of adipose tissue development because this tissue is composed not only of white and brown adipocytes, but also of vascular endothelial cells, smooth muscle cells, fibroblasts, local mast cells and macrophages. In addition, adipose tissue differs in its adipogenic potential and lipolytic response depending on its regional distribution.

Transcriptional regulation of early phases of adipogenesis

The mechanisms that regulate the switch between cell growth and differentiation in the adipogenic lineage are not yet completely elucidated; however, some molecular factors have been identified recently.

Cell cycle regulators

The appropriate cell cycle regulation is critical for the mitotic clonal expansion phase and is assured by the coordinated action of the E2F transcription factors and the family of retinoblastoma proteins. The E2F family of transcription factors are DNA-binding proteins that bind as a heterodimeric complex composed of an E2F protein and a DP protein (1, 2). E2F proteins are not only important to drive the re-entry into the cell cycle, but they also induce peroxisome proliferator activated receptor (PPAR)y expression early during the clonal expansion phase of adipocyte differentiation. Recently, our laboratory identified an E2F response element in the promotor of PPARyl gene, which is a key player in regulating downstream

www.annmed.org 0 The Finnish Medical Society Duodecim, Ann Med 2001; 33: 556-561

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REGULATION OF ADIPOCYTE DIFFERENTIATION 557

events in adipocyte differentiation (L Fajas, J Auwerx, unpublished observation, IGBMC, 2001). Interaction with hypophosphorylated retinoblastoma protein (Rb) or other pocket proteins (p107, p130) inhibits the action of E2F-DP heterodimers in the G, phase of cell cycle. This inhibitory effect is relieved once the pocket proteins are phosphorylated by cyclin-dependent kinase (cdk) ( 3 ) , which occurs early during adipocyte differentiation (4). The active E2F-DP heterodimer is inhibited by a feedback loop by ligand-activated PPARy through a decrease in gene expression of the serine-threonine phosphatase PP2A which increases the phosphorylation of DP-1 (5).

Interestingly, the Rb protein plays a dual role in cell cycle withdrawal and differentiation (6). First, Rb inactivation initially enables clonal expansion by stimulating E2F activity, whereas subsequent growth arrest after this expansion phase requires active Rb positively influencing adipocyte differentiation (6). In addition to these effects on the cell cycle, Rb binds to and stimulates the activity of the CCAATIenhancer binding proteins a and p (CIEBPa and p), which are the key downstream transcription factors implicated in terminal adipocyte differentiation (7).

The permanent exit from the cell cycle establishes the irreversible commitment of cells to undergo terminal adipocyte differentiation, and this transition is characterized by changes in gene expression of cdk inhibitors (cdkI) p18, p21 and p27 (8) . In the case of p21, PPARy may be responsible for this direct regulation (8) .

Antiadipogenic regulators

Induction of the early phases of adipogenesis requires a decreased activity of a number of antiadipogenic factors, which in general seem to block the induction of the transcriptional activity of PPARy and CIEBPa. The Wnt family of paracrine and autocrine factors, which signal through Frizzled seven-transmembrane receptor, have a critical role during adipogenesis. Activation of the Wnt signalling pathway blocks p- catenin degradation, resulting in p-catenin translocation into the nucleus and its association with the T-cell factor/lymphoid-enhancer factor (TCFILEF) transcription factors, which then regulate the expression of Wnt target genes. In preadipocytes, Wnt signalling maintains the cells in undifferentiated state through inhibition of CIEBPa and PPARy expression (9) . A decrease in Wnt signalling allows initiation of adipogenesis, and this can even cause a transdifferentiation of myoblasts into adipocytes (9) . The GATA-2 and GATA-3 are other transcription factors the down- regulation of which releases a direct suppression of PPARy and is also a prerequisite for the terminal differentiation (10). Retinoic acid (RA) also inhibits adipogenesis by blocking the induction of C/EBPa

Key message

Regulation o f adipogenesis is crucial to keep the body energy balance because a limited amount of adipose tissue, lipodystrophy, or an excess o f adipose tissue, such as occurs in obesity, both lead to profound metabolic dysfunctions and disease.

and PPARy (11, 12). This negative regulation of C/ EBPa and PPARy expression is mediated by the retinoic acid receptor (RAR) as a consequence of interference with CIEBPP action. In addition, RA can inhibit PPARy target gene induction by favouring the formation of the nonpermissive RARhetinoid X receptor (RXR) heterodimer over the PPAR/RXR dimer (13). Another player is Pref-1 (preadipocyte factor-1), a plasma membrane six epidermal growth factor repeats domain-containing inhibitor of adipocyte differentiation that is highly expressed in 3T3-Ll preadipocytes (14). Its gene expression is repressed by a synthetic glucocorticoid, dexamethasone, which is an adipogenetic agent (15). Pref-1 is proteolytically processed to generate an inhibitory soluble form with a molecular weight of 50 kDa (16). Finally, the tumour necrosis factor alpha (TNF-a) reverses adipocyte differentiation and inhibits adipogenesis by down-regulating the expression of PPARy and CIEBPa (17, 18).

The adipocyte enhancer binding protein (AEBP)l is a transcriptional repressor with carboxypeptidase activity (19) that is down-regulated during adipogenesis. AEBPl binds the y5 subunit of a hetero- trimeric G protein, and this interaction leads to a decrease in AEBPl transcriptional repression (20). In addition, AEBPl binds to mitogen-activated protein kinase (MAPK) while probably serving as a nuclear anchor for the MAPK nuclear accumulation (21). As a consequence, the nuclear accumulation of MAPK may modify phosphorylation status of different transcription factors and define the genes to be switched on, thereby influencing cell growth and differentiation in the adipogenic lineage. The effects of MAPK on adipogenesis are, however, more complex. The insulin- like growth factor (1GF)-I stimulates mitogenesis in proliferating preadipocytes, but when cells reach confluence and become growth arrested, IGF-I stimulates differentiation into adipocytes. IGF-I signals through the IGF-I receptor-mediated tyrosine phosphorylation of Shc leading to MAPK activation, and this activation is lost as preadipocytes begin to differentiate (22). Thus the down-regulation of MAPK activity is in this case linked to the switch leading to adipocyte differentiation.


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558 KOUTNIKOVA AUWERX

Proadipogenic factors in the early phase of adipocyte differentiation

In addition to insulin or glucocorticoids, few proadipogenic factors are known. Notch-1 is one of these positive regulators of adipogenesis. It is a transmembrane receptor for epidermal growth factor-like proteins that plays a role in cell-to-cell signalling during adipocyte differentiation. An inhibition of its expression leads to a decrease in the PPARy and 6 expression (23). Also, the extracellular leukaemia inhibitory factor (LIF) and its receptor play a positive role during adipocyte differentiation of embryonic stem cells as LIF stimulates expression of the early adipogenic transcription factors C/EBPP and C/EBP6 via the MAPK cascade (24).

Transcriptional regulation of terminal differentiation

In contrast to these early phases of adipogenesis, the terminal phase of adipogenesis is relatively well understood, and the key players in this process are the family of C/EBP transcription factors, PPARy, and the basic helix-loop-helix factor adipocyte determination and differentiation factor l/sterol regulatory element- binding protein l c (ADDUSREBPlc). The C/EBPs belongs to the basic-leucine zipper class of transcription factors, which are composed of C-terminal leucine zipper dimerization domain and a basic DNA- binding domain. Four members of the family, C/ EBPa, p, 6 and CHOP-10 (C/EBP homologous protein-lo), are expressed during adipogenesis, and each plays a distinct role (25-27). CEBP p and 6 are expressed early in adipogenesis and play critical roles in initiating the terminal phase (28). In vzvo, in double C/EBPP and 6 knock-out embryos a defect in differentiation of preadipocytes to adipocytes is observed. Only about one-fourth of these animals survive to adulthood having impaired adipogenesis and by consequence reduced fat mass (29). Two important downstream genes of C/EBPP and 6, ie CIEBPa and PPARy, however, are still normally expressed in these animal models. The transcriptional activity of C/EBPP is positively regulated by a direct interaction with high-mobility group I nonhistone chromosomal protein HMGI(Y), an architectural factor with a role in transcription (30). The importance of this interaction for the regulation of adipocyte differentiation is confirmed in vivo as a targeted disruption of another family member, the HMGIC, leads to a severe deficiency in adipose tissue (31). The transcriptional activity of CEBPP (also a) is negatively controlled by CHOP-10, a dominant-negative CEBP family member (32). CHOP-10 can transiently sequester C/EBPP by

heterodimerization. Once CHOP-1 0 expression is down-regulated, C/EBPP is released from the re- pressive effect and is able to induce adipogenesis (33).

The expression of CEBPP and 6 lose importance during the later phases of adipocyte differentiation, which is mainly coordinated by CIEBPa and PPARy that cooperate to establish the phenotype of mature adipocytes (28, 34). PPARy belongs to the nuclear hormone receptor family of ligand-activated transcription factors that act together with its heterodimerization partner, the retinoid X receptor. The two additional forms of PPAR, ie PPARcl and WARP (6) , are also expressed in adipose tissue, albeit to a lower extent. Although it has been reported that PPARa, but not PPARG, can drive adipogenesis, it is much less effective than PPARy (35). Ectopic expression of PPARy in NIH-3T3 fibroblasts leads to adipogenesis in the presence of its natural or synthetic ligands, such as prostaglandin derivatives, polyunsaturated fatty acids or thiazolidinediones, respectively (36-38). In vivo, PPARy deficiency is lethal because of a defect in development of the placenta and the heart (39, 40). When the PPARyI- embryos are rescued by the use of tetraploid strategy, animals suffer from severe lipodystrophy, confirming the important role of PPARy in adipogenesis. Additional evidence for a role of PPARy in adipogenesis was obtained by the lack of contri- bution of WART’- embryonic stem cells to white adipose tissue formation in chimeric animals (40). Furthermore, the heterozygote PPARy+’- animals are protected from adipocyte hypertrophy and insulin resistance induced by high-fat diet (41). In addition, in human, several mutations in PPARy were described. The most prevalent P12A mutation in the adipose tissue-specific PPARy2 isoform, which attenuates PPARy activity, is associated with a decreased body mass index and improved insulin sensitivity (42, 43). In contrast, two mutations in the ligand-binding domain of PPARy, the P467L and V290M, lead to a severe insulin resistance, type 2 diabetes and hypertension (44). In combination, all these data thus suggest that PPARy serves as a thrifty gene by enabling energy storage in times of plenty and by safeguarding energy stores at the time of carence (45).

CIEBPa regulates terminal adipocyte differentiation by turning on fat-specific genes required for the synthesis, uptake, and storage of long-chain fatty acids. CIEBPa is antimitotic, and its premature expression would block the mitotic clonal expansion required for differentiation. Therefore, C/EBPa is expressed relatively late during adipogenesis. This rather late induction is controlled by the nuclear factor C/EBP undifferentiated protein (CUP), an isoform of activator protein-2a (AP-2a), which re- presses the CEBPa gene promoter leading to its silencing until late in the differentiation process (46). The CUP regulatory element overlaps the binding site


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for Spl or Sp3, strong transcriptional activators of the CEBPa, and only one of these factors can bind the Sp element at a time. Following down-regulation of CUP during adipocyte differentiation, the Sp proteins that are stably expressed throughout adipogenesis can bind and induce CEBPa expression.

The in vivo role of CIEBPa was confirmed by using knock-out mice. C/EBPa-I- mice do not store hepatic glycogen, fail to accumulate lipids and die from hypoglycaemia on postnatal day 1 (47). The mRNA expression of glycogen synthase and uncoupling protein is decreased in these animals while the gene expression of two gluconeogenic enzymes, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, is delayed. Further experiments with fibroblasts from C/EBPa4- mice have shown that the differentiation of adipose tissue can be achieved by a positive cross- regulation between virally provided C/EBPa and PPARy (48). These CEBPa-’- cells also show a complete absence of insulin-stimulated glucose trans- port, secondary to reduced gene expression and tyrosine phosphorylation of the insulin receptor and

ADD-l/SREBPlc also plays a role in terminal adipocyte differentiation (49, 50). ADD-1hREBPlc is a membrane-bound basic helix-loop-helix leucine zip-

IRS-I.

per transcription factor, which is activated through a two-step intramolecular proteolytic cleavage facili- tated by the SREBP cleavage activation protein, the SCAP (51). This proteolysis is regulated by the sterol content within the cell through the sterol-sensing domain at the C-terminus of SREBP. There are at least two mechanisms by which SREBP functions during the phase of terminal differentiation. First, ADD1/ SREBPlc controls the production of endogenous ligand(s) for PPARy regulating thus its transcriptional activity (52). Second, ADDUSREBPlc induces directly PPARy activity (53). The activity of ADDUSREBPlc is negatively regulated by the inhibitor of DNA binding Id2 and Id3, two dominant negative members of bHLH family that are down-regulated during adipogenesis (54, 55). These proteins interact with ADDUSREBPl and decrease its DNA binding in preadipocytes. The in vivo role of ADDUSREBPlc was analysed in mice models that over-express SREBP- l c in adipose tissue. These animals have smaller depots of fully differentiated white adipose tissue and hypertrophic brown adipose tissue while showing, unexpectedly, the features of congenital generalized lipodystrophy (56). This finding shows the complexity of adipogenesis and limitation of a single-gene transgenic animal model.

Regulators

Target genes

GLUT4

SCDl UCP TNFa aP2 IR Resistin LPL IRS-1 ACS

GS PAR K l F c K IL

Flgure 1. Schematic representation of the regulation of adipocyte differentiation by different transcriptional or hormonal factors. The balance between positive and negative regulatory players will define which target genes will be switched on or off and whether the cell will undergo differentiation or remain in the nondifferentiated state. ACS, acyl-coenzyme A synthase; AEBPl , adipocyte enhancer binding protein 1 ; P-AR, beta adrenergic receptor; C/EBPa,P,G, CCAAT/enhancer-binding protein alpha, beta and delta; CHOP1 0, C/EBP homologous protein-1 0; CUP, C/EBP undifferentiated protein; GLUT4, glucose transporter-4; GS, glycogen synthase; GH, growth hormone; HMGIM, high-mobility group I nonhistone chromosomal protein; IL, interleukin; ld2,3, inhibitor of DNA binding 2 and 3; IR, insulin receptor; IRS-1, insulin receptor substrate 1 ; LIF, leukemia inhibitory factor; LPL, lipoprotein lipase; PEPCK, phosphoenolpyruvate carboxykinase; PPARy, peroxisome proliferator-activated receptor gamma; Pref-1 , preadipocyte factor-1 ; RAR, retinoic acid receptor; Rb, Retinoblastoma protein; RXR, retinoid X receptor; SCDl , stearoyl-coenzyme A desaturase 1 ; SREBP1 c, sterol regulatory element binding protein 1 c; TNF-a, tumour necrosis factor alpha; UCP, uncoupling protein.


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Conclusion

During the last 10 years our understanding of the process leading to adipocyte determination and differentiation has improved significantly (summarised in Fig 1). Adipocyte differentiation is dependent on a balance between factors that influence the adipocyte differentiation process either positively or negatively. The nuclear transcription factors of the C/EBP family and PPARy have emerged as the key coordinating factors of this differentiation process to which many more factors contribute. This new insight into the

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1997; 17: 1796-804.

873-80.


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