Keywords

1 Introduction

In the pathogenesis of type 2 diabetes mellitus (T2DM), the tight regulation of insulin sensitivity and secretion is dysbalanced. This is caused by both environmental and genetic factors.

While the physiological significance of nicotinamide phosphoribosyltransferase (Nampt) in obesity, T2DM, and other metabolic disorders is still unclear, the intracellular nicotinamide adenine dinucleotide (NAD) biosynthetic function of Nampt is well characterized. In the NAD biosynthetic pathway from nicotinamide , Nampt (EC 2.4.2.12) catalyzes the rate-limiting step, namely the transfer of a phosphoribosyl group from 5-phosphoribosyl-1-pyrophosphate (PRPP) to nicotinamide, forming nicotinamide mononucleotide (NMN ) and pyrophosphate (PPi) (Rongvaux et al. 2002) (Fig. 1). NMN is then converted into NAD by the isoenzymes nicotinamide mononucleotide adenylyltransferase (Nmnat, EC 2.7.7.1) 1 – 3 (Fig. 1). While tryptophan and nicotinic acid are also precursors for NAD biosynthesis in mammals, nicotinamide is predominantly used to synthesize NAD (Magni et al. 1999; Rongvaux et al. 2003). NAD is a coenzyme with a well-established role in cellular redox reactions. Recently, several lines of evidence have implicated NAD biochemistry in a broad range of biological functions. For example, NAD is used as a substrate in a number of important signaling pathways in mammalian cells, including poly(ADP-ribosyl)ation in DNA repair (Ménissier de Murcia et al. 2003), mono-ADP-ribosylation in both the immune response and G-protein-coupled signaling (Corda and Di Girolamo 2003), and synthesis of cyclic ADP-ribose and nicotinate adenine dinucleotide phosphate (NAADP) in intracellular calcium signaling (Lee 2001). Furthermore, NAD and its derivatives also play important roles in transcriptional regulation (Lin and Guarente 2003). In particular, the discovery that yeast and mammalian Sir2 (silent information regulator 2 ) proteins require NAD for their deacetylase activity (Imai et al. 2000) has drawn much attention to this novel regulatory role for NAD.

Fig. 1
figure 1figure 1

NAD biosynthetis from nicotinamide. The rate-limiting step in mammalian NAD biosynthesis from nicotinamide is the transfer of a phosphoribosyl residue from 5-phosphoribosyl-1-pyrophosphate (PRPP) to nicotinamide catalyzed by nicotinamide phosphoribosyltransferase (Nampt ) to produce nicotinamide mononucleotide (NMN ), which is then converted into NAD by nicotinamide mononucleotide adenylyltransferase (Nmnat)

Full size image

Although Nampt enzymatic activity was reported and characterized as early as 1957 (Preiss and Handler 1957), the gene encoding Nampt was first identified in Haemophilus ducreyi in 2001 (Martin et al. 2001). Since then, several groups have characterized the enzymological features of mammalian Nampt (Revollo et al. 2004; van der Veer et al. 2005). The K m value of Nampt for nicotinamide is ~1 μM, and it does not use nicotinic acid as a substrate (Revollo et al. 2004). The crystal structure of Nampt has been determined, which clearly demonstrates that this protein belongs to the dimeric class of type II phosphoribosyltransferases (Khan et al. 2006; Kim et al. 2006; Wang et al. 2006).

Whereas the biochemical and structural basis of Nampt as an intracellular NAD biosynthetic enzyme has been well established, this protein seems to have several other physiological functions. Human Nampt was originally characterized as a cytokine named pre-B-cell colony enhancing factor (PBEF ) (Samal et al. 1994). Nampt was also claimed to function as an insulin-mimetic adipocytokine, predominantly secreted from visceral fat and therefore named visfatin (Fukuhara et al. 2005). We will discuss these different functional aspects of Nampt and its potential roles in a variety of pathophysiological conditions including type 2 diabetes.

2 Nampt and Metabolic Disorders

The function of intracellular Nampt (iNampt) as NAD biosynthetic enzyme has been well characterized. In contrast, the physiological role of extracellular Nampt (eNampt) has been a matter of much debate. At least three different functions have been assigned to eNampt – an insulin-mimetic, a cytokine -like, and a function as an NMN producing enzyme (Pilz et al. 2007; Revollo et al. 2007a; Sethi 2007; Yang et al. 2006). It is not clear which of these functions is important in what physiological context. There is also no study that has demonstrated in what way eNampt enters extracellular space and what distinguishes iNampt and eNampt on the molecular level. This makes it difficult to investigate the role that iNampt and eNampt play in various pathophysiological metabolic states as is discussed in more detail below.

2.1 eNampt and iNampt: Regulation of Pancreatic β-Cell Function

The most controversial function assigned to the Nampt protein was the insulin-mimetic activity as an adipocytokine named “visfatin ” described by Fukuhara et al. (2005). This study found that eNampt acted like insulin by binding to the insulin receptor , activating the associated downstream signaling pathway and eliciting similar biological reponses in vitro and in vivo on adipogenesis, cellular glucose uptake, and blood glucose levels. Their results immediately drew attention to a possible connection between eNampt and metabolic complications, such as obesity and T2DM. However, this paper has been retracted (Fukuhara et al. 2007). Three subsequent studies have so far provided indirect evidence for the connection between eNampt and insulin signaling (Dahl et al. 2007; Song et al. 2008; Xie et al. 2007). One group has reported an insulin-like action of eNampt on osteoblasts, which was blocked by the pretreatment with the insulin receptor kinase inhibitor HNMPA-(AM)3 (Xie et al. 2007). In another study, it has been reported that the same inhibitor blocked the effect of eNampt on matrix metalloproteinase (MMP)-9 activity in THP-1 cells and the production of TNF-α and IL-8 in PBMC (Dahl et al. 2007). A third group has found multiple actions of eNampt on cultured kidney mesangial cells. eNampt induced uptake of glucose, glucose transporter (GLUT)-1 protein expression, and synthesis of profibrotic molecules, including transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and type I collagen (Song et al. 2008). Whereas a potent Nampt inhibitor FK866 (Hasmann and Schemainda 2003) blocked this eNampt-mediated glucose uptake, knockdown of the insulin receptor also inhibited this effect (Song et al. 2008). Unfortunately, none of the above studies has examined whether eNampt directly binds to the insulin receptor of respective target cells and whether the NAD biosynthetic activity is required for the observed effect.

In another study, it was demonstrated that eNampt does not exert insulin-mimetic effects in vitro or in vivo, but rather exhibits robust NMN biosynthetic activity and that this eNampt-mediated NMN biosynthesis plays a critical role in the regulation of glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells in vitro and in vivo (Revollo et al. 2007b). To address the physiological significance of Nampt function in vivo, Nampt-deficient mice were generated. While Nampt homozygous (Nampt −/−) mice are embryonic lethal likely due to failure of adequate NAD biosynthesis, Nampt heterozygous (Nampt +/−) mice do not differ visibly from wild-type mice but show significant decreases in total NAD levels in tissues (Revollo et al. 2007b). Nampt +/− female mice revealed moderately impaired glucose tolerance and a significant defect in GSIS. Whereas islet morphology and size in Nampt +/− mice do not differ from control mice, further analyses of isolated primary islets revealed that Nampt +/− islets have functional defects in NAD biosynthesis and GSIS. Remarkably, insulin secretion defects in Nampt +/− mice and islets can be corrected by administration of NMN, confirming that the defects observed in Nampt +/− mice and islets are due to a lack of the NAD biosynthetic activity of Nampt. Furthermore, FK866, a potent chemical inhibitor of Nampt, significantly inhibited NAD biosynthesis and GSIS in isolated wild-type primary islets. Again, administration of NMN ameliorated defects in NAD biosynthesis and GSIS in FK866-treated wild-type islets. Thus, pancreatic β-cells require Nampt-mediated NAD biosynthesis to maintain normal NAD biosynthesis and GSIS and are capable of incorporating NMN from the extracellular space.

These findings are supported by a study on the mouse pancreatic β-cell line βTC6. Incubation with recombinant Nampt caused significant changes in the mRNA expression of several key diabetes-related genes, including upregulation of insulin, hepatocyte nuclear factor (HNF)-1β, HNF-4α, and nuclear factor-κB. Significant downregulation was seen in angiotensin-converting enzyme and UCP2. Insulin secretion was increased compared to that of control at low glucose and this increase was blocked by coincubation with the specific Nampt inhibitor FK866. Both Nampt and NMN induced activation of insulin receptor and extracellular signal-regulated kinase (ERK)1/2. Nampt-induced insulin receptor and ERK1/2 activation were inhibited by FK866 (Brown et al. 2010).

The contradictory results on the insulin-mimetic activity of Nampt could be explained by a possible crosstalk between eNampt-mediated and insulin signaling pathways in a cell type-dependent manner. eNampt could possibly bind to and activate an unidentified receptor that might indirectly affect insulin signaling. Another possibility is that Nampt-mediated NAD biosynthesis might have an impact on the insulin signaling pathway. To address these possibilities in future studies, it is critical to examine (1) whether the existence of the insulin receptor is necessary for the observed insulin-mimetic effects by using mutant cells that lack the insulin receptor, (2) whether nicotinamide , which is usually included at very high concentrations in cell culture media, is necessary to observe those effects, and (3) whether mutant Nampt proteins that lack NAD biosynthetic activity can still mediate the activity of interest in each condition. These analyses will resolve contradictory results around the claimed insulin-mimetic activity of Nampt.

In humans, it has been reported that individuals who carry specific single nucleotide polymorphism variants in the Nampt gene promoter region have lower fasting plasma insulin levels (Bailey et al. 2006; Mirzaei et al. 2009), suggesting that Nampt-mediated NAD biosynthesis might also regulate insulin secretion in humans.

Aging is one of the greatest risk factors for developing T2DM and other metabolic complications (Chang and Halter 2003; Moller et al. 2003). Sirtuins are a group of NAD -dependent enzymes that regulate metabolic responses to nutritional availability in different tissues and cellular responses to a variety of stresses and are also involved in the regulation of aging. Sirtuins deacetylate and/or ADP-ribosylate lysine residues of many target regulatory factors (Blander and Guarente 2004; Schwer and Verdin 2008). In their deacetylation reactions, sirtuins produce acetyl-ADP-ribose, nicotinamide , and deacetylated proteins. Silent information regulator 2 (Sir2), as the prototypical enzyme of this group, regulates the replicative life span of yeast mother cells (Kaeberlein et al. 1999). Strikingly, Sir2 homologues also regulate life span in worms and flies (Rogina and Helfand 2004; Tissenbaum and Guarente 2001) and, depending on the genetic background, mediate life span extension caused by caloric restriction, the only dietary regimen that can retard aging and extend life span in a wide variety of organisms (Guarente 2005). It is not yet known whether Sirt1 , the mammalian Sir2 orthologue, regulates aging and longevity in mammals. Because sirtuins absolutely require NAD for their function, NAD biosynthesis and Nampt play a critical role in the regulation of mammalian sirtuin activity.

A recent study found that Nampt -mediated systemic NAD biosynthesis and Sirt1 activity are affected in pancreatic β-cells of aged mice. Pancreatic β-cell-specific Sirt1-overexpressing (BESTO) mice exhibited significantly enhanced GSIS and improved glucose tolerance (Moynihan et al. 2005). However, these phenotypes were completely lost in both BESTO males and females when they reached 18–24 months of age (Ramsey et al. 2008). Plasma NMN levels and Sirt1 activity in pancreatic islets were significantly reduced in those aged BESTO mice.

Consistent with this finding, NMN administration could restore enhanced GSIS and improved glucose tolerance in aged BESTO females but not in males (Ramsey et al. 2008), although the reason for the observed sex-dependent difference remained unclear. These findings suggest that an age-dependent decline in Nampt -mediated systemic NAD biosynthesis contributes to reduced Sirt1 activity in aged pancreatic islets and likely in other aged tissues. Because sirtuins have recently emerged as promising pharmaceutical targets to develop therapeutic interventions against age-associated diseases (Milne et al. 2007; Westphal et al. 2008), the systemic enhancement of NAD biosynthesis might provide another pharmacological means to activate Sirt1 and to convey benefits against metabolic diseases like T2DM (Imai and Kiess 2009).

2.2 eNampt in Human Circulation: A Biomarker for Obesity and T2DM?

Nampt possesses neither a signal sequence nor a caspase I cleavage site (Rongvaux et al. 2002). Therefore, several studies have suggested that eNampt might be released simply by cell lysis or cell death (Hug and Lodish 2005; Stephens and Vidal-Puig 2006). On the other hand, it was shown that eNampt release is governed by a highly regulated positive secretory process in a cell type-dependent manner (Revollo et al. 2007b). Fully differentiated mouse and human adipocytes are capable of secreting eNampt through a nonclassical secretory pathway , which is not blocked by inhibitors of the classical ER–Golgi secretory pathway, such as brefeldin A and monensin (Revollo et al. 2007b; Tanaka et al. 2007). There is evidence that other cell types, such as human primary hepatocytes (Garten et al. 2010) and leukocytes (D. Friebe, personal communication) are also a significant source of eNampt in human circulation.

Numerous studies have been published, addressing possible associations between plasma eNampt levels and anthropometric and metabolic parameters in obesity and T2DM. So far, results have been conflicting, showing positive, negative, or no association (Arner 2006; Revollo et al. 2007a; Sethi 2007; Stephens and Vidal-Puig 2006). For example, one study reported a positive correlation of plasma eNampt concentrations with body mass index (BMI) and percent body fat (Berndt et al. 2005), while another study found that plasma eNampt is reduced in human obesity and not related to insulin resistance (Pagano et al. 2006). Two other studies reported that higher plasma eNampt levels are independently and significantly associated with T2DM even after adjusting for known biomarkers (Chen et al. 2006; Retnakaran et al. 2008). These contradictory findings appear to be in part due to significant differences in immunoassays and the treatment and type of samples. Freeze–thaw cycles and different sample additives have considerable influence on the measurement of eNampt concentrations (Nüsken et al. 2007). Also, commercially available immunoassays differ considerably in the specificity and sensitivity of eNampt detection in human serum and plasma (Körner et al. 2007).

Looking at recent studies (as summarized in Table 1), it appears that most groups detected an elevation of plasma Nampt levels in obese subjects. However, the association between plasma eNampt levels and metabolic disorders, such as obesity and T2DM, is still unclear, and careful assessments with highly accurate assays for the measurement of eNampt will be necessary to address this critical issue.

Table 1 Most recent studies concerning correlation of plasma eNampt concentrations with anthropometric and metabolic parameters
Full size table

Interestingly, in a recent study, Nampt levels in cerebrospinal fluid (CSF) were found to decrease with increasing plasma Nampt concentrations, BMI, body fat mass, and insulin resistance, indicating that the transport of Nampt across the blood–brain barrier might be impaired in obesity and that central nervous Nampt insufficiency or resistance might be linked to pathogenetic mechanisms of obesity (Hallschmid et al. 2009).

2.3 Role of Hepatic Nampt in T2DM

Hepatic insulin resistance is an underlying cause of the metabolic syndrome and the development of T2DM. In particular, the failure of insulin to suppress hepatic gluconeogenesis leads to hyperglycemia and, consequently, to the persistent stimulation of insulin production (Leclercq et al. 2007).

Sirt1 has been implicated in the regulation of hepatic glucose metabolism through the induction of gluconeogenic genes (Rodgers et al. 2005). Nampt regulates Sirt1 activity and also seems to be involved in the regulation of insulin signaling in the liver, as has been shown in animal studies. One group reported upregulation of Sirt1 and PPAR-α together with increasing NAD levels and Nampt activity in fasting mice (Hayashida et al. 2010). In rats that were injected with a Nampt overexpression plasmid insulin sensitivity was increased, while total cholesterol plasma levels decreased. The animals also displayed an enhanced insulin receptor substrate (IRS)-1 tyrosine phosphorylation in response to insulin as well as increased mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and sterol regulatory element-binding protein 2 (SREBP-2) in the liver and adipose tissues (Sun et al. 2009). SIRT1 protein and activity was increased by treatment with metformin through an adenosine monophosphate kinase (AMPK)-mediated increase in gene expression of Nampt in db/db mice (Caton et al. 2010).

Hepatic insulin resistance and a dysregulation of hepatic glucose and lipid metabolism are also major reasons for the development of nonalcoholic fatty liver disease (NAFLD) , which has been recognized as a component of the metabolic syndrome and can lead to liver cirrhosis. There are few studies on Nampt expression in human livers. In patients with liver cirrhosis, it was found that hepatic Nampt mRNA expression and Nampt levels in circulation were decreased compared with healthy controls (de Boer et al. 2009). In severely obese patients with NAFLD, Nampt serum levels were shown to be increased. After bariatric surgery, Nampt expression in livers and Nampt serum levels decreased as the patients lost weight (Moschen et al. 2009). Another report demonstrated a correlation of serum Nampt levels with liver histology in NAFLD. Nampt levels predicted the presence of portal inflammation in NAFLD patients (Aller et al. 2009).

From these results in animal and human studies, one can speculate that Nampt is involved in regulating glucose metabolism in hepatocytes through activation of Sirt1 . The liver also seems to be a major source for circulating Nampt, and Nampt levels in circulation are consequently influenced by impaired liver function.

3 eNampt: A Link Between T2DM and Inflammation

Human Nampt was originally identified by a screen of a human peripheral blood lymphocyte cDNA library and named pre-B-cell colony enhancing factor (PBEF , see above). This 52 kDa protein was reported to act as a presumptive cytokine that increased pre-B-cell colony forming activity together with interleukin (IL)-7 and stem cell factor (SCF) (Samal et al. 1994). iNampt is also highly expressed in human fetal membranes, amnion, and placenta. Nampt mRNA expression increases in fetal membranes after labor and in severely infected amnion membranes. Interestingly, eNampt treatment upregulates the expression of inflammatory cytokines , such as IL-6 and IL-8, in amnion-like epithelial cells. Thus, it has been speculated that eNampt might have a cytokine-like function involved in the regulation of labor and in infection-induced preterm birth (Ognjanovic and Bryant-Greenwood 2002; Ognjanovic et al. 2005).

In the pathophysiology of obesity and T2DM, it has been revealed that chronic inflammation plays an important role in the development of insulin resistance and other associated complications, such as atherosclerosis (Guest et al. 2008; Poirier et al. 2006; Schenk et al. 2008; Sowers 2003). In this regard, one might speculate that eNampt could show an association with the development of vascular inflammation induced by obesity and T2DM, instead of an association with anthropometric and metabolic parameters. Indeed, it has been shown that eNampt induces the adhesion of leukocytes to endothelial cells and aortic endothelium by activating intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 (Adya et al. 2008). This phenomenon appears to be mediated through the proinflammatory transcription factor nuclear factor-κB (NF-κB) in a reactive oxygen species (ROS)-dependent manner. The same study also revealed that eNampt significantly increases the transcriptional activity of NF-κB in human vascular endothelial cells, resulting in the activation of the MMP-2/9.

A study that was aimed at investigating the expression of Nampt in circulating blood monocytes in obese and/or type 2 diabetic human subjects found that Nampt expression was significantly upregulated in obese type 2 diabetic patients, whereas obese nondiabetics exhibited similar levels compared to lean controls (Laudes et al. 2010).

In contrast, an upregulation of Nampt mRNA expression levels in peripheral blood cells (PBCs) of obese compared with lean subjects was reported, along with a correlation of Nampt plasma levels to cholesterol, triglycerides, and hepatic enzymes in circulation (Catalán et al. 2010). Another group determined Sirt1 expression in peripheral PBMC and found that insulin resistance and metabolic syndrome were associated with low PBMC Sirt1 gene and protein expression. Sirt1 gene expression was negatively correlated with carotid intima-media thickness (CIMT). In the monocytic THP-1 cell line, high glucose and palmitate reduced Sirt1 and Nampt expression and reduced the levels of intracellular NAD through oxidative stress. These effects on Nampt and Sirt1 were prevented by resveratrol in vitro (de Kreutzenberg et al. 2010). Moreover, a direct association of Nampt with advanced carotid atherosclerosis and CIMT in patients with T2DM was determined with increased Nampt serum levels, especially in patients with carotid plaques (Kadoglou et al. 2010). Therefore, eNampt might play an important role in the progression and/or the associated complications, especially inflammatory complications, of obesity and T2DM.

eNampt has also been shown to be involved in the regulation of apoptosis as a cytokine . In human neutrophils, eNampt inhibits their apoptosis in response to various inflammatory stimuli, although this particular effect of eNampt requires the presence of iNampt to some extent (Jia et al. 2004). Recently, Nampt was identified as an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis in healthy individuals and in individuals with severe congenital neutropenia. Both extracellularly and intracellularly administered Nampt induced granulocytic differentiation of CD34(+) hematopoietic progenitor cells by NAD -dependent Sirt1 activation and subsequent upregulation of G-CSF synthesis and G-CSF receptor expression (Skokowa et al. 2009).

Furthermore, serum eNampt levels are found to be upregulated in sepsis patients, and rates of neutrophil apoptosis are found to be profoundly reduced in those patients (Jia et al. 2004). In amniotic epithelial cells, eNampt treatment appears to confer protection from apoptosis as a stretch-responsive cytokine (Kendal-Wright et al. 2008). In patients with inflammatory bowel disease (Crohn’s disease and ulcerative colitis), Nampt mRNA levels are increased in colon biopsy samples, and plasma eNampt levels are elevated (Moschen et al. 2007). Because eNampt stimulates the production of proinflammatory cytokines in PBMCs and upregulates IL-6 mRNA and serum levels in vivo when given intraperitoneally to mice, it has been suggested that eNampt itself also functions as a proinflammatory cytokine (Moschen et al. 2007). Stimulation of the tumor necrosis factor family member TNF- and APOL-related leukocyte-expressed ligand (TALL)-1, which is involved in lupus-like autoimmune diseases, increased Nampt mRNA (Xu et al. 2002). Additionally, Nampt has been found to be upregulated in a variety of other immunological disorders including acute lung injury, rheumatoid arthritis, and myocardial infarction and is considered a novel mediator of innate immunity (Luk et al. 2008).

These studies all suggest that eNampt might function as an inflammatory cytokine . In most studies, it has not been fully addressed which activity of eNampt, NAD biosynthetic activity vs. cytokine-like activity, is responsible for the observed effects of eNampt. However, two studies have reported an enzyme-dependent proinflammatory action of Nampt : in inflammatory cells in vitro and in joints affected with rheumatoid arthritis in vivo (Busso et al. 2008) and in cultured human aortic smooth muscle cells (Romacho et al. 2009). In contrast, one group has demonstrated that eNampt protects macrophages from ER stress-induced apoptosis through its cytokine-like activity that is totally separated from its NAD biosynthetic activity (Li et al. 2008).

There is evidence that Nampt exerts its proinflammatory actions through the upregulation of monocyte chemoattractant protein (MCP)-1. MCP-1 levels were significantly increased after Nampt administration in cultured human adipocyte supernatant and serum of mice. The detectability of Nampt in serum predicted circulating MCP-1 independent of age and gender in humans (Sommer et al. 2010).

Therefore, although how eNampt exerts its cytokine -like activity in different cellular contexts still needs to be investigated, there is clear evidence that it functions as an immunomodulatory cytokine.

4 Concluding Remarks and Future Aspects

Nampt functions as an intra- and extracellular NAD biosynthetic enzyme that is important for the regulation of metabolism and stress resistance through sirtuins and other NAD-consuming regulators. On the other hand, eNampt appears to act as a cytokine , independent of its enzymatic activity, and plays a major role in the regulation of immune responses. The cytokine-like and the enzymatic functions of Nampt still need to be investigated extensively. Thorough assessments of these two roles will presumably greatly enhance our knowledge about its role in different physiological contexts. In this regard, it will also be important to analyze the mechanism and regulation of eNampt secretion and identify its putative receptor and upstream signaling.

To further clarify the effects of iNampt on cellular metabolism, it will also be important to understand the subcellular compartmentalization of Nampt and other enzymes involved in the biosynthesis and the breakdown of NAD and the regulation of their localization. Additionally, very little is known about the flux of NAD substrates, intermediates, and metabolites. Therefore, it will be critical to study not only the regulation of NAD biosynthesis and breakdown in each cellular compartment, but also the spatial and temporal dynamics of NAD metabolism at a systemic level using a metabolomics approach. For example, it will be of great interest to clarify how NMN as a product from the eNampt enzymatic reaction is distributed to target tissues, e.g., pancreatic β-cells, and how it mediates its physiological and pharmacological effects in these tissues.

To date, a substantial part of the studies on the biological functions of Nampt has been conducted in cell culture and mouse models, and the studies on possible correlations between human plasma eNampt levels and metabolic parameters have been contradictory. Therefore, more work needs to be done to elucidate the physiological relevance of the eNampt function in normal individuals and patients with metabolic and other diseases in humans.

Nampt itself or any component in Nampt-mediated systemic NAD biosynthesis could be an effective therapeutic target/reagent for the prevention and the treatment of metabolic disorders including obesity and T2DM, inflammation, and cancer. Because downstream regulators, such as sirtuins and PARPs, have pleiotropic functions, more rigorous investigations will be necessary to clarify possible benefits from the manipulation of Nampt-mediated NAD biosynthesis.