International Journal of Obesity (2013) 37, 163 - 166 & 2013 Macmillan Publishers Limited All rights reserved

0307-0565/13 www.nature.com/ijo

REVIEW

Activins in adipogenesis and obesity

C Dani Activins are secreted proteins members of the transforming growth factor-b family. They are involved in many biological responses including regulation of apoptosis, proliferation and differentiation of different cell types. Activins A, B and AB are highly expressed in adipose tissue, and in this review we will illustrate that activins have a role in several steps of physiological and pathological development of adipose tissue. Activin A has been shown to be a critical regulator of human adipocyte progenitor proliferation and a potent inhibitor of their differentiation. Activin A could also be a mediator of brosis observed in obese adipose tissue. Activin B/AB is proposed as a new adipokine having a role in energy balance and insulin insensitivity associated with obesity. Therefore, activin pathway could represent a potential therapeutic target both for controlling the size and the phenotype of the adipose precursor pool and for obesity-associated metabolic complications. International Journal of Obesity (2013) 37, 163--166; doi:10.1038/ijo.2012.28; published online 28 February 2012 Keywords: activin; adipocyte progenitors; adipocytes bioactivity of activins.8 - 11 Activin signals are transmitted through two types of transmembrane serine/threonine kinase receptors, type I and type II activin receptors (ActRIIA or ActRIIB). Once activins bind to ActRIIA or ActRIIB, type I receptors are recruited to the ligand/ActRII complex and become phosphorylated.12 Then, type I receptors activate the Smad pathway that recruit activators or repressors to regulate target genes.13 It has been reported, that in addition to the canonical Smad pathway, other intracellular pathways, such as p38MAPK, ERK1/2 and JNK, can be activated by activins in a cell-specic manner.14,15

INTRODUCTION Obesity adipose tissue is characterized by dysfunctional hypertrophic adipocytes, an increase in the proportion of human adipose progenitors,1 immune cell inltration with chronic inammation2,3 and brosis.4 The limitation of adipose tissue expansion, in part due to inhibition of adipocyte progenitor differentiation in an inammatory microenvironment, can lead to fat accumulation in ectopic tissues resulting in lipotoxicity and metabolic disorders. Adipocytes are renewed in physiological conditions. As mature adipocytes do not divide in vivo, regeneration of adipocytes depends on self-renewal of a pool of adipose progenitors that remains present during adult life and that can be recruited to form new fat cells.5,6 Many growth factors have been implicated in regulation of the size of progenitors in the rodent models. However, factors controlling self-renewal, that is, proliferation and differentiation, of human adipocyte progenitors are largely unknown. In this review, we will illustrate that activins have a role in several steps of physiological and pathological development of adipose tissue. ACTIVINS, ACTIVIN RECEPTORS AND SIGNALING PATHWAYS Activins are secreted proteins members of the transforming growth factor (TGF)-b family. They are expressed in various tissues where they have been shown to regulate various biological process including regulation of apoptosis, proliferation and differentiation of different cell types.7 Activins form dimers composed of inhibin b subunits and to date four b subunits have been identied in mammals (named bA, bB, bC and bE). Therefore, activins exist in different dimeric congurations. Homodimers of bA or bB subunits, named activin A and activin B, respectively, and heterodimer of bA and bB, named activin AB, are highly expressed in adipocyte progenitors and in mature adipocytes (Figure 1). Natural binding proteins for the TGF-b members exist and have an important role in the negative regulation of TGF-b signaling. For instance, follistatin is an extracellular glycoprotein that functions as an antagonist-binding protein neutralizing the

ACTIVIN A IS AN AUTOCRINE/PARACRINE REGULATOR OF HUMAN ADIPOCYTE PROGENITOR PROLIFERATION Activin A expression is correlated with the undifferentiated state of adipocyte progenitors isolated from omental, subcutaneous and mesenteric human white adipose tissues.16 Functional investigations revealed that activin A is a critical regulator of human adipose-derived stem cell proliferation. Cell proliferation decreases when adipocyte progenitors are treated with an activin A-neutralizing antibody, showing the existence of a basal activin A autocrine/paracrine signaling pathway involved in undifferentiated human adipocyte progenitor cell number. Activin A supplementation enhances human adipose-derived stem cell proliferating through Smad2 pathway activation as reported by Zaragosi et al.16 commented and illustrated by JK Sethi.17 A weak activation of ERK1/2 upon addition of activin A has been observed. However, its functional signicance has not been tested and inhibition of p38 MAPK has no effect on activin A-induced cell proliferation.16 Inhibin bB subunit is weakly expressed in undifferentiated human adipocyte progenitors, suggesting that activins B/AB do not have an important role in their biology (Figure 1). Collectively, these data show that activin A regulates the number of undifferentiated adipoctyte progenitors in an autocrine/paracrine manner and that this effect used Smad2dependent mechanisms. These observations are consistent with the mitogenic effect of activin A/Smad pathway observed on 3T3-L1 mouse preadipose cell line and on C3H10T1/2 broblasts.18

Institute Biology of Valrose (iBV), CNRS/Inserm, Faculty of Medicine, University of Nice Sophia-Antipolis, Nice, Cedex, France. Correspondence: Dr C Dani, Institute Biology of Valrose (iBV), Faculty of Medicine, University of Nice Sophia-Antipolis, CNRS/Inserm, Nice, Cedex 2, 06107, France. E-mail: dani@unice.fr Received 24 October 2011; revised 31 January 2012; accepted 5 February 2012; published online 28 February 2012

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Figure 1. Schematic expression of activins in adipocyte progenitors and adipocytes. Activin A, which is a homodimer of Inhba subunits (black box), is highly expressed in adipocyte progenitors. In contrast, activin B and activin A/B, which are heterodimers of Inhba and Inhbb subunits (white box), are more expressed in mature adipocytes.

Activin A displays also a proliferative effect on some other cell types such as on broblast-like synoviocytes in rheumatid arthritis. In that case, activin A proliferative activity is partially inhibited by follistatin.19 Human adipocyte progenitors secrete follistatin, but regulation of activin A/follistatin ratio and its role in proliferation remain to be investigated. ACTIVINS IN ADIPOCYTE DIFFERENTIATION AND POSSIBLE ROLE IN OBESITY Activin A has a negative autocrine/paracrine functional role in the early steps of human adipocyte progenitor differentiation. Activin A is secreted by human undifferentiated adipocyte progenitors and its level decreases markedly upon induction of adipocyte differentiation. Indeed, activin A downregulation is necessary for commitment toward the adipocyte lineage as supplementation with activin A during the initial stages of the adipocyte differentiation program inhibits formation of lipid-containing cells. In the opposite, inhibition of activin A pathway markedly promote adipocyte differentiation. As for the proliferative effect, the anti-adipogenic effects of activin A are mediated through Smad pathway. The anti-adipogenic effect of Smad2 pathway in human adipogenesis is consistent with its anti-adipogenic effects previously reported for human umbilical cord perivascular cells20 and mouse 3T3-L1 preadipose cell line.21 Together, these reports show the existence of an autocrine/paracrine loop comprising the activin A/Smad2 pathway that has a critical negative role on adipocyte differentiation of human adipocyte progenitors. Overexpression of C/EBPb prevents anti-adipogenic of activin A,16 suggesting that activin A functions upstream or through direct inhibition of C/EBPb. The molecular mechanisms involved in inhibition of C/EBPb by activin A remain to be determined. In contrast to activin A, activin B/AB is weakly expressed during the early steps of adipogenesis but is highly expressed in human mature adipocytes. Authors propose activin B/AB as a new adipokine having a role in energy balance and insulin insensitivity associated with obesity.22,23 Consistent with this hypothesis, it has been reported that activin B/AB inhibits lipolysis of 3T3-L1 preadipose cell line.24 In addition, expression of activin B/AB is higher in adipose tissue of obese diabetic ob/ob mice than in non-obese mice. More importantly, inhibin bB expression in adipose tissue of ob/ob mouse is regulated upon administration of leptin.25 Finally, it has been reported several years ago that expression of inhibin bB with spatiotemporal expression of inhibin bA leads to reduce the mass of adipose tissue, which contains small and immature adipocytes, and thus impairs insulin sensitivity.26 In addition, the basal metabololic rates of these mice are elevated with upregulation of mitochondriogenesis.27 It is interesting to note that expression of PAI-1, the expression of which is associated with insulin resistance, and of interleukin-6 are stimulated upon activin A treatment of human adipocyte
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progenitors.16,28 Therefore, increase activity of activins may lead to insulin resistance and inammatory states. All these observations support the hypothesis that the different activin isoforms are regulators of the different steps of adipogenesis and could have a role in energy balance, insulin insensitivity associated with obesity and energy expenditure. Expression of myostatin, another member belonging to TGF-b superfamily, is modulated in skeletal muscle and adipose tissue of obese ob/ob mice, and in wild-type mice in response to dietary obesity.29 Inhibition of myostatin in mice leads to increase muscle mass, to reduce fat mass, and mutant mice are resistant to dietinduced obesity.30 More recently, it has been shown that suppression of TGF-b/Smad3 pathway regulates the acquisition of brown fat features by white adipose tissue and protects mice from obesity and diabetes.31 Altogether, these reports point out the emerging role of TGF-b superfamily members and Smad pathway in regulating adiposity, as recently reviewed by Zamani and Brown.32 The role of follistatin in human adipogenesis has been recently evaluated.33 Follistatin is secreted both from subcutaneous and visceral adipose tissues and the major source has been identied in the CD34 /CD31 fraction that contains adipocyte progenitors. The authors have also observed a decrease of follistatin expression in subcutaneous adipose tissue of obese patients compared with with non-obese controls that can be recovered by antiobesity intervention. Interestingly, in contrast to activin A, follistatin promotes adipogenesis in vitro. It is interesting to note that follistatin displays opposite effect that activins on adipogenesis and as predicted for the proliferative effect of activin A on adipocyte progenitors, it is likely that the the follistatin/activins ratio should have a critical role. Levels of this ratio in adipose tissue of healthy subjects and obese patients remain to be investigated. REGULATORS OF ACTIVIN EXPRESSION Obesity is associated with new macrophages that are recruited into adipose tissue and is accompanied by chronic low-grade inammation in this tissue.2,3 Some studies report that the differentiation potential of human adipocyte progenitors, isolated from subcutaneous fat, is inversely correlated with obesity whereas the pool of precursors cells is positively correlated to body mass index.1,34,35 Therefore, these results suggest that the obese microenvironment is capable of inducing proliferation of human adipocyte progenitors while inhibiting their differentiation. Concordantly, human adipose tissue-macrophage-secreted factors stimulate proliferation of human preadipocytes in vitro.36,37 Moreover, adipose tissue macrophages have been shown to inhibit adipogenesis of the progenitor CD34 /CD31 cell population.38 Interestingly, activin A levels are signicantly increase in subcutaneous adipose tissue of obese subjects compared with lean ones and are upregulated by adipose tissue macrophagesecreted factors,16 suggesting a functional link between adipose progenitor proliferation, inhibition of their differentiation and macrophages mediated by activin A. Adipose-tissue macrophagesecreted factors involved in the stimulation of activin A expression remain to be identied. However, interleukin-1b, tumor necrosis factor-a and TGF-b are potent candidates as previous studies have shown in other cell model, that activin A secretion is increased upon treatment with these cytokines.39,40 Therefore, immunoinammatory cells that accumulate within adipose tissue with obesity might contribute to fat mass enlargement through paracrine effects on progenitor cells (Figure 2). It is tempting to propose that the disappearance of macrophages, for instance as a consequence of dieting, and in consequence reduction of activin A levels in adipose tissue might be favorable to the formation of additional adipocytes from adipose progenitors upon ending dietary restriction. This is a situation reminiscent of the yoyo
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Activins in adipogenesis and obesity C Dani

is in phase I clinical trials for the treatment of bone diseases.47 However, further studies to determine the activin A and follistatin circulating levels in lean subjects and in obese patients are required to better dene the clinical role of activin A and to validate activin A as a secreted biomarker. CONFLICT OF INTEREST
The author declares no conict of interest.

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1 Maumus M, Sengenes C, Decaunes P, Zakaroff-Girard A, Bourlier V, Lafontan M et al. Evidence of in situ proliferation of adult adipose tissue-derived progenitor cells: inuence of fat mass microenvironment and growth. J Clin Endocrinol Metab 2008; 93: 4098 - 4106. 2 Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante Jr AW. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003; 112: 1796 - 1808. 3 Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ et al. Chronic inammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 2003; 112: 1821 - 1830. 4 Divoux A, Tordjman J, Lacasa D, Veyrie N, Hugol D, Aissat A et al. Fibrosis in human adipose tissue: composition, distribution, and link with lipid metabolism and fat mass loss. Diabetes 2010; 59: 2817 - 2825. 5 Hauner H, Entenmann G, Wabitsch M, Gaillard D, Ailhaud G, Negrel R et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically dened medium. J Clin Invest 1989; 84: 1663 - 1670. 6 Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O et al. Dynamics of fat cell turnover in humans. Nature 2008; 453: 783 - 787. 7 Phillips DJ. Activins, inhibins and follistatins in the large domestic species. Domest Anim Endocrinol 2005; 28: 1 - 16. 8 Phillips DJ, de Kretser DM. Follistatin. A multifunctional regulatory protein. Front Neuroendocrinol 1998; 19: 287 - 322. 9 Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H. Activin-binding protein from rat ovary is follistatin. Science 1990; 247: 836 - 838. 10 Lee SJ, McPherron AC. Regulation of myostatin activity and muscle growth. Proc Natl Acad Sci USA 2001; 98: 9306 - 9311. 11 Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery). J Tissue Eng Regen Med 2008; 2: 81 - 96. 12 Tsuchida K, Nakatani M, Hitachi K, Uezumi A, Sunada Y, Ageta H et al. Activin signaling as an emerging target for therapeutic interventions. Cell Commun Signal 2009; 7: 15. 13 Feng XH, Derynck R. Specicity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol 2005; 21: 659 - 693. 14 Bao YL, Tsuchida K, Liu B, Kurisaki A, Matsuzaki T, Sugino H. Synergistic activity of activin A and basic broblast growth factor on tyrosine hydroxylase expression through Smad3 and ERK1/ERK2 MAPK signaling pathways. J Endocrinol 2005; 184: 493 - 504. 15 de Guise C, Lacerte A, Raei S, Reynaud R, Roy M, Brue T et al. Activin inhibits the human Pit-1 gene promoter through the p38 kinase pathway in a Smadindependent manner. Endocrinology 2006; 147: 4351 - 4362. 16 Zaragosi LE, Wdziekonski B, Villageois P, Keophiphath M, Maumus M, Tchkonia T et al. Activin a plays a critical role in proliferation and differentiation of human adipose progenitors. Diabetes 2010; 59: 2513 - 2521. 17 Sethi JK. Activatin human adipose progenitors in obesity. Diabetes 2010; 59: 2354 - 2357. 18 Stewart A, Guan H, Yang K. BMP-3 promotes mesenchymal stem cell proliferation through the TGF-beta/activin signaling pathway. J Cell Physiol 2010; 223: 658 - 666. 19 Ota F, Maeshima A, Yamashita S, Ikeuchi H, Kaneko Y, Kuroiwa T et al. Activin A induces cell proliferation of broblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 2003; 48: 2442 - 2449. 20 Turner NJ, Jones HS, Davies JE, Caneld AE. Cyclic stretch-induced TGFbeta1/ Smad signaling inhibits adipogenesis in umbilical cord progenitor cells. Biochem Biophys Res Commun 2008; 377: 1147 - 1151. 21 Horie T, Ono K, Kinoshita M, Nishi H, Nagao K, Kawamura T et al. TG-interacting factor is required for the differentiation of preadipocytes. J Lipid Res 2008; 49: 1224 - 1234. 22 Sjoholm K, Palming J, Lystig TC, Jennische E, Woodruff TK, Carlsson B et al. The expression of inhibin beta B is high in human adipocytes, reduced by weight loss, and correlates to factors implicated in metabolic disease. Biochem Biophys Res Commun 2006; 344: 1308 - 1314.

Figure 2. Regulators of activins and effects on adipogenesis. Activin A stimulates adipocyte progenitor proliferation and could induce a mybroblast-like phenotype, source of brosis in obese adipose tissue. Activin B and A/B expression is correlated with adipocyte insulin resistance. Macrophage factors promote expression of activin A in adipocyte progenitors. Dexamethasone, follistatin and the soluble ActRIIA receptor are inhibitors of activins.

phenomenon. Activin A is also a critical mediator of inammation (for a recent review see Phillips et al.41) and it is interesting to note that dexamethasone, an anti-inammatory molecule, downregulates activin A secretion from human adipocyte progenitors.16 Inhibin bb is also negatively regulated by dexamethasone in murine adipocyte.25 It is tempting to speculate that antiinammatory steroids could both promote the formation of new adipocytes via inhibition of activin A secretion in adipocyte progenitors and reduce insulin resistance in existing adipocytes via inhibition of activin B/AB (Figure 2). However, it has been shown in the animal model, that dexamethasone treatment impairs glucose tolerance and is associated with perturbation of lipid metabolism.42 In addition to its stimulating effect on expression of proinammatory cytokines in macrophages, activin A is positioned as a probrotic factor in adipose tissue of obese patients.37 Therefore, a question that should be addressed is related to the phenotype of adipocyte progenitors under conditions leading to the increase activity of activin A? The possibility that over activity of activin A turns adipocyte progenitors into myobroblasts, source of brosis observed in obese adipose tissue 4 is a possibility that remains to be analyzed in details. Induction of myobroblast markers in human adipocyte progenitor populations upon activin A or TGF-b treatment support this hypothesis.43 CONCLUSIONS In conclusions, activin A promotes proliferation of human adipocyte progenitors, with the possibility to induce their brotic phenotype in a pathological context. Excess levels of activin A block differentiation of adipocyte progenitors. This anti-adipogenic effect could participate to limit adipose tissue expandibility and as a consequence to deposition of fat to ectopic sites.44 Therefore, blocking activin A in adipose tissue of obese patients could represent a potential therapeutic avenue for controlling the size and the phenotype of the adipose precursor pool in adipose tissue and obesity-associated metabolic complications. Activin pathway inhibitors have been shown to have potential medical applications.45 It has been reported that injection of follistatin reduces inammatory disease severity mediated by activin A in the mouse animal models.46 Soluble ActRIIA receptor (ACE-011)
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