Horm Mol Biol Clin Invest 2015; 24(1): 1124
Jolle Dupont*, Xavier Pollet-Villard, Maxime Reverchon, Namya Mellouk and Rachel Levy
Adipokines in human reproduction
DOI 10.1515/hmbci-2015-0034
Received July 27, 2015; accepted October 5, 2015; previously published
online November 17, 2015
Abstract: Adipose tissue communicates with other central
and peripheral organs by the synthesis and release of sub-
stances called adipokines. The most studied adipokine is
leptin but others have been recently identified including
resistin, adiponectin, chemerin, omentin and visfatin.
These adipokines have a critical role in the development
of obesity-related complications and inflammatory condi-
tions. However, they are also involved in other functions
in the organism including reproductive functions. Indeed,
many groups have demonstrated that adipokine receptors,
such as adiponectin and chemerin, but also adipokines
themselves (adiponectin, chemerin, resistin, visfatin and
omentin) are expressed in human peripheral reproduc-
tive tissues and that these adipokines are likely to exert
direct effects on these tissues. After a brief description of
these new adipokines, an overview of their actions in dif-
ferent human reproductive organs (hypothalamus, pitui-
tary, ovary, testis, uterus and placenta) will be presented.
Finally, comments will be made on the eventual altera-
tions of these adipokines in reproductive disorders, with
special attention to polycystic ovary syndrome, a disease
characterized by dysfunction of gonadal axis and systemic
nerve endocrine metabolic network with a prevalence of
up to 10% in women of reproductive age.
Keywords: adipose tissue; endocrine signaling; fertility;
human; male and female.
*Corresponding author: Dr. Jolle Dupont, INRA, UMR85, Unit
Physiologie de la Reproduction et des Comportements, Nouzilly,
France; CNRS, UMR7247, Nouzilly, France; Universit Franois
Rabelais, Tours, France; and LInstitut franais du cheval et de
lquitation (IFCE), Nouzilly, France, Phone: +33 2 47 42 77 89,
Fax: +33 2 47 42 77 43, E-mail: jdupont@tours.inra.fr
Xavier Pollet-Villard: Service de Medecine de la Reproduction,
Hopital Tenon (AP-HP), 4 Rue de la Chine, 75020, Paris
Maxime Reverchon and Namya Mellouk: INRA, UMR85, Unit
Physiologie de la Reproduction et des Comportements, Nouzilly,
France; CNRS, UMR7247, Nouzilly, France; Universit Franois
Rabelais, Tours, France; and LInstitut franais du cheval et de
lquitation (IFCE), Nouzilly, France
Rachel Levy: Service de Medecine de la Reproduction, Hopital
Tenon (AP-HP), 4 Rue de la Chine, 75020, Paris
Introduction
In a few decades, our view of adipose tissue has changed
from lipid storage to an endocrine tissue [1]. In fact,
white adipose tissue may be the largest endocrine tissue
in humans and is currently considered as an endocrine
organ in and of itself, secreting more than 600 potential
cell signaling mediators [2]. It communicates with other
central and peripheral organs by synthesis and release of
substances from adipocytes, adipocyte progenitors, mac-
rophages or stroma cells. These substances, called adi-
pokines, include cytokines, hormones, growth factors,
chemokines, complement factors, and proteins involved
in various functions including lipid metabolism, glucose
homeostasis, angiogenesis, haemostasis, inflammation
and regulation of blood pressure. The plasma levels of
some adipokines are associated to specific metabolic
states [3]. For example, a dysregulation of plasma adi-
pokines is implicated in obesity, type 2 diabetes and
hypertension. Obesity is a risk factor for infertility and
adverse reproductive outcomes in both men and women.
In male patients, there is evidence that being obese or
overweight negatively affects reproductive potential,
not only by reducing sperm quality, but also by altering
the physical and molecular structure of germ cells in the
testes and consequently affecting the maturity and func-
tion of sperm cells [4]. In female patients, obesity can
affect the reproductive tissue at different levels: oocyte
maturation, embryo development and implantation, pla-
centa and uterine environment [5]. Furthermore, interest
in the reproductive endocrine aspects of adipose tissue
has increased partly due to interest in polycystic ovary
syndrome (PCOS), one of the most investigated and prev-
alent endocrinopathies in women of reproductive age
[6]. PCOS is manifested by hyperandrogenism, polycys-
tic ovaries on ultrasound, oligomenorrhoea and anovu-
lation. Excess adipose tissue is present in most of PCOS
patients [7].
It has been shown that adipokines are functionally
involved at different levels of the reproductive axis includ-
ing the gonad and hypothalamic-pituitary axis. Many
studies described the presence and the role of the adi-
pokines and their receptors in the male and female repro-
ductive tract of different species including humans. These
adipokines regulate ovarian steroidogenesis, oocyte
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12Dupont etal.: Adipokines and human reproductive organs
maturation, and embryo development. They are also
present in the uterus and placenta. Since the discovery
of leptin in 1994, other new adipokines synthesized and
released by the adipose tissue have been identified. Here,
we review the recent progress regarding the role of some
of these new adipokines including resistin, adiponectin,
chemerin, omentin, and visfatin in the human reproduc-
tive organs. In human, these new adipokines have not
been extensively studied at the hypothalamus-pituitary
axis and at the cellular level in the testis. Thus, for these
latter organs, we will report some data obtained in animal
models.
Resistin
Resistin is a 12.5 kDa adipokine belonging to a family
of cysteine-rich protein known as resistin-like mole-
cules (RELM) or found in the inflammatory zones (FIZZ)
proteins, characterized in 2001 by 3 different research
teams [810]. Resistin is secreted by adipocytes and
functionally impairs glucose metabolism, inducing
insulin resistance [9]; it has also been associated with
proinflammatory changes in the vascular endothelium
[11], pathways linked to various inflammatory diseases
[12] and angiogenesis [13]. In humans, resistin is mainly
produced by macrophages, rather than adipocytes,
and is implicated mostly in inflammatory pathways
[14]. Animal studies have demonstrated a contributory
function in testosterone production and pubertal hypo-
thalamicpituitary signaling, attributing a role as an
endocrine mediator of the reproductive axis [1517] and
a potential one concerning obesity-associated insulin
resistance [9, 18]. In reproduction, there has been a con-
troversy on its possible linkage with anovulatory PCOS
[1921], or non PCOS women undergoing in vitro ferti-
lization (IVF) [22], suggesting that resistin might have
negative effects on pregnancy [23, 24]. In women under-
going IVF, it was demonstrated that oocyte and embryo
number correlated positively with resistin levels in fol-
licular fluid [25].
Although no specific receptor for resistin has been
described, resistin is a ligand to several putative recep-
tors. Resistin is an agonist of toll like receptor-4 (TLR-4)
and competes for binding with its pathogen-associated
molecular pattern well-known ligand, the endotoxin
lipopolysaccharide (LPS). It is also able to trigger the
inflammatory pathways associated with TLR-4 activation
[26]. Interestingly, a low level elevation of gut-derived
LPS has been associated with obesity. This phenomenon,
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described as metabolic endotoxemia, may play a role in
obesity-related metabolic disorder [27]. It has also been
hypothesized that activation of TLR-4 could positively reg-
ulate the expression of resistin through NF-B, enabling
an autoregulation of resistin secretion through this recep-
tor [28]. Other receptors have been described for resistin,
such as a cytosolic protein called adenylyl cyclase associ-
ated protein 1 (CAP-1) in monocytes [29]. Also, an isoform
of decorin, a proteoglycan of the extracellular matrix
acting as a pan-receptor tyrosine kinase inhibitor [30],
has been described as a receptor for resistin in adipocyte
progenitors [31]. It presents as a membrane protein most
likely generated by proteolytic cleavage of decorin and is
referred to as delta-decorin. Activation of delta-decorin
by resistin promotes adipocyte progenitor migration and
proliferation and impedes lipid droplet accumulation in
mice [31]. Lastly, resistin inhibits the activity of receptor
tyrosine kinase-like orphan receptor 1 (ROR1) in murine
pre-adipocytes [32], a receptor implicated in non canoni-
cal Wnt signaling involving Wnt5a as an activating ligand
[33]. The binding of resistin to ROR1 promotes adipogen-
esis and inhibits glucose cellular uptake in murine pre-
adipocytes [32].
Ovary
Recent studies have demonstrated the presence of resis-
tin in human granulosa [34, 35], as well as in cumulus,
theca cells and oocytes [35]. Also, possible positive
feedback through luteinizing hormone (LH) and pro-
gesterone and negative feedback through E2 (estradiol)
have been postulated [15]. In biological terms, resistin
reduces the secretion of both P450scc and P450 aro-
matase protein levels, and IGF-IR signaling in response to
IGF-I in human granulosa cells ([35], Figure 1). In human
thecal cells in culture, resistin increases the expression
of 17--hydroxylase in the presence of forskolin and/
or forskolin and insulin, suggesting a role of resistin in
androgen production ([16], Figure 1). Receptors to resistin
may be found in the ovary, although data are scarce and
no direct interactions have been reported to date. TLR-4
is expressed in bovine granulosa cells and promotes
inflammation and oocyte meiotic progression disruption
[36]. Decorin is a constituent of the extracellular matrix
of the ovary in primates and may regulate folliculogen-
esis, ovulation, and survival of the corpus luteum [37],
but no published studies mentioned delta-decorin in
the ovary. ROR1 is expressed in ovarian cancer and may
represent a bad prognosis marker, but ROR1 staining has
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 Dupont etal.: Adipokines and human reproductive organs13

Follicle

Ovary
Uterus

Uterus Granulosa Oocyte Theca

cells cells
Endometrial stromal E2, Pg
Adiponectin IVM (pig [74], T (pig [139])
cell proliferation [87] in response
Mouse [70]) Pg and and rostedione
to IGF-1 [69]
in response to insulin (bovine) [138]
E2, Pg
nd in response Competency
Visfatin nd
to IGF-1 [128] (aged mice) [135]
E2, Pg IVM (cow [95])
Chemerin nd in response
to IGF-1 [94] nd

Apoptosis [97]

Resistin nd E2, Pg nd
in response 17 hydroxylase
to IGF-1 [35] activity insulin induced [16]
E2, Pg
Omentin nd nd nd
in response
to IGF-1 [125]

Figure 1:In vitro effect of chemerin, adiponectin, resistin, visfatin and omentin on ovarian follicle cells.
When the data were not from human studies, the species was indicated in brackets. nd, Undetermined; , decreases; , increases;
IVM, in vitro maturation; T, testosterone; Pg, progesterone; E2, oestradiol.

been also reported in healthy ovarian tissue [38]. Interest-
ingly, CAP-1 is overexpressed in human epithelial ovarian
cancer, where it promotes cell proliferation and is associ-
ated with poor outcomes.
Pituitary-Hypothalamus
resistin exerts its proinflammatory effects and promotes
insulin resistance through the binding to TLR-4 in the rat
hypothalamus [41]. Also, decorin is secreted by follicu-
lostellar cells and pericytes in the rat anterior pituitary
glands [42]. However, the role of resistin in the hypo-
thalamus and the pituitary remains to be determined in
humans.

To control the functions of reproduction, resistin may

also act on the hypothalamic-pituitary axis. Indeed,
it is present in the hypothalamus and pituitary gland
in humans and rodents [39]. In the pituitary, resistin
expression is low at birth in rats and increases until the
age of 28 days. It increases during weaning in females
and during puberty in males. Moreover, its concentration
in the pituitary is two to three times higher in males than
in females. On the other hand, resistin decreases expres-
sion of AdipoR1 and AdipoR2 receptors in rat pituitary
cells in culture [40]. Recently, it has been shown that
Testis
In humans, no studies about the localization of resis-
tin in testis have been performed. In rat testis, resistin
is localized in the Leydig and Sertoli cells and in the
seminiferous tubules. Its expression is regulated by
fasting, gonadotropins and leptin. Moreover, it varies
during postnatal development peaking in adulthood
[43]. Also, the expression of resistin in mouse testes
may be directly or indirectly regulated by RHOX-5, an

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14Dupont etal.: Adipokines and human reproductive organs
androgen receptor and androgen-dependent transcrip-
tion factor mainly expressed in Sertoli cells and belong-
ing to a large X-linked homeobox gene cluster selectively
expressed in reproductive organs. Interestingly, Rhox-
5 null mice exhibit impaired insulin signaling in testis
and an enhancement of germ cell apoptosis and show
striking resemblances to a strain of infertile male mice
characterized by a defect in the Ins2 gene. The fact that
Rhox-5 null mice exhibit a significant up-regulation of
resistin expression in testicular tissue and in Leydig cells
during postnatal development compared to wild-type
controls indicates that Rhox-5 inhibits resistin expres-
sion indirectly in interstitial cells and perhaps directly
in Sertoli cells [44]. Although delta-decorin has not yet
been described in testis, decorin is secreted by human
peritubular cells surrounding seminiferous tubule and
high levels of decorin in the extracellular matrix of the
tubular wall is associated with testis inflammation,
fibrosis and male infertility in humans, rhesus monkeys
and mice [45].
Semen
Resistin has been found in human seminal plasma and
this seminal resistin correlated positively with IL-6 and
elastase levels, two markers of semen inflammation
[46]. In the same study, seminal resistin levels were not
correlated with semen quality, BMI or plasma testos-
terone and FSH levels. However, Thomas et al. showed
that seminal resistin was positively correlated with BMI
and waist circumference but not with semen parameters
[47]. F
urthermore, seminal resistin was not significantly
altered in vasectomised patients [46], showing that the
main resistin production takes place downstream of the
vas deferens, possibly by the prostate or seminal vesicles.
Seminal resistin may thus play a regulatory role in inflam-
mation of the male reproductive tract; this aspect has been
emphasized in a more recent study [48]. Seminal resistin
levels showed negative correlations with sperm motility
and positive correlations with the proportion of apop-
totic and necrotic spermatozoa. Seminal resistin was also
higher when patients presented with leukocytospermia,
which is commonly considered as a male accessory gland
inflammation marker. An eventual effect of seminal resis-
tin at the spermatozoa level has not yet been described,
although TLR-4, known as a binding site for resistin, has
been found in human sperm. Interestingly, in mouse and
human spermatozoa, the activation of this receptor by
endotoxins reduces sperm motility and promotes sperm
apoptosis [49].
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Placenta
Resistin was identified in the human placenta [50]. In
human, resistin is mainly expressed by trophoblast cells.
Resistin is also present in the amniotic membrane. The
expression pattern of placental resistin is not yet known.
However, a study shows that resistin is able to modulate
glucose transport in human trophoblast cells [51]. Resis-
tin, by interfering with placental development, may affect
pregnancy outcome and fetal growth. Strikingly, ROR-
Wnt5a signaling has recently been implicated in decidu-
alization and implantation as the conditional deletion of
ROR and/or Wnt5a in female mice led to poor placentation
and pregnancy outcomes [52].
Adiponectin
Adiponectin is a protein of 244 amino acids mainly pro-
duced by white adipose tissue but also found in other tissues
such as bone and muscle [53, 54]. Adiponectin is involved
in lipid and carbohydrate metabolism, and appears to
play a key role in the pathophysiology of obesity, type 2
diabetes and coronary heart disease. Contrary to resistin,
adiponectin seems to exert anti-inflammatory and anti-
diabetic effects [1]. In a healthy man, plasma adiponectin
is about 530 mg/L, which represents 0.01% of the total
plasma protein. Low adiponectin is predictive of insulin
resistance or type 2 diabetes. Serum adiponectin concen-
tration is also higher in men with normal weights than
in overweight or obese men, and significantly positively
correlates with total serum testosterone [47]. Consistent
findings have been reported in bulls, where high fertility
individuals presenting with higher serum adiponectin and
testosterone levels than average and low fertility bulls [55].
Plasma adiponectin exists in various molecular forms:
monomeric and multimeric form, in which adiponectin
monomers are organized in a more complex structure
through disulfide bonds. The multimeric form can be clas-
sified into high molecular weight (HMW), average molecu-
lar weight (MMW) and low molecular weight (LMW). To act
at the cellular level, adiponectin primarily binds to two
receptors, AdipoR1 and AdipoR2, mainly expressed in the
muscle and liver, respectively. The AdipoR receptors have
seven transmembrane domains, but have a reversed topol-
ogy compared to the same type of G protein associated
receptors; the amino-terminal part is intracellular and the
carboxy-terminal part is extracellular [56]. Once activated,
the AdipoR receptor binds an adapter protein, APPL,
which relays the activation of adenosine monophosphate-
activated kinase (AMPK) [57]. AMPK is a major component
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of the signaling pathway involved in the metabolic effects
of adiponectin. Another putative receptor for adipokine,
T-cadherin (CDH13), has been described in smooth muscle
and endothelial cells [58]. This GPI-anchored receptor
binds hexameric and HMW forms of adiponectin and has
been implicated in liver fibrosis, cardiovascular protection
and anti-diabetic effects in rodents [5861]. Various data
have indicated that adiponectin is influential in male and
female fertility and that adiponectin produced locally in
reproductive organs or by endocrine pathways could be
an energy sensor capable of regulating female and male
gonadal function.
Pituitary-Hypothalamus
In mice, adiponectin inhibits GnRH secretion in an
immortalized hypothalamic neurons cell-line through
activation of AMPK [62], most likely by inhibiting Kiss-1
gene transcription [63]. AdipoR1 and R2 are also expressed
in a gonadotrope pituitary cell-line. In this cell line, adi-
ponectin down-regulates basal and GnRH-stimulated LH
secretion through phosphorylation of AMPK [64]. More-
over, in rat pituitary cell cultures, adiponectin inhibits
GH and LH release [65]. Thus, in rodents, adiponectin,
AdipoR1 and AdipoR2 are expressed in the pituitary and
may be involved in gonadotrope regulation in a paracrine
way [65]. In swine, AdipoR1 and R2 are expressed in the
pituitary and their expression patterns depend upon the
estrous cycle [66]. Adiponectin expression in the porcine
pituitary is also dependent of the estrous cycle phase and
affects gonadotropin secretion in a manner dependent
on the phase of this cycle [67]. During in vitro studies,
adiponectin increases FSH release by porcine anterior
pituitary cells [67]. The expression of adiponectin and
adiponectin receptors has been studied in the human
brain [68]. Adiponectin and adiponectin receptors are
expressed in gonadotrope, thyreotrope and somatotrope
cells in the adenohypohyse, suggesting local regulation
of these endocrine axes [39, 68]. Overall, these findings
suggest that adiponectin may act as a negative regulator
of the gonadotrophin pathways at a central level through
a decrease in GnRH and LH secretion. However, in swine,
adiponectin effects on gonadotropin secretion may
depends on the estrous cycle phase [67].
Ovary
In the human ovary, adiponectin has been identified in
the ovarian follicle, particularly in follicular fluid [69].
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Dupont etal.: Adipokines and human reproductive organs15
However, low adiponectin expression was detected in
human granulosa cells and cumulus cells [69, 70]. The
AdipoR1 and AdipoR2 receptors have been identified in
different cell types of the human follicle (oocyte cumulus
oophorus, granulosa cells and theca). In the human gran-
ulosa cells, adiponectin is implicated in the regulation of
steroidogenesis by modulating the action of insulin and
insulin like growth factor 1 (IGF-1) ([69, 71], Figure1). Similar
results have been observed in rats where this adiponectin
effect is explained by an increase in the signaling of the
IGF-1 receptor [72]. In human granulosa, this improvement
of steroidogenesis by adiponectin is partially due to an
increase in the expression of the aromatase enzyme respon-
sible for the biosynthesis of estrogen. In human granulosa
KGN cells, specific inactivation of AdipoR1 and AdipoR2
shows that AdipoR1 is involved in cell survival, whereas
AdipoR2 is mainly involved in steroidogenesis [71]. In 2009,
Gutman et al. [73] showed an increase in the concentra-
tion of adiponectin in follicular fluid in ovarian response
to gonadotropins after administration of recombinant LH.
Adiponectin enhances oocyte maturation and early embryo
development in mouse, pig and human IVF procedures
([70, 74], Figure 1). Several polymorphisms of the genes
encoding adiponectin and its two receptors have been iden-
tified. Some variants and haplotypes identified are associ-
ated with sizes larger litters, a smaller number of stillborn
and mummified piglets and shorter weaning-estrus inter-
val [75]. Thus, in human ovary, adiponectin could modulate
not only follicle growth but also embryo development.
In women with PCOS, the concentration of adiponec-
tin is impaired, after controlling for BMI-related effects, but
is associated with abdominal obesity and hyperandrogen-
ism [76]. Plasma adiponectin is reduced in a mouse model
of PCOS [77]. Moreover, in this syndrome, metformin, an
anti-diabetic agent which improves insulin sensitivity,
increases the ovulation rate in some studies [78], and
plasma adiponectin levels [79]. Sarray etal. observed some
differences in adiponectin but not leptin or resistin serum
levels between women with PCOS and control women sug-
gesting that ratios of adiponectin/leptin and adiponectin/
resistin could constitute novel predictor factors to explain
PCOS and its associated features [80]. Thus, adiponectin
could be a pathophysiological link between metabolic
disturbances (insulin resistance and obesity) and fertility
disorders found in patients suffering from PCOS.
Testis
In chickens, an increase in adiponectin receptors in
sexual maturation has been reported, and suggests a role
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16Dupont etal.: Adipokines and human reproductive organs

of adiponectin in steroidogenesis and spermatogenesis, adiponectin negatively regulating testosterone secretion

and in the function of Sertoli cells and sperm motility [81].
In rat testis, adiponectin is mainly present in the intersti-
tial Leydig cells, while its receptors (mainly AdipoR1) are
present in the seminiferous tubules, although AdipoR2 is
also expressed in Leydig cells [82]. Adiponectin decreases
in vitro testosterone production in the presence or
absence of hCG (human chorionic gonadotropin) through
down-regulation of the Steroidogenic Acute Regulatory
protein (StAR) expression, whereas it has no effect on the
expression of genes coding for anti-Mullerian hormone
(AMH) and stem cell factor (SCF), specifically in Sertoli
cells [82, 83]. In mice, a deficiency in the AdipoR2 recep-
tor leads to atrophy of the seminiferous tubules and
aspermia without modifying the testosterone concentra-
tion [84]. Adiponectin gene expression, like resistin, is
significantly up-regulated in Leydig cells obtained from
Rhox5 null mice compared to wild-type animals, linking
adiponectin expression, insulin and androgen signaling
in mice testis [44].
Altogether, data in rodents suggest that adiponec-
tin and classic adiponectin receptors are involved in the
regulation of spermatogenesis and steroidogenesis, with
by Leydig cells. Furthermore, in murine Leydig cells, adi-
ponectin may also have a protective effect against pro-
inflammatory cytokines by suppressing NF-B activation
through promotion of AMP-activated protein kinase phos-
phorylation [85]. There are currently no available data on
the role of adiponectin in the human testis (Figure 2), nor
on an eventual function of CDH13 in the male gonad.
Semen
Adiponectin and adiponectin receptors have been
described in bull sperm and they are immunolocalized
in acrosomal, post-acrosomal, equatorial and tail regions
of bull spermatozoa [55]. Adiponectin and its receptors
may be implicated in capacitation and their presence on
spermatozoa after the acrosomal reaction has led to the
hypothesis that they could participate in sperm-egg inter-
actions [55]. In human, Thomas and colleagues showed
that concentration of adiponectin is higher in seminal
plasma than in serum [47]. Accordingly, seminal plasma
adiponectin levels are significantly higher in normal

Testis
Spermatozoa

Sertoli cells:
Adiponectin = no effect [82, rat]
Resistin, omentin, visfatin, chemerin = nd

Germ cells

Blood vessel

Leydig cells:
-In vitro testosterone production:

Resistin [43, rat], visfatin [137, rat]

Chemerin [102, 103, rat], adiponectin [82, 83, rat]

Omentin: nd

Figure 2:In vitro effect of chemerin, adiponectin, resistin, visfatin and omentin on testicular cells.
nd, Undetermined; , increases; , decreases.

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weight men than in overweight or obese men [47] and
plasma adiponectin levels positively correlate with sperm
count and normal morphology, suggesting a role in sper-
matogenesis. Like resistin, adiponectin is found in seminal
plasma in vasectomized men, suggesting that adiponectin
may be produced downstream of the vas deferens.
Endometrium
There is in vitro evidence that AdipoR1 and R2 are expressed
in the human myometrium and that their expression level
changes throughout gestation [86]. The expression of both
genes is increased in the midluteal phase, the period of
embryo implantation [86]. Adiponectin inhibits human
endometrial stromal cell proliferation in a dose and time
dependant manner, and causes cell death. Therefore, it
has suggested as an anti-endometriosis agent [87]. Some
studies showed that changes of AdipoR expression pro-
files could be implicated in the development of uterine
receptivity, and might therefore be new potential targets
for prediction of implantation failure [88]. Thus, the
effects of adiponectin might be relevant to pathological
and physiological endometrium-related events such as
implantation and endometriosis.
Embryo
In mice, adiponectin receptors are expressed in mature
oocytes and preimplantation embryos. Full-length adi-
ponectin may act as an embryotrophic factor increasing
blastocyst cell number, whereas other adiponectin iso-
forms, such as mutated trimeric adiponectin, exert the
opposite effect [89]. However, after implantation, full-
length adiponectin seems to decrease fetal-growth by lim-
iting fetal nutrient availability through down-regulation
of placental amino-acid transporter activity [90].
Chemerin
Chemerin is a recently identified adipose hormone. It is
initially involved in regulation of the immune system, adi-
pogenesis and energy metabolism. Chemerin is a chem-
oattractant composed of 163 amino acids, synthesized as
a pre-prochemerin then secreted as an inactive precursor
called prochemerin. Prochemerin is activated by cleav-
age of its C-terminal leading to different isoforms lacking
more terminal amino acids [91]. Chemerin is expressed in
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Dupont etal.: Adipokines and human reproductive organs17
several tissues, mainly the liver, kidney, and pancreas but
also in brown and white adipose tissue. It is also present
in the pituitary, placenta, ovary and testis. These data
suggest a potential role of chemerin in reproduction. To
exert its cellular effects, chemerin can bind to three seven
transmembrane G protein-coupled receptors: CMKLR1
(like chemokine receptor 1 also known as ChemR23 and
DEZ) GPR1 (G protein-coupled receptor 1) and CCRL2 (CC
chemokine receptor-like 2, for review [92, 93]. In humans,
serum chemerin concentration is positively correlated
with BMI and waist circumference and significantly
higher in overweight or obese patients than in those with
a normal weight [47]. There is also a statistically signifi-
cant negative correlation between serum chemerin and
serum testosterone[47].
There is currently no available data on the role (if any)
of chemerin in the reproduction functions at the brain
level in the pituitary and hypothalamus.
Ovary
Chemerin and three receptors are present in the ovarian
follicle in women [94], cows [95] and rats [96, 97]. Spe-
cifically in the latter species, they are expressed in differ-
ent cells of the ovarian follicle (granulosa cells and theca,
cumulus cells and oocytes) [95]. Several in vitro studies in
rodents, humans and bovines show that chemerin plays
a role in the functions of the ovary including steroido-
genesis, apoptosis, cell proliferation and oocyte matura-
tion (Figure1). In rats, chemerin removes the stimulatory
effect of FSH on the secretion of progesterone and estra-
diol in cultured pre-antral follicles and granulosa cells
[96]. It also inhibits the expression of the nuclear recep-
tor NR5A1 and NR5A2 in response to FSH. These receptors
bind to the promoter regions of the genes of steroidogenesis
enzymes, P450scc and P450arom. These inhibitory effects
of chemerin on the in vitro production of steroids by granu-
losa cells are found in other species such as cattle [95] and
humans ([94], Figure 1). In cow granulosa cells, chemerin
also inhibits the expression of the cholesterol transporter,
StAR, P450 aromatase and cholesterol de novo synthe-
sis; these effects involve the CMKLR1 receptor [95]. In rats
treated with 5alpha-dihydrotestosterone (used to mimic
polycystic ovarian syndrome), chemerin not only reduced
the secretion of estradiol by the granulosa cells but also
induced apoptosis of these cells [97]. Chemerin blocks the
expression of oocyte factor, Growth/differentiation factor
9 (GFD9), which promotes cell proliferation and differen-
tiation of pre-antral follicles in antral follicles [97]. In addi-
tion to negative effects on steroidogenesis and the survival
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18Dupont etal.: Adipokines and human reproductive organs
and proliferation of granulosa cells, chemerin blocks
the in vitro maturation of bovine oocytes in the germinal
vesicle stage ([95], Figure 1). Chemerin thus appears to be
an important intra-ovarian regulator and could contribute
to deregulation of follicular development. A significant
increase in the amount of chemerin in plasma and adipose
tissue was observed in patients with PCOS [98100]. This
increase in plasma chemerin was abolished after treat-
ment with metformin, an anti-diabetic agent [99]. Finally,
expression (mRNA and protein) of chemerin and its recep-
tor (CMKLR1) is higher in the rat ovary stimulated with
5-dehydrotestosterone used to induce PCOS [97]. It has
been proposed that chemerin plays a role in the pathologi-
cal process of PCOS in negatively controlling the synthesis
of follicular steroids that are stimulated by FSH [101].
Testis
In humans and rodent, chemerin and its receptors
(CMKLR1, GRP1 and CCRL2) are present in the testes [102,
103]. In rats, the expression of chemerin decreases during
postnatal development (590 days), whereas expression
of its three receptors increases [102]. In humans and rats,
chemerin and two of these receptors, CMKLR1 and GPR1,
are specifically localized to Leydig cells ith low levels in the
germ cells [102]. Moreover, in primary cultures of Leydig
cells, chemerin inhibits in vitro testosterone secretion in
response to hCG ([102, 103], Figure 2). These results could
be explained by a reduction in the expression of the dehy-
drogenase 3-b-hydroxysteroid (3bHSD) enzyme and phos-
phorylation of the MAPK signaling pathway ERK1/2. Thus,
in males, as in females, chemerin exerts an inhibitory
effect on steroidogenesis in vitro (Figures 1 and 2).
Semen
In human seminal plasma, chemerin is negatively corre-
lated with sperm motility, suggesting an effect on spermat-
ogenesis or sperm maturation in the epididymides, where
spermatozoa acquire their progressive motility during
epididymal transport. This hypothesis is reinforced by the
fact that chemerin levels in vasectomized patients are sig-
nificantly reduced [47]. Thus, it has been suggested that
chemerin secretion from epididymal adipose tissue could
increase with obesity and reduce sperm motility through
direct effects on spermatozoa or indirect effects during
epidydimal maturation and transport. Seminal plasma
chemerin also positively correlates with sperm concentra-
tion, but not with sperm count [47].
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Placenta
In humans and rats, chemerin is localized to the tropho-
blast cells of the placenta. At the last stage of pregnancy
in women, serum levels of several adipocytokines such
as leptin [104, 105], visfatin [104], resistin [104, 105] and
TNF- [105] are higher, while circulating levels of adi-
ponectin [104, 105] are reduced. Similarly, contrary to the
rat, the concentration of chemerin increases during preg-
nancy in women [106, 107]. The high plasma concentration
of chemerin in late pregnancy suggests that it plays a role
in embryonic growth [106, 108]. Finally, several studies
have shown an increase in plasma chemerin in the case
of pre-eclampsia, which is a complication of pregnancy
characterized by development of hypertension associ-
ated with proteinuria [109]. The more elevated the plasma
chemerin is, the more severe the preeclampsia is [109].
This disease affects 2%5% of pregnancies in women and
is a major factor in fetal mortality.
Omentin
Omentin-1 (also named omentin, intelectin-1, endothelial
lectin HL-1 and intestinal lactoferrin receptor) is another
recently discovered adipokine predominantly produced
by visceral adipose tissue in humans and rhesus monkeys
[110112]. The mature omentin is a 120-kDa homotrimer in
which 40-kDa polypeptides are bridged by disulfide bonds.
A homolog of omentin-1, referred to as omentin-2, shares
83% amino acid identity with omentin-1 [110]. Omentin-1
is the major circulating form in human plasma [113]. Some
evidence shows that omentin-1 expression is altered by
inflammatory states and obesity [113115]. Omentin-1
enhances insulin action [116]. It is inversely related to
obesity [113] and is increased after weight loss [117], and
down-regulated by insulin and glucose [118]. Omentin-1
has also been linked to metabolic syndrome and PCOS
[118]. Plasma omentin-1 levels are higher in women com-
pared with men [113] and are decreased in women with
PCOS compared with those without PCOS in BMI-matched
control subjects [118, 119]. Treatment with metformin for
3 or 6 months significantly increased serum omentin-1
levels, as well as the ratio of omentin-1 to insulin in PCOS
patients [118, 120]. There is also a significant difference in
omentin-1 plasma levels between regular menstrual cycles
and irregular menstrual cycles in PCOS patients suggest-
ing that omentin-1 could affect the secretion of hormones
that regulate ovarian and menstrual function or affect
receptors for these hormones [121]. Omentin-1 is expressed
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in adipose tissue but also in reproductive tissues includ-
ing the placenta and ovary in humans, monkeys and
sheep [116, 122, 123]. In humans, lower omentin-1 expres-
sion in the placenta and the maternal plasma is associ-
ated with pre-existing maternal obesity. Thus, alteration
in omentin-1 in pregnancy may influence the develop-
ment of metabolic disorders in offspring later in life [124].
Furthermore, in our lab, we have showed that omentin-1
is expressed in the human ovarian follicle [125]. In con-
trast to control patients, omentin-1 levels are higher in
follicular fluid than in plasma in PCOS patients [125]. In
human luteinized granulosa cells, omentin-1 expression is
increased at short term (12 or 24 h) by various hormones
involved in follicle development, including FSH, insulin,
and IGF-1), and the insulin sensitizer, metformin. Further-
more, omentin-1, through induction of visfatin expression,
ameliorates IGF-1-induced steroidogenesis and IGF-1R
signaling (Figure 1). Thus, omentin-1 could be involved in
folliculogenesis and may contribute to the pathophysiol-
ogy of PCOS.
There is currently no available data on the role (if any)
of omentin-1 in the testis and on higher levels of the repro-
ductive axis.
Visfatin
Visfatin is a novel adipokine mainly produced by perivas-
cular adipose tissue [126]. It is also known as a Nicoti-
namide phosphorybosyltransferase (NAMPT), or a pre-B
cell colony-enhancing factor (PBEF), and is a 52kDa
mammalian protein that is constitutively synthesized by
adipose tissue and many other tissues [127], including
reproductive tissue [128, 129]. NAMPT has been shown
to have several intra- and extra-cellular functions, and
two isoforms, intracellular and extracellular, have been
reported. Intracellular NAMPT plays a critical role in
maintaining the activity of nicotinamide adenine dinu-
cleotide (NAD)-dependent enzymes [127]. It contributes
to the biosynthesis of NAD by acting to convert nicoti-
namide into nicotinamide mononucleotide (NMN), and
it represents the limiting factor for this enzymatic reac-
tion [130]. The pattern of changes in circulating visfatin
concentrations differs between normal and obese preg-
nant women [131]. Its plasma level is increased during
the development of obesity [132] and in pregnant women
at term [133]. Studies found that visfatin at relatively low
doses (110 nM), decreases both spontaneous and oxy-
tocin induced contractions of pregnant human and rat
myometrial tissue in vitro [133]. In humans, a recent study
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Dupont etal.: Adipokines and human reproductive organs19
showed that higher plasma visfatin/NAMPT may prevent
a labor-associated decrease in SIRT1 leading to post-term
delivery in obesity [133].
In mammals, there is some evidence to suggest that
NAMPT is directly involved in regulating human repro-
ductive functions. NAMPT is present in human ovarian
follicles and increases insulin-like growth factor 1 (IGF1)-
induced steroidogenesis in primary human granulosa
cells ([128], Figure 1). Furthermore, in women who are
undergoing controlled ovarian stimulation, there is a cor-
relation between the concentration of NAMPT in the fol-
licular fluids and the number of oocytes retrieved [134]. In
rats, the administration of NAMPT during superovulation
has been shown to play an important role in the regula-
tion of oocyte quality, and it can improve oocyte quality
and fertility in aged female mice ([135], Figure 1). NAMPT
is expressed in the testes of male rats, more specifically in
Leydig cells, spermatocytes and sperm [136]. In cultured
Leydig cells, NAMPT has been shown to increase testoster-
one production ([137], Figure 2). In humans, NAMPT levels
are significantly higher in seminal plasma than in serum,
which suggests that testicular cells produce NAMPT [47].
Conclusions
It is now clear that adipose tissue may communicate with
the brain, gonads, and uterus to regulate reproductive
functions via these new adipokines. However, since these
molecules are also produced by the gonadotrope axis
and genital tractus, we cannot exclude local autocrine
or paracrine effects. Do these adipokines have beneficial
or negative effects on human fertility? Most studies have
been performed in in vitro ovarian cells, so it is difficult
to give an answer about the whole organism. However,
in the human ovary, and more precisely in granulosa
cells, adiponectin, visfatin and omentin increase in vitro
steroid production induced by IGF-1, whereas resistin and
chemerin have the opposite effect. In these ovarian cells,
the effects of these adipokines appear to be mainly IGF-1-
or insulin-dependent. Indeed, in human granulosa cells,
omentin, visfatin and adiponectin increase phosphoryla-
tion of the beta subunit of IGF-1R, whereas chemerin and
resistin inhibit it (Figure 3). Abnormal levels of adipokines
have been shown to be strongly associated with insulin
resistant and type 2 diabetes. Thus, further work will be
necessary to better understand the role of adipokines in
reproductive functions that may act as a link between
obesity and PCOS. Fertility is strongly dependent on the
pituitary-hypothalamus axis. Few data are available on
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20Dupont etal.: Adipokines and human reproductive organs
IGF-1
Adiponectin
C-Term IGF-1R
AdipoR1
or AdipoR2
+ -
P P
N-Term
+ Subunit Subunit
-
Omentin ?
MAPK ERK1/2
- Inhibits
Human
+ Stimulates granulosa cells
Steroids secretion (Pg, E2)
Figure 3:In vitro effect of chemerin, adiponectin, resistin, visfatin and omentin on IGF-1R signaling in human granulosa cells.
the effects of these new adipokines on this axis, except
for adiponectin, which can be a negative regulator of in
vitro gonadotrophin secretion in rodent pituitary cells.
Adipokines also have crucial modulatory effects during
pregnancy and are reported to be involved in the patho-
physiology of pregnancy-related complications. Changes
in serum levels of several adipokines throughout human
gestation have been well documented. Further inves-
tigation should focus on the effects of endogenous adi-
pokines on blastocyst development, as well as in patients
with metabolic dysregulations such as obesity and PCOS.
Taken together, all these adipokines produced locally
or by the endocrine pathway could be energy sensors
capable of regulating human fertility at different levels
of the reproductive axis. However, their detailed role in
reproduction awaits further clarification through future
studies.
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