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An update on visfatin/pre-B cell colony-enhancing factor,an ubiquitously expressed, illusive cytokine that is regulatedin obesityJacqueline M. Stephens and Antonio Vidal-Puig Sponsorship: J.M.S. is supported by the American Diabetes Foundation and the The aim of this article is to summarize all of the recent NIH. A.V.P. is supported by The Wellcome Trust and Medical Research Council.
studies on pre-B cell colony-enhancing factor (PBEF)/ Current Opinion in Lipidology 2006, 17:000–000 visfatin, a ubiquitously expressed secreted protein that has been implicated in obesity and insulin resistance. Although PBEF was discovered over 10 years ago, there are many remaining questions about the regulation and function ofthis protein.
ß 2006 Lippincott Williams & Wilkins Studies in the last decade have revealed the endocrineproperties of fat cells. One of the most recent proteinsshown to be highly expressed in adipose tissue is visfatin, originally identified as PBEF. Visfatin/PBEF appears to be Adipocytes are important endocrine cells and secrete preferentially produced by the visceral adipose tissue and several hormones and cytokines that are involved in has insulin mimetic actions. Studies by many groups metabolic diseases such as obesity and type 2 diabetes.
indicate that obesity-related diabetes and accompanying The endocrine properties of adipocytes continue to be an metabolic disorders in humans have been specifically linked active and forthcoming area of investigation. Ten years to increased visceral adipose tissue mass. The different after the identification of a novel protein secreted from roles of various adipocyte depots, however, are still poorly lymphocytes it was shown that this protein is also understood. It has been hypothesized that understanding secreted from adipose tissue This may come as little the differences in the biology of visceral and subcutaneous surprise given that immune cells and adipocytes are human adipose tissue may hold the key to therapeutic known to express many of the same genes. In the past strategies aimed at reducing obesity-induced insulin 11 years, several groups have studied the functions of pre- resistance and alleviating symptoms of the metabolic B-cell colony-enhancing factor (PBEF). These studies syndrome. Interestingly, some observed actions of visfatin reveal that PBEF has some interesting roles in several indicate that this secreted protein may be an interesting tissues and has two fairly unique features including the therapeutic target. Several recent studies, however, lack of a signal sequence and the ability to localize in the indicate that our understanding of visfatin is still speculative.
nucleus. The recent discovery that PBEF, now also termed visfatin, is highly expressed in visceral fat and This review summarizes all of the papers in the last year on circulating levels correlate with obesity is of great the expression and function of visfatin/PBEF and highlights interest to many researchers. Although a recent study inconsistent observations from various investigators confirmed the modulation of visfatin expression in studying this protein. It also highlights previous obesity these observations are not without contro- observations on the role of PBEF. We suggest that that versy Moreover, it has been suggested that visfatin pathophysiologic role of visfatin/PBEF in humans remains can act as an insulin analog on the insulin receptor but no follow-up studies have confirmed this originalobservation. Clearly, our understanding of PBEF/visfatin is in its infancy and its pathophysiologic role in humans adipokine, adipose tissue, diabetes, insulin mimetic, Curr Opin Lipidol 17:000–000. ß 2006 Lippincott Williams & Wilkins.
PBEF was originally identified as a 52 Kd protein that isprimarily expressed in bone marrow, liver, and muscle Department of Clinical Biochemistry, University of Cambridge, Addenbrooke’sHospital, Cambridge, UK PBEF is also upregulated in neutrophils by IL-1b and Correspondence to Antonio Vidal-Puig, Department of Clinical Biochemistry, functions as a novel inhibitor of apoptosis in response to a University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 variety of inflammatory stimuli Both genomic 2QR, UKTel: +44 1223 336855; fax: +44 1223 330598; e-mail: and genetic studies have identified PBEF as a novel candidate gene and biomarker in acute lung injury subcutaneous visfatin mRNA expression. Overall, this and recent studies indicated that PBEF is critically study concluded that plasma concentrations of visfatin or involved in thrombin-induced lung endothelial cell visceral visfatin mRNA expression correlated with barrier dysregulation Other studies showed that measurements of obesity but not with visceral fat mass PBEF is constitutively expressed by fetal membranes or waist-to-hip ratio An additional independent during pregnancy and is expressed throughout gestation study in a rodent model of metabolic syndrome also in the amniotic epithelium and mesenchymal cells as observed that visfatin gene expression was not associated well as in the chorionic cytotrophoblast and parietal with the metabolic syndrome in diseased rats compared deciduas and it has been hypothesized that PBEF with lean controls Since only a handful of studies has a central role in the mechanism of infection-induced have examined the expression of visfatin in obesity preterm birth PBEF has also been shown to regulate related disorders, the regulation of visfatin/PBEF under nicotinamide adenine dinucleotide (NADþ)-dependent these conditions is still not entirely clear.
protein deacetylase activity and promote vascular smoothmuscle cell maturation. In this study, the authors sug- gested that PBEF did not have standard attributes of a thiazolidinediones, adipocyte differentiation, cytokine but instead imparted the cell with increased nicotinamide phosphoribosyltransferase activity that was Although the biological role of visfatin is still illusive, involved in the acquisition of a mature smooth muscle there are some studies that have investigated the regu- cell phenotype Previous studies had revealed that lation of this protein by other cytokines or by anti- PBEF was a nicotinamide phosphoribosyltransferase, a diabetic thiazolidinediones. The expression of adipocy- cytosolic enzyme involved in NAD biosynthesis tokines in visceral fat depots of Otsuka Long-Evans Overall, these studies indicated that PBEF is ubiquitou- Tokushima fatty (OLETF) rats from early to advanced sly expressed and is associated with a variety of functions diabetic stage (28–40 weeks of age) was recently examined As expected, serum glucose and insulinconcentrations were significantly decreased in rosiglita- zone treated OLETF rats compared with untreated expression of visfatin in obesity and non- OLETF rats. In addition, rosiglitazone significantly increased serum adiponectin concentration in these rats PBEF was also termed visfatin when the levels of this from 20 to 40 weeks of age. The expression of both protein were shown to be increased in visceral adipose visfatin and adiponectin mRNA in visceral fat deposits tissue of KKAy mice and in human female participants was elevated by rosiglitazone when compared with compared with its levels in subcutaneous adipose tissue untreated OLETF rats If visfatin can act as an This original observation is supported by a recent insulin mimetic, then it makes some sense that an insu- study that demonstrated that visfatin levels are altered in lin-sensitizing drug like rosiglitazone might increase the patients with type 2 diabetes mellitus In this study, expression levels of visfatin/PBEF. Another study on the visfatin, adiponectin and resistin levels were measured by expression and regulation of visfatin mRNA was per- enzyme-linked immunosorbent assay in type 2 diabetic formed by studying 3T3-L1 adipocytes during adipogen- and non-diabetic subjects. A decrease in adiponectin and esis and after treatment with various hormones known to an increase in visfatin was observed in type 2 diabetic alter insulin sensitivity. In this study, visfatin expression patients and the authors suggested that the increasing was about sixfold higher in 3T3-L1 adipocytes in vitro as concentrations of visfatin were independently and sig- compared with epididymal fat in vivo This is an nificantly associated with type 2 diabetes mellitus interesting observation and an interesting comparison to Another study in which visceral fat mass was calculated the first visfatin paper which showed that visfatin levels from computed tomography scans indicated, however, in the liver of c57BL mice or KKAy mice were shown to that there was no correlation between plasma visfatin be much higher than the levels in subcutaneous white concentrations and visceral fat mass In fact, no adipose tissue of c57BL mice Nonetheless, both significant correlation between visfatin plasma concen- studies indicate that visfatin expression is increased trations and various parameters of insulin sensitivity, during adipogenesis of 3T3-L1 cells. It has also been including fasting insulin, fasting plasma glucose concen- shown that dexamethasone treatment of 3T3-L1 adipo- trations, and the glucose infusion rate during the steady cytes significantly increased visfatin mRNA levels, state of an euglycemic –hyperinsulinemic clamp that whereas growth hormone, TNFa, and isoproterenol sub- were independent of percent body fat were observed stantially downregulated visfatin mRNA in a dose and The results from this study did indicate, however, a time dependent manner Insulin did not influence significant correlation between visceral visfatin gene the synthesis of visfatin in these cells It should be expression and percent body fat, but no significant associ- noted that this study only examined visfatin mRNA and ation between body mass index or percent body fat and did not examine the secretion or sub-cellullar location of Pre-B cell colony-enhancing factor Stephens and Vidal-Puig this protein. Taken together, these studies demonstrate It is quite a paradox that an insulin mimetic protein is increased expression of visfatin during adipocyte differ- highly produced by visceral fat in a state of insulin entiation and an increase of visfatin levels by a thiazo- resistance. It could be perceived that the adipocyte is lidinedione in diabetic rodents, and modulation by employing whatever means necessary to provide an insu- cytokines, which are known effectors of adipogenesis lin response in obese adipose tissue. Clearly, there are many studies that need to be performed to enhanceour understanding of visfatin biology. For example, it In an amniotic epithelial cell line, lipopolysaccharide, will very important to determine whether visfatin, work- IL-1b, TNFa and IL-6 all significantly increased the ing through the insulin receptor, can modulate all the expression of PBEF after a 4-h cytokine treatment In signaling proteins known to be modulated by insulin.
these cells, the addition of dexamethasone to IL-1b It will also be interesting to determine if visfatin has and TNFa significantly reduced the response of its own receptor or solely works through the insulin PBEF to these cytokines, whereas in cultured adipocytes receptor. Also, it will be critical to determine if intracrine dexamethasone alone increased visfatin mRNA levels signaling is a pathway used by visfatin since PBEF has Interestingly, PBEF expression is upregulated in been shown to be present in the nucleus under some amniotic epithelial cells by cytokines that promote conditions Finally, it will be important to determine insulin resistance such as lipopolysaccharide, IL-1b, how visfatin is secreted. Perhaps, visfatin/PBEF is TNFa and IL-6 In cultured adipocytes, however, secreted when fat cells die. Recent studies have clearly shown a large increase in the amount of dead adipocytes visfatin mRNA levels. Overall, these studies do not in white adipose tissue of obese mice and these obser- greatly enhance our understanding of the modulation vations suggest that necrotic-like adipocyte death as a of visfatin/PBEF expression and do not clearly support pathologic hallmark of obesity Perhaps, the paradox many recent speculations that this cytokine might be an of visfatin might be more clearly understood if this interesting novel candidate that links components of protein was shown to be released from dying adipocytes? the metabolic syndrome such as obesity and insulin This is just one of many hypotheses that require rigorous Interestingly, the original paper on the identification of Most interesting discoveries are accompanied by some PBEF demonstrated that PBEF itself had no activity but confounding observations. When visfatin was shown by synergized the pre-B-cell colony formation activity of Fukuhara and colleagues to be induced during adipogen- stem cell factor and IL-7 If visfatin is a legitimate esis, secreted from fat cells, and highly and specifically insulin mimetic as has been suggested, then it is sort of expressed in visceral adipose tissue they also observed surprising that only a few well characterized biological an unexpected finding. Contrary to the most intuitive effects of PBEF have been observed in the last 10 years hypothesis, visfatin treatment did not promote insulin given the broad range of insulin action. The literature on resistance, but actually exhibited insulin mimetic proper- PBEF and visfatin is sparse and although PBEF was ties by causing a glucose lowering effect In a discovered over 10 years ago, several studies suggest that manner similar to insulin, visfatin increased glucose this protein does not have expected cytokine like proper- transport and lipogenesis when administered to 3T3- ties. In some ways, this is not surprising since visfatin/ L1 adipocytes or L6 myocytes and decreased glucose PBEF is lacking a signal sequence and can be found in production by hepatocytes When delivered directly the nucleus of Swiss 3T3 cells following cytokine treat- to diabetic mice visfatin also improved insulin sensitivity ment Since studies on the regulation of this protein in vivo and resulted in decreased glucose and insulin are in its infancy, we think it is premature to speculate on levels. The significance of endogenous visfatin control- the role of PBEF in metabolic diseases.
ling whole body insulin sensitivity was observed bystudying heterozygous visfatin mice that have two-thirds the amount of visfatin of wild type mice These The discovery of this curious new adipokine has the animals displayed mild but reproducible hyperglycemia potential to enhance our understanding of metabolic Subsequent analysis of this insulin mimetic effect diseases such as obesity, type 2 diabetes, and metabolic revealed two surprising findings; that the effects of vis- syndrome. Yet, as with all novel discoveries, these initial fatin are mediated by the insulin receptor itself with observations need to be reproduced and several new remarkably similar affinities but via a distinct binding related questions need to be addressed before the role site, and that this insulin sensitizing effect of visfatin of visfatin in metabolic disease can be carefully evalu- appears to be additive to the effect of insulin ated. For example, it will be critical to determine the suggesting that visfatin may activate insulin receptor contribution of visceral adipose tissue derived visfatin activated pathways via a novel mechanism.
and it ability to modulate whole body insulin sensitivity.
Although the affinity of visfatin for insulin receptor Jia SH, Li Y, Parodo J, et al. Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis. J Clin appears to be similar to insulin, its concentration in plasma is much lower (3–10%) under physiological con- These data identify PBEF as a novel inflammatory cytokine that plays a requisiterole in the delayed neutrophil apoptosis of clinical and experimental sepsis.
ditions. Moreover, visfatin/PBEF is not regulated by Ye SQ, Simon BA, Maloney JP, et al. Pre-B-cell colony-enhancing factor as a fasting and feeding. These observations raise some potential novel biomarker in acute lung injury. Am J Respir Crit Care Med doubts about the physiological importance of the This paper shows that PBEF is highly expressed in mouse, canine, and human systemic insulin sensitizing effects of visfatin. As acute lung injury and demonstrates that PBEF is strong candidate as a biomarker suggested above, perhaps the elevation of visfatin in visceral adipose tissue of obese mice is due to its release Ye SQ, Zhang LQ, Adyshev D, et al. Pre-B-cell-colony-enhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregula- from dying adipocytes. In this review, we have posed tion. Microvasc Res. 2005; Sep 23 [Epub ahead of print].
various questions relevant to visfatin/PBEF biology and This study followed up previous work indicating that PBEF was a novel candidategene and biomarker in acute lung injury and demonstrated that PBEF play a role in summarized all the recent papers on visfatin/PBEF.
thrombin-induced lung endothelial cell barrier dysregulation.
Overall, we were surprised that our survey of the litera- Ognjanovic S, Bryant-Greenwood GD. Pre-B-cell colony-enhancing factor, a ture revealed minimal progress on the regulation and novel cytokine of human fetal membranes. Am J Obstet Gynecol 2002;187:1051–1058.
action of PBEF in the last 10 years and there is no current Ognjanovic S, Bao S, Yamamoto SY, et al. Genomic organization of the gene literature supporting the observation that visfatin has coding for human pre-B-cell colony enhancing factor and expression in humanfetal membranes. J Mol Endocrinol 2001; 26:107–117.
insulin mimetic properties. Clearly, this protein is diffi- 10 van der Veer E, Nong Z, O’Neil C, et al. Pre-B-cell colony-enhancing factor cult to study and for this reason the role of visfatin/PBEF regulates NADþ-dependent protein deacetylase activity and promotes vas- cular smooth muscle cell maturation. Circ Res 2005; 1:25–34.
These findings identify PBEF as a regulator of NADþ dependent reactions insmooth muscle cells and indicate that this protein is important in the acquisition ofa mature smooth muscle cell phenotype.
11 Rongvaux A, Shea RJ, Mulks MH, et al. Pre-B-cell colony-enhancing factor, Papers of particular interest, published within the annual period of review, have whose expression is upregulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis.
12 Kloting N, Kloting I. Visfatin: gene expression in isolated adipocytes and Additional references related to this topic can also be found in the Current sequence analysis in obese WOKW rats compared with lean control rats.
World Literature section in this issue (pp. 000–000).
Biochem Biophys Res Commun 2005; 332:1070–1072.
This paper demonstrated that visfatin expression was not modulated in a rodent Samal B, Sun Y, Stearns G, et al. Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Mol Cell Biol 13 Choi KC, Ryu OH, Lee KW, et al. Effect of PPAR-alpha and -gamma agonist on the expression of visfatin, adiponectin, and TNF-alpha in visceral fat of Fukuhara A, Matsuda M, Nishizawa M, et al. Visfatin: a protein secreted OLETF rats. Biochem Biophys Res Commun 2005; 336:747–753.
by visceral fat that mimics the effects of insulin. Science 2005; 307:426– This was the first study to demonstrate that visfatin levels were increased in diabetic rats following rosiglitazone treatment.
This paper demonstrates that PBEF is produced in fat cells, regulated during 14 Kralisch S, Klein J, Lossner U, et al. Isoproterenol, TNFalpha, and insulin adipogenesis and highly expressed in mouse and human visceral adipose tissue downregulate adipose triglyceride lipase in 3T3-L1 adipocytes. Mol Cell in obesity. In addition, it was shown that visfatin has insulin mimetic prop- erties in various cell types and administration to animal could increase insulin This study examined the modulation of visfatin by various cytokines in cultured adipocytes. Although, these observations are interesting, only the levels of visfatin Chen MP, Chung FM, Chang DM, et al. Elevated plasma level of visfatin/pre-B mRNA were examined. This group had previously shown that IL-6 also modulates cell colony-enhancing factor in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2005; Oct 18 [Epub ahead of print].
15 Kralisch S, Klein J, Lossner U, et al. Interleukin-6 is a negative regulator of To date, this is the only study to confirm the novel observations by Fukuhara et al.
visfatin gene expression in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab that demonstrate elevated levels of visfatin in type II diabetes.
Berndt J, Kloting N, Kralisch S, et al. Plasma visfatin concentrations and fat 16 Kitani T, Okuno S, Fujisawa H. Growth phase-dependent changes in the depot-specific mRNA expression in humans. Diabetes 2005; 54:2911– subcellular localization of pre-B-cell colony-enhancing factor. FEBS Lett This was the first major study to cast some doubt on the modulation of visfatinexpression in subcutaneous versus visceral adipose tissue and indicated that there 17 Cinti S, Mitchell G, Barbatelli G, et al. Adipocyte death defines macrophage was no significant correlation between visfatin plasma concentrations and para- localization and function in adipose tissue of obese mice and humans. J Lipid Current opinion in Lipidology
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