Over the last few years, it has become obvious that obesity and insulin resistance are linked by a variety of proteins secreted by adipocytes. Visfatin/PBEF (pre-B-cell colony-enhancing factor) has recently been identified as a novel adipokine with insulin-mimetic effects. Furthermore, an enzymatic function has been reported that reveals visfatin/PBEF as Nampt (nicotinamide phosphoribosyltransferase; EC 2.4.2.12.). Moreover, reports on the structure and hormonal regulation of visfatin/PBEF/Nampt have given further insights into its potential physiological role. The present review summarizes studies on visfatin/PBEF/Nampt as a novel adipokine.

INTRODUCTION

Obesity is a rapidly growing disease in industrialized countries that is characterized by an excessive accumulation of adipose tissue [1]. Both hyperplasia and hypertrophy of adipocytes are found in this disorder [1]. Adipose tissue has been shown to secrete various proteins, so-called adipokines. Over the last few years, it has become obvious that obesity and various components of the metabolic syndrome, such as insulin resistance and hypertension, are strongly linked due to the differential secretory function of adipose tissue. Thus adipokines, including adiponectin, IL (interleukin)-6, leptin, MCP-1 (monocyte chemoattractant protein-1), resistin, TNF-α (tumour necrosis factor-α), vaspin and visfatin, might play an important role in the pathogenesis of insulin resistance and cardiovascular disease. Fukuhara et al. [2] isolated visfatin, which is also known as PBEF (pre-B-cell colony-enhancing factor) and Nampt (nicotinamide phosphoribosyltransferase), as a novel adipokine that improved glucose tolerance and might play a role in the development of obesity-associated insulin resistance and T2DM (Type 2 diabetes mellitus). Visfatin/PBEF/Nampt was shown to mimic the effects of insulin by binding to the insulin receptor at a site different from that of insulin [2]. The same study demonstrated that visfatin/PBEF/Nampt is preferentially expressed by visceral adipose tissue compared with subcutaneous fat [2]. Recently, the structure of visfatin/PBEF/Nampt has been determined which has helped to elucidate its properties as a phosphoribosyltransferase and adipokine [3,4]. The present review summarizes recent findings concerning the role of visfatin/PBEF/Nampt as a novel adipokine with an emphasis on studies published over the last 2 years.

STRUCTURE OF VISFATIN/PBEF/NAMPT

The gene encoding visfatin/PBEF/Nampt (PBEF1) was first isolated from a human peripheral blood lymphocyte cDNA library [5]. The gene is located on the long arm of chromosome 7 between 7q22.1 and 7q31.33 [6] and encodes a polypeptide of 491 amino acids with a molecular mass of 52 kDa (National Center for Biotechnology Information accession number AAA17884). There is no signal sequence in the primary structure of visfatin/PBEF/Nampt. The crystal structure of visfatin/PBEF/Nampt with regard to its enzymatic function in synthesizing NMN (nicotinamide mononucleotide) from nicotinamide and PRPP (phosphoribosylpyrophosphate) has been described by Wang et al. [3] and Kim et al. [4]. These studies suggested that visfatin/PBEF/Nampt is a homodimeric protein with low sequence identity with other type II phosphoribosyltransferases, such as NAPRTase (nicotinic acid phosphoribosyltransferase; EC 2.4.2.11) and QAPRTase (quinolinic acid phosphoribosyltransferase; EC 2.4.2.19) (Figure 1A). However, visfatin/PBEF/Nampt has been identified as structural homologue of NAPRTase from Thermoplasma acidophilum and has limited structural similarity to Mycobacterium tuberculosis QAPRTase, although the topology of the residues in the active site differs among the three enzymes [3,4]. Visfatin/PBEF/Nampt has two active sites at the interface of the dimeric protein, suggesting that dimerization is essential for the catalytic activity of the enzyme. The extensive dimeric interface with a total surface area of 8077Å2 (where 1 Å= 0.1 nm) is formed by ten segments from each subunit. A total of 89 almost evenly polar and hydrophobic distributed residues form the interface, and 42 hydrogen bonds are involved in the intramolecular interactions. A non-crystallographic 2-fold pseudosymmetry axis reveals the relationship of the two subunits, which also have a high similarity with each other [3,4].

Structure of visfatin/PBEF/Nampt

Figure 1
Structure of visfatin/PBEF/Nampt

(A) Mouse visfatin/PBEF/Nampt in complex with NMN. The monomeric subunits are shown in green and violet respectively, whereas the carbons of NMN are in yellow. (B) Schematic ribbon diagram of a visfatin/PBEF/Nampt monomer. The individual domains are shown in blue and green respectively. (C) Active site of mouse visfatin/PBEF/Nampt in complex with NMN. The monomeric subunits are shown in green and violet respectively, whereas the carbons of NMN are in yellow. Figures 1(A) and 1(C) were reprinted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology [3], copyright (2006); http://www.nature.com/nsmb/index.html. Figure 1(B) was reprinted from Journal of Molecular Biology, volume 362, M.-K. Kim, J. H. Lee, H. Kim, S. J. Park, S. H. Kim, G. B. Kang, Y. S. Lee, J. B. Kim, K. K. Kim, S. W. Suh and S. H. Eom, Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866, pp. 66–77, Copyright (2006), with permission from Elsevier; http://www.sciencedirect.com/science/journal/00222836.

Figure 1
Structure of visfatin/PBEF/Nampt

(A) Mouse visfatin/PBEF/Nampt in complex with NMN. The monomeric subunits are shown in green and violet respectively, whereas the carbons of NMN are in yellow. (B) Schematic ribbon diagram of a visfatin/PBEF/Nampt monomer. The individual domains are shown in blue and green respectively. (C) Active site of mouse visfatin/PBEF/Nampt in complex with NMN. The monomeric subunits are shown in green and violet respectively, whereas the carbons of NMN are in yellow. Figures 1(A) and 1(C) were reprinted by permission from Macmillan Publishers Ltd: Nature Structural & Molecular Biology [3], copyright (2006); http://www.nature.com/nsmb/index.html. Figure 1(B) was reprinted from Journal of Molecular Biology, volume 362, M.-K. Kim, J. H. Lee, H. Kim, S. J. Park, S. H. Kim, G. B. Kang, Y. S. Lee, J. B. Kim, K. K. Kim, S. W. Suh and S. H. Eom, Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866, pp. 66–77, Copyright (2006), with permission from Elsevier; http://www.sciencedirect.com/science/journal/00222836.

Each monomer consists of 491 residues that form 19 β-strands and 13 α-helices and is organized into two structural domains [4]. The first structural domain is arranged into a seven-stranded antiparallel β-sheet, two antiparallel β-strands and an α-helix bundle (Figure 1B) [4]. The second structural domain consists of an alternative folding of the classical (β/α)8-barrel (Figure 1B). Kim et al. [4] have suggested that two sections of the (β/α)8-barrel might be tilted towards the other subunit of the dimer when NMN is bound to visfatin/PBEF/Nampt. The intramolecular location of the two NMN product molecules is close to the centre of the (β/α)8-barrel. Alignment of 13 sequences of visfatin/PBEF/Nampt homologues provides evidence that most of the residues in the active site are highly conserved. The residues involved in the binding of the nicotinamide ring of the NMN product (Asp16, Tyr18, Phe193 and Arg311) are highly conserved. The same applies to Arg311, Asp313, Gly353 and Asp354, which are part of the ribose-binding site.

POTENTIAL FUNCTION OF VISFATIN/PBEF/NAMPT

Catalytic mechanism of visfatin/PBEF/Nampt

Visfatin/PBEF/Nampt catalyses the rate-limiting step in the NAD+ salvage pathway in mammals and is, therefore, involved in the regulation of many cellular processes [3,7,8]. The catalytic mechanism of visfatin/PBEF/Nampt was proposed on the basis of its crystal structure and similarity to other type II phosphoribosyltransferases. As both subunits of visfatin/PBEF/Nampt are involved in the catalytic mechanism, it appears plausible that Phe193 from one monomer and Tyr18 from the other are framing the nicotinamide moiety of the NMN molecule (Figure 1C) [3]. This conformation is stabilized by π-stacking interactions [3]. A hydrogen bond is formed between Asp219 and the amide of the nicotinamide molecule (Figure 1C), which explains the specificity of visfatin/PBEF/Nampt to its substrate nicotinamide and excludes the binding of other negatively charged substrates, such as nicotinic or quinolinic acid, which can be bound by the related enzymes NAPRTase and QAPRTase respectively [3]. Wang et al. [3] suggested that the nicotinamide substrate might bind in a close or even analogous position with that of the nicotinamide moiety of NMN. Other interesting characteristics of visfatin/PBEF/Nampt are the highly conserved residues Ser280-His247-Asp313, as well as Tyr281 and Asp279 (Figure 1C). Tyr281 is in van der Waals contact with Ser280, and Asp279 forms a hydrogen bond with His247. These residues are near the NMN moiety, whereas Asp313 is directly adjacent to NMN, and Ser280 lies in the interface of the two subunits of visfatin/PBEF/Nampt (Figure 1C). This orientation of the residues is unlikely to permit catalytic activity as seen in serine proteases. Interestingly, visfatin/PBEF/Nampt is autophosphorylated on His247 when incubated with ATP. The assumption is that a phosphorylated His247 could stabilize formation of a positively charged oxocarbenium intermediate that is formed during cleavage of pyrophosphate from PRPP. The NMN product could then be formed out of pyrophosphate and nicotinamide [3].

The NAD+ salvage pathway is essential when the cellular NAD+ pool is depleted, for example through poly-ADP-ribosylation during DNA repair and NAD+-dependent protein deacetylase activity [8,9]. Visfatin/PBEF/Nampt regulates the function of the Sir (silent information regulator) 2 orthologue Sirt1/Sir2α in mammalian cells. Sirt1/Sir2α is implicated in the transcriptional regulatory activity of a variety of cellular processes, including stress, cytokine responses, differentiation and metabolism [7]. In another study [10], visfatin/PBEF/Nampt was shown to optimize Sirt1-mediated p53 degradation in human vascular smooth muscle cells, thereby delaying senescence and substantially lengthening cellular lifespan.

Taking these studies into consideration, there is convincing evidence to suggest that visfatin/PBEF/Nampt catalyses the rate-limiting step in the production of NAD+ from nicotinamide.

Insulin-mimetic function of visfatin/PBEF/Nampt

The first study to identify the potential role of visfatin/PBEF/Nampt as an insulin mimetic was by Fukuhara et al. [2] and provided a comprehensive characterization of this adipokine. A dose-dependent glucose-lowering effect of visfatin/PBEF/Nampt was observed when C57BL/6J mice were injected with recombinant visfatin/PBEF/Nampt. The same regulation was found in KKAy mice, an animal model for T2DM. Furthermore, chronic adenoviral visfatin/PBEF/Nampt expression in C57BL/6J and KKAy mice significantly lowered plasma glucose concentrations. As visfatin/PBEF/Nampt-knockout mice were not viable, heterozygous visfatin/PBEF/Nampt+/− mice were studied by the authors [2] in more detail. These animals had approx. 33% lower plasma visfatin/PBEF/Nampt levels compared with wild-type mice and had moderately higher plasma glucose levels under fasting, as well as feeding, conditions. Furthermore, plasma glucose levels in visfatin/PBEF/Nampt+/− mice were significantly higher during glucose tolerance tests compared with controls.

The binding affinity of visfatin/PBEF/Nampt to the IR (insulin receptor) was found to be similar compared with that of insulin, and, in a competitive binding assay, visfatin/PBEF/Nampt did not bind to the same site as insulin, suggesting that visfatin/PBEF/Nampt stimulated the IR in a different way compared with insulin [2]. Insulin-mimetic effects, including glucose uptake, were also found in 3T3-F442A adipocytes, L6 myocytes and H4IIEC3 hepatocytes in vitro. Surprisingly, visfatin/PBEF/Nampt stimulated the phosphorylation of insulin signalling molecules at a 10-fold lower molar concentration compared with insulin. Furthermore, visfatin/PBEF/Nampt stimulated the accumulation of triacylglycerols (triglycerides) in pre-adipocytes similarly to cells treated with insulin [2].

Another study [11] has also shown insulin-like effects of visfatin/PBEF/Nampt on human osteoblasts, with visfatin/PBEF/Nampt increasing glucose uptake, stimulating expression of osteogenic markers at the mRNA and protein levels, and also causing an increase in mineralization of osteoblasts in a manner similar to insulin. These insulin-mimetic effects were inhibited by the IR-specific inhibitor HNMPA-(AM)3 [11]. Again, visfatin/PBEF/Nampt induced the same responses as insulin at a 10-fold lower molar concentration [11], results which were comparable with the study by Fukuhara et al. [2].

In accordance with the original findings, Moschen and co-workers [12] found a significant approx. 2-fold up-regulation of glucose uptake in human SGBS adipocytes in vitro at a visfatin/PBEF/Nampt concentration of 100 nmol/l. Interestingly, the stimulatory effect of visfatin/PBEF/Nampt on glucose uptake could not be enhanced further by increasing the concentration of the adipokine to 2 μmol/l [12].

The concept that visfatin/PBEF/Nampt mediates its effects via activation of the IR has been supported by Dahl et al. [13], who demonstrated that the visfatin/PBEF/Nampt-induced secretion of IL-8 and TNF-α from peripheral blood mononuclear cells and the visfatin/PBEF/Nampt-stimulated MMP-9 (matrix metalloproteinase-9) activity in THP-1 cells were abolished after treatment with the IR-specific inhibitor HNMPA-(AM)3.

Taken together, several independent studies suggest that visfatin/PBEF/Nampt has insulin-like effects; however, further elucidation of the signalling molecules used by visfatin/PBEF/Nampt is necessary to confirm its potential role as a novel insulin-mimetic adipokine. Furthermore, most recently, Fukuhara and co-workers [14] retracted their paper on visfatin/PBEF/Nampt [2] at the suggestion of the Editor of Science following the recommendations of a Committee for Research Integrity from the Osaka University's Graduate School of Medicine. In their retraction, the authors emphasized that they continue to stand by their conclusions [14]; however, they acknowledged that not all of the preparations of visfatin/PBEF/Nampt bound to an activated IR in their hands [14], although four different batches of purified recombinant visfatin/PBEF/Nampt protein studies had both adipogenic and insulin-mimetic activities [14]. Therefore the outcomes of further investigations are awaited.

Immunomodulatory functions of visfatin/PBEF/Nampt

Another function of visfatin/PBEF/Nampt is the regulation of inflammatory and immunomodulating processes. Recombinant visfatin/PBEF/Nampt activated human leucocytes and induced cytokine production [12]. In CD14+ monocytes, visfatin/PBEF/Nampt induced the production of IL-1β, TNF-α and IL-6 [12]. In addition, the protein enhanced the surface expression of the co-stimulatory molecules CD54, CD40 and CD80 [12]. Visfatin/PBEF/Nampt-mediated stimulation of monocytes resulted in augmented dextran–FITC uptake and increased the capacity to induce alloproliferative responses in lymphocytes [12]. In vivo, visfatin/PBEF/Nampt enhanced concentrations of circulating IL-6 in BALB/c mice [12]. Moreover, in patients with inflammatory bowel disease, plasma levels of visfatin/PBEF/Nampt were elevated and its mRNA expression was significantly increased in colonic tissue from patients with Crohn's and ulcerative colitis compared with healthy controls [12]. Previously, visfatin/PBEF/Nampt was implicated in the regulation of the anti-apoptosis of neutrophils [6] and was shown to be up-regulated in a variety of pathophysiological conditions of the immune system, including psoriasis [15], acute lung injury [16], lung endothelial cell barrier dysregulation [17] and rheumatoid arthritis [18,19]. Most recently, Oki and co-workers [20] have convincingly demonstrated that serum levels of visfatin/PBEF/Nampt were independently correlated with CRP (C-reactive protein) and IL-6 in 295 Japanese Americans; however, there was no association between circulating visfatin/PBEF/Nampt and markers of insulin sensitivity.

In agreement with a potential immunomodulatory function of visfatin/PBEF/Nampt, macrophages have been suggested as a significant source of this protein in addition to adipose cells, as visfatin/PBEF/Nampt-positive macrophages have been identified in adipose tissue and in the submucosa of the colonic wall by confocal microscopy [12]. Furthermore, the up-regulation of visfatin/PBEF/Nampt expression in THP-1 monocytes by pro-inflammatory stimuli, including oxLDLs (oxidized low-density lipoproteins) and TNF-α, has been demonstrated [13]. Moreover, both stimuli had an additive positive effect on visfatin/PBEF/Nampt synthesis [13]. Interestingly, the up-regulation of visfatin/PBEF/Nampt in macrophages from human unstable atherosclerotic lesions has been postulated as a potential contributor to plaque destabilization in atherosclerotic disease [13].

Taken together, it appears plausible that adipocyte- and macrophage-derived visfatin/PBEF/Nampt might be an important pro-inflammatory and immunomodulating regulator.

REGULATION OF VISFATIN/PBEF/NAMPT

In vivo studies

In this section, studies on the in vivo regulation of visfatin/PBEF/Nampt are considered with a focus on those in humans. The major findings of these are described below and are summarized in Table 1.

Table 1
Correlation of serum/plasma visfatin/PBEF/Nampt concentrations in vivo with clinical and metabolic parameters without adjustment for influencing factors

↑, positive correlation; ↓, negative correlation; ↔, no correlation; empty fields, not determined.

Visfatin mRNA expression inFasting plasma
First authorAmount of VATVATSATGenderAgeBMIWHR/waist circumferenceHOMAIRInsulinGlucosePlasma adiponectinAdditional major finding
Fukuhara [2↑            
Berndt [21↔ ↑ ↓ ↔ ↔ ↑ ↔  ↔ ↔   
Varma [22     ↔       
Dogru [23   ↔  ↔  ↔ ↔ ↔  ↑ in T2DM 
Pagano [24  ↑ ↔ ↔ ↓ in obese patients ↔ ↔ ↔ ↔  ↓ in obese patients 
Hammarstedt [25↔ in T2DM     ↑ ↔    ↔ ↑ in T2DM 
Chen [26   ↔ ↑ ↔ ↑ ↑ ↑ ↔ ↓ ↑ in T2DM 
Haider [27    ↔ ↔      ↑ in obese children 
Lopez-Bermejo [28    ↔ ↔ ↔  ↓ in non-diabetic men   ↑ in known T2DM; ↔ in newly diagnosed T2DM; ↑ in T1DM 
Krzyzanowska [29    ↔ ↔  ↔ ↔ ↔  ↑ in women with GDM 
Lewandowski [30       ↑ ↑   ↑ in women with GDM 
Chan [31    ↓ ↓      ↓ in women with GDM 
Chan [32    ↔ ↑ in women with PCOS   ↔   ↑ in women with PCOS 
Tan [33 ↑ ↑   ↔ ↔ ↑ ↑   ↑ in women with PCOC 
Haider [34        ↓ after weight loss in obese women ↓ after weight loss in obese women ↓ after weight loss in obese women ↓ after gastric banding 
Manco [35           ↓ after >20% loss of BMI 
Krzyzanowska [36           ↑ after gastroplastic surgery 
Frydelund-Larsen [37           ↔ by exercise 
Haider[38           ↓ by exercise in T1DM 
Axelsson [39           ↑ in subjects with CKD; predicts mortality in CKD 
Visfatin mRNA expression inFasting plasma
First authorAmount of VATVATSATGenderAgeBMIWHR/waist circumferenceHOMAIRInsulinGlucosePlasma adiponectinAdditional major finding
Fukuhara [2↑            
Berndt [21↔ ↑ ↓ ↔ ↔ ↑ ↔  ↔ ↔   
Varma [22     ↔       
Dogru [23   ↔  ↔  ↔ ↔ ↔  ↑ in T2DM 
Pagano [24  ↑ ↔ ↔ ↓ in obese patients ↔ ↔ ↔ ↔  ↓ in obese patients 
Hammarstedt [25↔ in T2DM     ↑ ↔    ↔ ↑ in T2DM 
Chen [26   ↔ ↑ ↔ ↑ ↑ ↑ ↔ ↓ ↑ in T2DM 
Haider [27    ↔ ↔      ↑ in obese children 
Lopez-Bermejo [28    ↔ ↔ ↔  ↓ in non-diabetic men   ↑ in known T2DM; ↔ in newly diagnosed T2DM; ↑ in T1DM 
Krzyzanowska [29    ↔ ↔  ↔ ↔ ↔  ↑ in women with GDM 
Lewandowski [30       ↑ ↑   ↑ in women with GDM 
Chan [31    ↓ ↓      ↓ in women with GDM 
Chan [32    ↔ ↑ in women with PCOS   ↔   ↑ in women with PCOS 
Tan [33 ↑ ↑   ↔ ↔ ↑ ↑   ↑ in women with PCOC 
Haider [34        ↓ after weight loss in obese women ↓ after weight loss in obese women ↓ after weight loss in obese women ↓ after gastric banding 
Manco [35           ↓ after >20% loss of BMI 
Krzyzanowska [36           ↑ after gastroplastic surgery 
Frydelund-Larsen [37           ↔ by exercise 
Haider[38           ↓ by exercise in T1DM 
Axelsson [39           ↑ in subjects with CKD; predicts mortality in CKD 

Visfatin/PBEF/Nampt in obesity, insulin resistance and T2DM

Circulating visfatin/PBEF/Nampt levels were shown by Fukuhara et al. [2] to be strongly correlated with the amount of visceral adipose tissue in 101 female and male subjects; however, there was only a weak correlation between human plasma visfatin/PBEF/Nampt concentrations and the amount of subcutaneous fat. A separate study by Berndt et al. [21] in a population of 189 subjects showed that plasma visfatin/PBEF/Nampt concentrations correlated positively and significantly with BMI (body mass index) and percentage body fat, as well as visfatin/PBEF/Nampt mRNA expression in VAT (visceral adipose tissue). In contrast, there was a negative correlation between circulating visfatin/PBEF/Nampt levels and mRNA expression in subcutaneous fat. Plasma visfatin/PBEF/Nampt concentrations were not associated with visceral fat mass, which had been calculated by CT (computed tomography) scans in a subgroup of 73 subjects. Furthermore, there was no association between plasma visfatin/PBEF/Nampt concentrations on one hand, and gender, age or WHR (waist-to-hip ratio) on the other. Plasma visfatin/PBEF/Nampt levels did not correlate with fasting plasma insulin and glucose concentrations. Similarly, the glucose infusion rate during the steady state of an euglycaemic–hyperinsulinaemic clamp was not associated with plasma visfatin/PBEF/Nampt concentrations.

Recently, Varma et al. [22] have determined circulating visfatin/PBEF/Nampt in patients with a wide range of obesity and BMI and either IGT (impaired glucose tolerance) or NGT (normal glucose tolerance); however, plasma visfatin/PBEF/Nampt concentrations did not correlate with BMI and insulin sensitivity. In another study, Dogru et al. [23] examined 22 subjects with untreated T2DM, 18 patients with IGT and 40 controls with NGT. No correlation was found between circulating visfatin/PBEF/Nampt on one hand and BMI, BP (blood pressure), adiponectin, high-sensitive CRP, insulin, glucose and lipid levels as well as HOMAIR (homoeostasis model assessment of insulin resistance) on the other hand. Interestingly, in the diabetic subgroup, significantly higher visfatin/PBEF/Nampt levels were found compared with controls. Circulating visfatin/PBEF/Nampt concentrations in patients with IGT did not significantly differ from those of subjects with T2DM. Furthermore, plasma visfatin/PBEF/Nampt levels were not significantly different between subjects with IGT and controls, and there was no difference in plasma visfatin/PBEF/Nampt according to gender [23].

Circulating visfatin/PBEF/Nampt and visfatin/PBEF/Nampt mRNA expression in SAT (subcutaneous adipose tissue) was determined in a study population of 30 lean and 39 obese subjects by Pagano et al. [24]. Circulating levels of the adipokine were decreased by approx. 50% in obese patients compared with controls. In both subgroups, plasma visfatin/PBEF/Nampt levels were not different between men and women. Furthermore, in obese patients, a negative correlation was found between circulating visfatin/PBEF/Nampt levels and BMI. In contrast, no association between plasma visfatin/PBEF/Nampt and waist circumference, fat mass, fasting glucose, fasting insulin, HOMAIR and age was found in lean, as well as obese, subjects. Nevertheless, plasma visfatin/PBEF/Nampt concentrations positively correlated with visfatin/PBEF/Nampt mRNA expression in the subcutaneous fat depot [24].

Hammarstedt et al. [25], in a small study composing six healthy subjects and seven untreated patients with T2DM, reported a 2-fold increase in plasma visfatin/PBEF/Nampt concentrations in individuals with T2DM compared with healthy controls. Plasma visfatin/PBEF/Nampt levels and BMI had a weak positive correlation in both groups, whereas there was no correlation between visfatin/PBEF/Nampt concentrations and WHR or waist circumference. Circulating visfatin/PBEF/Nampt concentrations did not correlate with plasma adiponectin levels in either group or the amount of visceral fat in the diabetic group.

Another study in patients with T2DM (61 patients with T2DM and 59 sex- and age-matched controls) showed that visfatin/PBEF/Nampt plasma levels were significantly increased in T2DM compared with controls, and a significant relationship between plasma visfatin/PBEF/Nampt and T2DM persisted even after adjustment for known biomarkers influencing glucose metabolism, such as age, gender, BMI, WHR, SBP (systolic BP), DBP (diastolic BP), lipid profile and smoking status [26]. The authors suggested that the association between T2DM and increased visfatin/PBEF/Nampt levels might be due to an impaired visfatin/PBEF/Nampt signalling in patients with T2DM. An association was found between plasma visfatin/PBEF/Nampt concentrations and age, fasting plasma insulin, adiponectin levels and HOMAIR; however, these correlations disappeared after multiple regression analysis was performed. In contrast, WHR was the only parameter that had a significant positive association with plasma visfatin/PBEF/Nampt concentrations in simple and multiple regression analysis. No correlation was observed between plasma visfatin/PBEF/Nampt concentrations and gender, BMI or fasting glucose in both simple and multiple regression analysis.

Haider et al. [27], in a study population of 83 obese children compared with 40 lean controls, reported an approx. 2-fold increase plasma visfatin/PBEF/Nampt concentrations; however, no correlation between circulating visfatin/PBEF/Nampt and BMI or age was observed.

An increase in serum visfatin/PBEF/Nampt levels with progressive β-cell deterioration has been observed by Lopez-Bermejo et al. [28]. Circulating visfatin/PBEF/Nampt was increased in subjects with known T2DM compared with non-diabetic subjects, but not in newly diagnosed subjects with T2DM compared with non-diabetic subjects. Interestingly, visfatin/PBEF/Nampt levels were significantly increased in patients with long-standing T1DM (Type 1 diabetes mellitus) compared with subjects with T2DM or non-diabetic subjects. In non-diabetic men, serum visfatin/PBEF/Nampt levels correlated significantly with fasting insulin and insulin sensitivity. In contrast, there was no correlation found between circulating visfatin/PBEF/Nampt concentrations and age, BMI or waist circumference [28].

Visfatin/PBEF/Nampt in GDM (gestational diabetes mellitus) and PCOS (polycystic ovary syndrome)

Several studies have quantified circulating visfatin/PBEF/Nampt levels in GDM. Krzyzanowska et al. [29] studied visfatin/PBEF/Nampt plasma concentrations in 64 women with GDM and 30 healthy pregnant subjects during pregnancy and after delivery. Plasma visfatin/PBEF/Nampt concentrations in women with GDM were increased approx. 1.4-fold compared with controls; however, there was no correlation between visfatin/PBEF/Nampt concentrations and fasting plasma glucose, plasma insulin, HOMAIR and BMI. In a subgroup of 24 pregnant women with GDM, a significant increase in plasma visfatin/PBEF/Nampt concentration during gestation was observed, which increased further within 2 weeks after delivery [29]. Similarly, Lewandowski and co-workers [30] found elevated visfatin serum levels in GDM that significantly correlated with HOMAIR and fasting plasma insulin. However, Chan et al. [31], determining circulating visfatin/PBEF/Nampt levels in 20 women with GDM compared with 20 healthy pregnant controls, reported, in contrast with the other two studies [29,30], that visfatin/PBEF/Nampt levels were decreased by approx. 25% in GDM compared with controls. They also found a significant negative correlation between plasma visfatin/PBEF/Nampt concentrations and first trimester BMI as well as maternal age [31]. Multiple linear regression analysis revealed an independent correlation of plasma visfatin/PBEF/Nampt with maternal age, but there was no correlation between circulating visfatin/PBEF/Nampt concentrations and gestational age [31].

Increased circulating visfatin/PBEF/Nampt levels have been found in women with PCOS [32,33]. Chan et al. [32] observed a positive correlation of visfatin/PBEF/Nampt levels and BMI in women with PCOS but not in the control group, whereas visfatin/PBEF/Nampt concentrations were not significantly associated with age and fasting plasma insulin. However, a positive correlation has been reported by Tan et al. [33] between plasma visfatin/PBEF/Nampt concentrations and fasting plasma insulin, HOMAIR and visfatin/PBEF/Nampt mRNA expression in SAT as well as VAT, although there was no significant association found between plasma visfatin/PBEF/Nampt levels and BMI or WHR.

Visfatin/PBEF/Nampt after weight loss

The influence of weight loss on circulating visfatin/PBEF/Nampt levels has also been investigated. A decrease in circulating visfatin/PBEF/Nampt concentrations 6 months after gastric banding, which was accompanied by a decrease in BMI, waist circumference and percentage body fat, has been reported [34]. A similar decrease in circulating visfatin was found in morbidly obese women who lost more than 20% of their BMI [35]. Furthermore, circulating visfatin/PBEF/Nampt levels were negatively related to plasma adiponectin, fasting insulin and fasting glucose concentrations in obese women after weight loss [35]. In contrast, Krzyzanowska et al. [36] reported an increase in circulating visfatin/PBEF/Nampt after weight loss induced by gastroplastic surgery, which was paralleled by a decrease in fasting plasma insulin levels and HOMAIR.

Visfatin/PBEF/Nampt and exercise

Frydelund-Larsen et al. [37] have determined the influence of exercise on visfatin/PBEF/Nampt. Plasma visfatin/PBEF/Nampt concentrations were not altered by exercise, whereas mRNA expression of this adipokine in abdominal SAT increased [37]. In contrast, Haider and co-workers [38] demonstrated that elevated visfatin/PBEF/Nampt concentrations in patients with T1DM were lowered by regular physical exercise.

Visfatin/PBEF/Nampt and renal function

Axelsson and co-workers [39] were the first to show that plasma visfatin/PBEF/Nampt levels are increased with deteriorating kidney function. Serum visfatin/PBEF/Nampt concentrations correlated with truncal fat mass and surrogate markers of insulin resistance. Furthermore, high plasma visfatin/PBEF/Nampt concentrations predicted mortality in patients with CKD (chronic kidney disease), also after adjustment for age and sex. This study suggests that renal elimination is a major route by which physiological visfatin/PBEF/Nampt levels are maintained.

Regulation of visfatin/PBEF/Nampt in animal models

In contrast with the findings by Fukuhara and co-workers [2], Kloting and Kloting [40] were unable to find a relationship between visfatin/PBEF/Nampt gene expression in visceral and subcutaneous adipocytes and the metabolic syndrome in WOKW rats. However, Choi et al. [41] demonstrated convincingly that PPAR (peroxisome-proliferator-activated receptor) α and PPARγ agonists significantly induced visfatin/PBEF/Nampt expression in VAT of OLETF rats. Similarly, the PPARδ agonist L-165041 stimulated visfatin/PBEF/Nampt synthesis in visceral fat from Wistar rats fed a high-fat diet [42]. Visfatin/PBEF/Nampt synthesis was elevated in white adipose tissue of rats at day 21 of pregnancy [43]. Furthermore, in perigonadal adipose tissue of C57/6J mice, visfatin/PBEF/Nampt had a 24 h circadian rhythmicity, which was attenuated in obese and diabetic animals [44].

Summary

Studies on the in vivo regulation of visfatin/PBEF/Nampt have often yielded contradictory results. Differences in sample size, study populations and genetic background of the patients might explain the different findings. In addition, Nusken et al. [45] have shown a considerable influence of preanalytical conditions on visfatin/PBEF/Nampt detection in the enzyme immunoassays that are most widely used for determining the levels of the circulating adipokine. Furthermore, Körner et al. [46] recently compared the three currently available visfatin/PBEF/Nampt immunoassays and found significant discrepancies between these assays in the qualitative and quantitative detection of visfatin/PBEF/Nampt in human serum samples. Moreover, only a few studies have performed multiple regression analysis to control for well-defined biomarkers of the metabolic syndrome. As various studies cannot correlate visfatin/PBEF/Nampt expression in fat and circulating visfatin/PBEF/Nampt on one hand and parameters of insulin resistance and obesity, including fasting insulin, fasting glucose, HOMAIR, BMI, WHR and adiponectin, on the other hand, it is safe to conclude that visfatin/PBEF/Nampt is probably not a major link between obesity and insulin resistance in human disease. Furthermore, based on the results summarized in this section, it is unlikely that visfatin/PBEF/Nampt will be a useful biomarker for different components of the metabolic syndrome, including visceral obesity, in the future.

In vitro studies

A variety of studies have investigated the hormonal regulation of visfatin/PBEF/Nampt in vitro. Some of these are outlined below and are summarized in Table 2.

Table 2
Regulation of visfatin/PBEF/Nampt in vitro in various studies

↑, up-regulation; ↓, down-regulation; ↔, no regulation.

Hormone/drug/agentEffect on visfatin/PBEF/Nampt
Dexamethasone ↑ mRNA expression in 3T3-L1 cells [47,48
GH ↓ mRNA expression in 3T3-L1 cells [47
TNF-α ↓ mRNA expression in 3T3-L1 cells [47
Isoprenaline ↓ mRNA expression in 3T3-L1 cells [47
Forskolin ↓ mRNA expression in 3T3-L1 cells [47
Cholera toxin ↓ mRNA expression in 3T3-L1 cells [47
Insulin ↔ mRNA expression in 3T3-L1 cells [47
 ↓ mRNA expression in 3T3-L1 cells [48
IL-6 ↓ mRNA expression in 3T3-L1 cells [49
 ↑ mRNA expression in amniotic epithelial cells [50
Thiazolidinediones ↔ mRNA expression in human SAT [22,25
 ↑ protein secretion from human adipocytes [53
 ↓ mRNA expression in 3T3-L1 cells [48
Glucose ↑ protein secretion from human adipocytes [54
Hypoxia-inducing agents ↑ mRNA expression in 3T3-L1 cells [56
 ↑ mRNA expression in MCF-7 cells [57
Oleate/palmitate ↓ mRNA expression in 3T3-L1 cells [48,58
NEFAs ↔ mRNA expression in human SAT [24
Hormone/drug/agentEffect on visfatin/PBEF/Nampt
Dexamethasone ↑ mRNA expression in 3T3-L1 cells [47,48
GH ↓ mRNA expression in 3T3-L1 cells [47
TNF-α ↓ mRNA expression in 3T3-L1 cells [47
Isoprenaline ↓ mRNA expression in 3T3-L1 cells [47
Forskolin ↓ mRNA expression in 3T3-L1 cells [47
Cholera toxin ↓ mRNA expression in 3T3-L1 cells [47
Insulin ↔ mRNA expression in 3T3-L1 cells [47
 ↓ mRNA expression in 3T3-L1 cells [48
IL-6 ↓ mRNA expression in 3T3-L1 cells [49
 ↑ mRNA expression in amniotic epithelial cells [50
Thiazolidinediones ↔ mRNA expression in human SAT [22,25
 ↑ protein secretion from human adipocytes [53
 ↓ mRNA expression in 3T3-L1 cells [48
Glucose ↑ protein secretion from human adipocytes [54
Hypoxia-inducing agents ↑ mRNA expression in 3T3-L1 cells [56
 ↑ mRNA expression in MCF-7 cells [57
Oleate/palmitate ↓ mRNA expression in 3T3-L1 cells [48,58
NEFAs ↔ mRNA expression in human SAT [24

Dexamethasone has been shown to stimulate an increase visfatin/PBEF/Nampt mRNA expression in a time- and dose-dependent manner, although adipogenic markers, such PPARγ, C/EBPα (CCAAT/enhancer-binding protein) and GLUT4 (glucose transporter 4), were not altered [47]. A similar finding has also been observed recently by Maclaren et al. [48].

In contrast, GH (growth hormone), TNF-α and the β-adrenergic agonist isoprenaline suppressed visfatin/PBEF/Nampt gene expression in 3T3-L1 cells in a time- and dose-dependent manner compared with cells grown under control conditions [47]. As treatment of 3T3-L1 cells with forskolin and cholera toxin also caused a significant down-regulation of visfatin/PBEF/Nampt mRNA, the effect of isoprenaline on visfatin/PBEF/Nampt synthesis is probably mediated via a classical Gs-protein-coupled pathway.

Insulin did not alter visfatin/PBEF/Nampt expression in 3T3-L1 adipocytes in our hands [47]. In contrast, in another study [48], a 23% decrease in visfatin/PBEF/Nampt mRNA synthesis has recently been shown at an insulin concentration of 1 mmol/l.

Treatment of 3T3-L1 adipocytes with IL-6 also significantly suppressed visfatin/PBEF/Nampt mRNA expression and, again, this regulation was time- and dose-dependent [49]. The signalling mechanisms underlying this effect was studied further by Kralisch et al. [49], and they found that p44/42 MAPK (mitogen-activated protein kinase), but not JAK2 (Janus kinase 2) or p38 MAPK, was involved in the IL-6-mediated effect. Furthermore, PI3K (phosphoinositide 3-kinase) was suggested to contribute to basal visfatin/PBEF/Nampt synthesis in adipocytes [49]. However, it appears that the regulation of visfatin/PBEF/Nampt by IL-6 may be cell-type dependent, as Ognjanovic et al. [50] have shown that IL-6 treatment stimulated visfatin/PBEF/Nampt mRNA expression in amniotic epithelial cells.

Thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, are insulin-sensitizing agents that reduce the effects of TNF-α and IL-6 on 3T3-L1 adipocytes by the activation of PPARγ [51,52]. Their effect on TNF-α- and IL-6-mediated suppression of visfatin/PBEF/Nampt synthesis has been determined by Kralisch et al. [49]. However, pretreatment with troglitazone and rosiglitazone did not significantly influence visfatin/PBEF/Nampt mRNA down-regulation by the two cytokines. Other studies have confirmed these findings in an in vivo setting by comparing the regulation of visfatin/PBEF/Nampt in patients treated with thiazolidinediones with controls, but no differences in circulating visfatin/PBEF/Nampt concentrations and subcutaneous mRNA expression of the adipokine were found between the two groups [22,25]. Therefore it has been suggested that thiazolidinediones do not regulate visfatin/PBEF/Nampt. Another study [53] has shown that visfatin/PBEF/Nampt release into the supernatants of human adipocytes was increased by acute addition and long-term treatment with rosiglitazone. In contrast with these results, rosiglitazone treatment of 3T3-L1 adipocytes significantly down-regulated visfatin/PBEF/Nampt mRNA expression by 28% [48].

In preadipocytes obtained from SAT of lean subjects, visfatin/PBEF/Nampt concentrations increased significantly in supernatants by approx. 50% after stimulation with 11.1 mmol/l glucose for 4 h [54], and this effect was time- and dose-dependent. Glucose-induced visfatin/PBEF/Nampt synthesis in these adipocytes was suppressed when insulin, as well as PI3K or Akt inhibitors, were added to the cell culture medium [54]. Interestingly, a glucose-mediated increase in visfatin/PBEF/Nampt plasma concentrations could also be demonstrated in the same study in vivo. However, it should be pointed out that Pfützner and Forst [55] have suggested that some degradation of visfatin/PBEF/Nampt in the serum samples studied might limit the conclusions reported by Haider et al. [54].

Hypoxia has been identified as a positive regulator of visfatin/PBEF/Nampt mRNA expression. Interestingly, this effect was mediated via HIF-1α (hypoxia-inducible factor-1α) in both 3T3-L1 adipocytes [56] and in the breast cancer cell line MCF-7 [57].

The fatty acids oleate and palmitate significantly decreased visfatin/PBEF/Nampt mRNA expression in 3T3-L1 adipocytes in vitro [48,58]. Furthermore, the rosiglitazone-induced secretion of visfatin/PBEF/Nampt was reversed by synthetic fatty acids in human adipocytes [53]. In contrast, plasma visfatin/PBEF/Nampt levels, as well as visfatin/PBEF/Nampt mRNA expression in subcutaneous fat, were not altered when insulin resistance was induced by infusion of NEFAs (non-esterified fatty acids; ‘free fatty acids’) in vivo [24].

Taken together, studies on the in vitro regulation of visfatin/PBEF/Nampt have shown that expression of this adipokine is tightly regulated by different hormones and drugs influencing insulin sensitivity. Furthermore, regulation of visfatin/PBEF/Nampt synthesis appears to be cell-type- and tissue-specific. A major drawback of most of the published studies is that only mRNA expression, but not protein secretion, was quantified.

CONCLUSIONS

At least three specific functional properties have been suggested for visfatin/PBEF/Nampt: (i) as an enzyme in the catalysis of the rate-limiting step in the production of NAD+ from nicotinamide; (ii) as a novel insulin-mimetic fat-secreted factor; and (iii) as a regulatory factor in pro-inflammatory and immunomodulating processes. Although the catalytic properties of visfatin/PBEF/Nampt were elucidated better after the crystal structure of this protein was described, various questions remain to be addressed concerning its insulin-mimetic and pro-inflammatory effects. Thus it is unclear how visfatin/PBEF/Nampt binds to and activates the IR. Furthermore, there are insufficient results available to define which signalling pathways are involved in the pro-inflammatory and immunomodulating function of this adipokine. It is unknown by which mechanism visfatin/PBEF/Nampt is transported into the circulation. Typical peptide hormones, such as insulin, contain a signal sequence in their primary structure in order to be secreted into the circulation via an ER (endoplasmic reticulum)-mediated process. Surprisingly, visfatin/PBEF/Nampt lacks such a signal sequence [5]; however, significant concentrations of the protein have been detected in plasma and serum [2,13,2139,54,59,60]. Furthermore, visfatin/PBEF/Nampt secretion from various cells has been observed [6,54,61]. In contrast, other groups have suggested that the presence of visfatin/PBEF/Nampt in supernatants of various cell types is only as a result of cell death, and is primarily found in the nucleus and cytoplasm [62,63]. Additional studies are clearly needed to better define the steps leading to visfatin/PBEF/Nampt secretion.

Studies on the in vivo and in vitro regulation of visfatin/PBEF/Nampt have yielded contradictory results. At present, the majority of results obtained do not support the hypothesis that visfatin/PBEF/Nampt is a major link between obesity and insulin resistance or a useful biomarker for different components of the metabolic syndrome. However, it has to be pointed out that no well-controlled prospective trials have been published to date determining the potential prognostic value of circulating visfatin/PBEF/Nampt in the prediction of metabolic and cardiovascular disease.

Although the concept of visfatin/PBEF/Nampt as an adipocyte-derived insulin-mimetic factor is still compelling, more detailed and better controlled in vivo and in vitro studies are necessary to elucidate further its function, regulation and potential clinical value.

Abbreviations

     
  • BMI

    body mass index

  •  
  • BP

    blood pressure

  •  
  • CKD

    chronic kidney disease

  •  
  • CRP

    C-reactive protein

  •  
  • GDM

    gestational diabetes mellitus

  •  
  • GH

    growth hormone

  •  
  • HOMAIR

    homoeostasis model assessment of insulin resistance

  •  
  • IGT

    impaired glucose tolerance

  •  
  • IL

    interleukin

  •  
  • IR

    insulin receptor

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • Nampt

    nicotinamide phosphoribosyltransferase

  •  
  • NAPRTase

    nicotinic acid phosphoribosyltransferase

  •  
  • NEFA

    non-esterified fatty acid

  •  
  • NGT

    normal glucose tolerance

  •  
  • NMN

    nicotinamide mononucleotide

  •  
  • PBEF

    pre-B-cell colony-enhancing factor

  •  
  • PCOS

    polycystic ovary syndrome

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PPAR

    peroxisome-proliferator-activated receptor

  •  
  • PRPP

    phosphoribosylpyrophosphate

  •  
  • QAPRTase

    quinolinic acid phosphoribosyltransferase

  •  
  • SAT

    subcutaneous adipose tissue

  •  
  • Sir

    silent information regulator

  •  
  • T1DM

    Type 1 diabetes mellitus

  •  
  • T2DM

    Type 2 diabetes mellitus

  •  
  • TNF-α

    tumour necrosis factor-α

  •  
  • VAT

    visceral adipose tissue

  •  
  • WHR

    waist-to-hip ratio

The study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG), KFO 152: ‘Atherobesity’, project FA476/4-1 (TP 4) to M. F., project BL833/1-1 (TP 3) to M. B., and project BE1264/10-1 (TP 5) to A. G. B.-S. Furthermore, the study was supported by a grant from the IZKF Leipzig to M. F. (Project B25).

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