Keywords
visfatin - newborns - pregnancy - gestational diabetes mellitus - preeclampsia - breast-feeding
Introduction
Adipose tissue is considered as an endocrine organ secreting numerous neuroendocrine
and peripheral peptides, called adipokines (adiponectin, leptin, resistin,[1] vaspin, apelin, visfatin, tumor necrosis factor-α [TNF-α], acylation-stimulating
protein [ASP], interleukin-6 [IL-6], plasminogen activator inhibitor-1 [PAI-1], and
transforming growth factor-β [TGF-β][2]
[3]). They act as inflammatory molecules, playing a critical role in both short- and
long-time energy homeostasis, metabolic processes, and body fat regulation.[4]
Moreover, these peptides are considered as a new link between obesity, insulin resistance,[5] cardiovascular disease, hypertension, as well as hyperlipidemia.[6]
This review aims to emphasize the molecular and endocrine mechanisms of visfatin and
its role in fetal development.
Review
Nicotinamide phosphoribosyltransferase (Nampt) has been identified originally as pre–B-cell
colony-enhancing factor (PBEF), capable of promoting the maturation of B-cell precursors
together with IL-7 and stem cell factor (SCF).[7] It was rediscovered as an adipocytokine, also known as “visfatin,” found in visceral
adipose tissue, playing a role in glucose homeostasis.[8]
[9] Nampt has also been identified as nicotinamide adenine dinucleotide (NAD) biosynthetic
enzyme. However, some of its functions are controversial and are still being discussed.
Nampt exists in two different types: intracellular (iNampt) and extracellular (eNampt)
forms.
iNampt
In 1957,[10] iNampt was identified as NAD biosynthetic enzyme.[11] In mammals, tryptophan, nicotinic acid, and nicotinamide are the major precursors
for NAD, but nicotinamide is mainly used to synthesize it.[12]
Nampt promotes the transfer of a phosphoribosyl group from 5-phosphoribosyl-1-pyrophosphate
(PRPP) to nicotinamide, forming nicotinamide mononucleotide (NMN) and pyrophosphate
(PPi).[13] NMN is then converted to NAD by nicotinamide mononucleotide adenylyltransferase.
NAD plays a critical role in cellular redox reactions. Furthermore, NAD is useful
for deacetylase activity of proteins and synthesis of transcriptional regulation factor
(e.g., silent information regulator [SIR]).[14]
[15] SIR, NAD-dependent enzymes called sirtuins, mediates life span extension cell (mouse fibroblasts, human vascular smooth muscle
cells, cardiac myocytes, and pancreatic B cells) caused by variety of stresses as
well as nutritional restriction.[16] In fact, pancreatic B-cell–specific Sirt2-overexpressing (BESTO) mice show strongly
enhanced glucose-stimulated insulin secretion (GSIS) and enhanced glucose tolerance.
These findings suggest a further Nampt-mediated role in metabolic balance.[17]
[18]
eNampt
The molecular mechanism of secretion (through passive and/or active secretory pathway)[18]
[19] and the role of eNampt are not still clear.[20] Three different functions have been assigned to eNampt: insulin-mimetic hormone
(adipocytokine named “visfatin”), cytokine, and aNAD biosynthetic enzyme.[21]
Visfatin has a molecular weight of 52 kDa. The coding region of the gene encodes for
491 amino acids.[22] It is synthesized by the bone marrow, liver, lungs, skeletal muscle, brain, heart,
pancreas, and peripheral blood lymphocytes.[23]
In particular, it is mostly expressed in human visceral fat.[24] In a case–control study conducted on prepubertal obese children, it was demonstrated
that obese patients have higher concentrations than normal-weight people. Elevated
serum visfatin levels were also positively correlated with body fat mass; in fact
visfatin concentration decreases when weight loss occurs.[25]
Friebe and colleagues, in an experimental study, revealed that its expression is higher
in adipocytes compared with preadipocytes,[9] suggesting that visfatin is a differentiated adipocytes-specific molecule and its
production is influenced by serum lipid levels.
The role of visfatin in glucose metabolism is still unclear.
Several case–control studies assessed that visfatin was related to several conditions
such as insulin resistance, obesity, dyslipidemia, and metabolic syndrome.[26]
[27]
[28]
[29]
In fact, Tascilar and colleagues noted that visfatin is correlated with homeostatic
model assessment-insulin resistance (HOMA-IR) in children.[27] However, in comparative study, Berndt and colleagues noted that plasma visfatin
correlates significantly with percent body fat, body mass index (BMI), and visfatin
messenger RNA (mRNA) level in visceral adipose tissue, but not with visceral fat mass
or waist-to-hip ratio.[28] Furthermore, no relationship was observed between serum visfatin levels and fasting
plasma insulin, fasting glucose and insulin sensitivity in nondiabetic subjects. In
two recent studies, plasma visfatin was higher in patients with type 2 diabetes mellitus
(T2DM) than in control group.[29]
Probably, visfatin promotes a glucose uptake (through 3T3l1 on adipocytes and L6 on
myocytes and glycolysis, regardless insulin).[30] In fact, visfatin binds the same insulin receptor through a distinct epitope.[24]
Visfatin, stimulated phosphorylation of insulin receptor substrate (IRS)-1/2 and activate
phosphatidyl inositol 3-kinase (PI3K), induced glucose uptake, glucose transporter
(GLUT)-1 protein expression, production of profibrotic factors (including type I collagenase,
TGF-β 1, PAI-1), increased metalloproteinase-9 activity in THP-1 cells (monocyte-like
cell line derived from a patient with acute monocytic leukemia), and production of
TNF-α and IL-8 in peripheral blood mononuclear cells.[31]
Friebe and colleagues assessed that Nampt influenced leucocyte count and this latter
is also correlated to insulin resistance and obesity.[32]
In fact, eNampt, proinflammatory transcription factor nuclear factor-κB (NF-κB) in
a reactive oxygen species (ROS)–dependent manner, induces the adhesion of leukocytes
to endothelial cells, by activating intercellular adhesion molecule (ICAM)-1 and vascular
cell adhesion molecule (VCAM)-1.
These evidences suggest underlying low-grade vascular inflammation in obesity and
T2DM.[33]
Visfatin and Inflammation
Visfatin and Inflammation
In experimental research, Moschen and colleagues demonstrated inflammatory activities
of visfatin. In fact, its serum levels were higher in patients with inflammatory disease
than in healthy controls[20]
[30] ([Table 1]). Visfatin seemed to induce human leukocytes and pro- and anti-inflammatory cytokine
production: IL-1b, IL-1Ra, IL-6 (in synovial[34] and amniotic epithelial cells), IL-8 (in neutrophils[35]), IL-10, and TNF-α (in monocytes,[31] macrophages,[36] and neutrophils).[20]
[30] Furthermore, visfatin increased the surface expression of costimulatory molecules
CD54, CD40, and CD80 ([Fig. 1]). These effects involved p38 as well as MEK1 pathways as determined by inhibition
with MAPK inhibitors and activation of NF-κB. In addition, macrophages, dendritic,
and epithelial cells might be a source of visfatin. These data confirmed a proinflammatory
role of this adipocytokine.[30]
Fig. 1 Visfatin secretion and function. HDL, high-density lipoprotein; IL-6, interleukin-6;
TNF-α, tumor necrosis factor-α.
Table 1
Descriptive table of the most important studies conducted on Visfatin function
|
Type of study
|
Authors
|
|
Case–control
|
Tascilar and colleagues[27]
|
|
Chen and colleagues[29]
|
|
Cekmez and colleagues[42]
|
|
Chan and colleagues[55]
|
|
Pagano and colleagues[56]
|
|
Yanni and colleagues[61]
|
|
Giapros and colleagues[62]
|
|
Cekmez and colleagues[63]
|
|
Kim and colleagues[72]
|
|
Demir and colleagues[73]
|
|
Experimental
|
Friebe and colleagues[9]
|
|
Moschen and colleagues[30]
|
|
Yonezawa and colleagues[65]
|
|
Cross-sectional
|
Mazaki-Tovi and colleagues[51]
|
|
Comparative
|
Berndt and colleagues[28]
|
|
Zhaoxia and colleagues[57]
|
|
Research support
|
Martos-Moreno and colleagues[25]
|
|
Mu and colleagues[26]
|
|
Ferreira and colleagues[70]
|
|
Prospective
|
Malamitsi-Puchner A and colleagues[52]
|
|
Review
|
Garten A and colleagues[20]
|
|
Abstract
|
Milovanov and colleagues[71]
|
Visfatin and Pregnancy
During pregnancy, changes in maternal metabolism and redistribution of maternal adipose
tissue occur in response to growing and metabolic needs of fetus and placenta. In
particular, during fetal development, visfatin is expressed in exocrine and endocrine
tissue. iNampt is highly released by fetal membranes, amnion, myometrium, placenta,
and adipose tissue.
The amnion and deciduae at term contained higher levels of PBEF mRNA.[37]
However, the release and regulatory mechanisms of visfatin in the fetus and the neonate
remain unclear. Probably, it may be regulated by glucose and insulin,[38] and it increases with progressive B-cell deterioration, insulin resistance, and
maternal weight.[29]
[39]
Serum visfatin levels fluctuate with advancing gestation. Mastorakos and colleagues
recorded that median concentration of visfatin were higher in the second (24–26 weeks)
and third trimesters (34–36 weeks).[40]
Nampt seems to confer protection from apoptosis[41] and to increase infection-induced response. It also promotes the release of inflammatory
cytokines, such as IL-6 and IL-8, in amnion-like epithelial cells in sepsis patients.[20] Therefore, Cekmez and colleagues, in case–control study ([Table 1]), proposed that visfatin could be used as a diagnostic marker similar to C-reactive
protein (CRP), procalcitonin, and IL-6 in neonatal sepsis.[42]
After birth, Nampt expression decreases in exocrine tissue but remains in endocrine
cells, predominately β cells.[23]
Unlike term newborns, a preterm infant frequently shows glucose homeostasis imbalance.[43] After hypoglycemic phase, because of limited glycogen and fat stores, hyperglycemia
occurs for a condition of insulin resistance, relative insulin deficiency, and increased
ratio of the glucose transporters (Glut)-1/Glut-2 in fetal tissues.[44] Several studies have confirmed that alterations in circulating adipokines can be
associated with adaptations to gestation, as well as in complications of pregnancy.[45] Precisely, hypoadiponectinemia has been shown to be associated with insulin resistance,[46] leptin may influence the “programming” of satiety,[47]
[48] and visfatin can increase in parallel with hyperglycemia for insulin-like effect.[49]
In fact, several studies demonstrated that higher maternal plasma visfatin concentration
is associated with insulin resistance, gestational diabetes mellitus (GDM), patients
with small-for-gestational-age (SGA),[50]
[51] and neonates with intrauterine growth restriction (IUGR).[52]
Visfatin and Gestational Diabetes Mellitus
Visfatin and Gestational Diabetes Mellitus
It has been reported increased serum visfatin levels during pregnancy, in T1DM or
T2DM, and in obese patients.[39] Insulin resistance is accompanied by increased visfatin production and/or secretion,
it reflect a compensatory mechanism favoring insulin deficiency. In fact, a gradually
increasing insulin resistance during 1st and 2nd trimester of pregnancy may be compensated
for by a sustained increase of visfatin, an insulinomimetic molecule.[8]
[53] However, visfatin did not change in a similar way during all 3 trimesters. This
condition can be attributable to an increase of visfatin production by an additional
source other than adipose tissue, the placenta. Therefore, the increased serum concentration
observed in gestational diabetes mellitus (GDM) may result from placental oversecretion.[54] Insulin resistance is physiologic in women with normal pregnancies and it is directly
correlated with gestational age. Women affected by GDM showed hyperglycemia and hyperinsulinemia.
Insulin response can decrease by up to 40% in late pregnancy.[40] Other studies, however, have revealed opposite effects in gestational diabetes[55] and obesity.[56] Zhaoxia and colleagues evaluated visfatin levels in normal pregnancy and in women
with GDM. They found that visfatin levels increased following oral glucose in normal
pregnancy, and this directly correlated with glycemia, cholesterol, and insulin resistance.
Otherwise, serum visfatin levels were lower in women with GDM[57] ([Fig. 1]).
Visfatin in IUGR and SGA Newborns
Visfatin in IUGR and SGA Newborns
Recently, a relationship between circulating maternal visfatin and fetal growth has
been proposed. In the third trimester of pregnancy, Fasshauer and colleagues reported
that women with fetal growth restriction (FGR) presented higher plasma maternal visfatin
than with control group.[58] It has been hypothesized that visceral adipose tissue is the major source of visfatin,[8] and data suggest that low-birth-weight (LBW) and IUGR newborns may have increased
visceral fat stores. Therefore, Malamitsi-Puchner and colleagues prospectively considered
that visfatin might be considered as biomarker for metabolic syndrome in IUGR.[52] However, Harrington and colleagues did not note differences in fat distribution
between newborns with IUGR and control group.[59] Other authors noted that cord blood visfatin concentrations did not differ between
SGA and adequate-for-gestational-age (AGA) newborns. Some studies showed that cord
serum visfatin is closely associated with indices of fetal size in infants from smoking
mothers, but not control group.[60] Otherwise, other authors achieved opposite results finding higher visfatin levels
in large-for-gestational-age (LGA) newborns. In cross-sectional study Mazaki-Tovi
and colleagues investigated the linkage between visfatin and risk of development of
GDM and fetal size, precisely in LGA neonate.[45] In response to maternal hyperglycemia, fetus develops hyperglycemia and hyperinsulinemia
due to pancreatic islet cells stimulation. In LGA neonates, hyperinsulinemia in utero
leads to fetal macrosomia. LGA, SGA, and LBW newborns have an increased risk for developing
metabolic syndrome in adulthood.[49]
Recently, however, it has been reported that preterm newborn, whether SGA or AGA,
with normal BMI, did not show insulin resistance in childhood. There were no detected
significant differences in adipocytokine levels between the preterm SGA and AGA groups.[61]
[62]
However, in a control study, it has been suggested that, independent of being SGA
or LBW, visfatin might be an early indicator of insulin resistance.[63] It was also noted lower adipopectic and higher visfatin levels in LGA and SGA than
AGA neonates.[52] Consistently, an increased release of visfatin was demonstrated in the amnion of
twins and triplets. It can be assumed maternal plasma visfatin also derived from the
stretched fetal membranes of women with LGA fetuses.[64] These data suggest that visfatin is a possible link between maternal and fetal environment.
Visfatin and Breast-Feeding
Visfatin and Breast-Feeding
In the first 6 months of lactation, Yonezawa and colleagues demonstrated, in animal/experimental
study, the presence of mRNA-visfatin in cloned bovine mammary gland and human breast
cancer cell line.[65] Moreover, milk visfatin levels are directly related to preconceptional maternal
BMI. In fact, it has been found higher breast milk visfatin concentrations for a BMI
greater than 28 to 30 kg/m2. Visfatin seems to limit a weight loss in newborns.[66]
Visfatin and Preeclampsia
Visfatin and Preeclampsia
Preeclampsia (PE) is a multisystemic disorder of pregnancy, characterized by onset
hypertension, endothelial dysfunction, and proteinuria that develop after 20 weeks
of gestation in previously normotensive women.[67] The precise cause of PE is still unclear, but it is believed to be likely multifactorial.
The role of visfatin in PE was investigated by several studies. Circulating visfatin
concentrations are increased in PE in some studies,[68] whereas other investigators show similar[52] or even decreased concentrations.[69] Ferreira and colleagues hypothesized that visfatin develops PE, promoting an impaired
placental vascularization, due to increased serum vascular endothelial growth factor
(VEGF) levels[70] ([Fig. 1]). Conversely, Milovanov and colleagues noted decreased expression of VEGF as well
as visfatin in pregnancies complicated by PE.[71] During the third trimester of pregnancy, in women affected by PE, Kim and colleagues
further showed decreased placental visfatin levels.[72] Although the severity of PE did not influence serum visfatin values, authors investigated
relationship between PE, gestational age (SGA), and maternal circulating visfatin
concentrations. These were higher in women who delivered SGA newborns than normal
pregnancy and PE groups.[73] However, further studies did not confirm these data.[51]
In conclusions, though the primary purpose of adipose tissue is energy storage, it
has been also identified as an active endocrine-immune organ releasing many cytokines
(adipocytokines) and hormones. In response to an autocrine and paracrine manner to
impair adipocyte function, it has been reported that phenotypic changes of adipocytes
occur into inflammatory response and promote a variety of diseases. Here, we have
focused on visfatin expression, a recently identified adipocytokine. Although its
precise function remains to be established, this review aims to emphasize the molecular
and endocrine mechanisms of visfatin and to clarify its role in the pathophysiology
of inflammatory-endocrine disorders, also during normal and pathologic pregnancy (e.g.,
PE, GDM, and alteration of fetal growth). Moreover, for its potential diagnostic and/or
prognostic role in the prediction of any associate disease or condition, visfatin
could also be considered as a new biomarker, indicating specific disorders in the
neonatal metabolic profile, determining the interconnection of the different processes,
and defining disease severity. In addition, several diseases could be treated by normalization
and/or regulation of the proinflammatory cytokine/adipokine profile. For these novel
concepts, visfatin might be promising candidates for future pharmacologic treatment
strategies. Further research will bring new insight into linkage between visfatin
and humans, during pregnancy and perinatal period.
