Accepted: 11 December 2017

DOI: 10.1111/and.12965

INVITED REVIEW

Review of the role of leptin in the regulation of male

reproductive function

J. Zhang  | M. Gong

Department of Urology, Shanghai Pudong

Hospital, Fudan University, Shanghai, China
Correspondence
Min Gong, Department of Urology, Shanghai
Pudong Hospital, Fudan University, Shanghai,
China.
Email: mg813@hotmail.com
Summary
Since discovered in 1994, leptin has been thought to be a pleiotropic hormone that
regulates food intake, controls energy balance in the body and influences multiple tis-
sues in the body. Leptin plays an important mediating role in the regulation of neu-
roendocrine and can transmit the nutritional status signals to the reproductive-­related

Funding information
This work was supported by Research
Grant for Health Science and Technology of
Shanghai Municipal Commission of Health
and family Planning (201440455) and Key
Discipline Construction Project of Pudong
Health and Family Planning Commission of
Shanghai (PWZxk2017-­21).
central nervous system. Many studies have shown that leptin may play an important
role in the control of reproductive function. Leptin can act on all levels of the hypo-
thalamus–pituitary–gonadal (HPG) axis and may have local effects on the function of
testis and spermatogenesis. Leptin is critical for puberty initiation and can also modu-
late testosterone synthesis by downregulating cAMP-­dependent activation of steroi-
dogenic genes expressions. Leptin is found to be higher in infertile men than in normal
subjects. Yet, the exact role of leptin in the regulation of male reproductive function
remains incomplete. The purpose of this review was to summarise the recent research
about the biological effects of leptin on male reproductive system. In-­depth study of
leptin in reproductive system will help to reveal the pathogenesis of infertility and
provide new treatment ideas for human assisted reproductive technology.

KEYWORDS
infertility, leptin, leptin receptor, male reproductive system

1 |  INTRODUCTION
In 1994,Zhang et al. (1994) obtained the obese gene using the posi-
tional cloning technique of mutant genes and initiated the study of
leptin. Leptin, secreted by adipose tissue, is the hormonal product
of the obese gene. It is found that leptin is a metabolic signal that
connects nutrition and other physiological functions (Barash et al.,
1996). Leptin not only plays an important role in energy metabolism
but also participates in a series of important physiological activi-
ties such as immune regulation, angiogenesis, inflammatory reac-
tion and bone formation (Budak et al., 2006; Huang & Li, 2000).
Obese gene mutations in mice (ob/ob) show obesity and infertility
(Caprio et al., 1999), and leptin administration to leptin-­deficient
ob/ob mice can promote their sexual maturity (Cravo et al., 2013),
suggesting that leptin may play an important role in the reproduc-
tive system. Emerging studies are mainly concentrated in the female
reproductive system regulation and demonstrate that leptin partic-
ipates in reproductive regulation (Gonzalez et al., 2000; Henson &
Castracane, 2006; Messinis & Milingos, 1999). However, there are
still many problems to be explored in the regulation mechanism of
leptin on male reproductive system. In this review, we highlight
the regulation of leptin and leptin receptor on male reproductive
system.
2 | STRUCTURE AND EXPRESSION OF
LEPTIN AND LEPTIN RECEPTOR
Leptin is a 16-­kDa protein hormone composed of 167 amino acids.
The N-­terminal of leptin has a signal peptide sequences, consisting of
21 amino acid residues, and the C-­terminal has a ring structure with
intramolecular disulphide bond, consisting of two cysteine residues

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(Imagawa et al., 1998). After entering the blood circulation, the N-­
terminal signal peptide is removed to form a biologically active lep-
tin. Leptin is free in the blood or binds to the leptin binding protein.
It reaches the central or peripheral tissue and plays a biological role
in combination with a variety of leptin receptors (Margetic, Gazzola,
Pegg, & Hill, 2002; Sainz, Barrenetxe, Moreno-­Aliaga, & Martinez,
2015). Leptin is predominantly expressed in adipose tissue and also
found in other tissues or cells such as hypothalamus, pituitary, gas-
tric epithelium, embryo, skeletal muscle, testis and sperm (Gale,
Castracane, & Mantzoros, 2004; Ishikawa, Fujioka, Ishimura, Takenaka,
& Fujisawa, 2007).
In 1995, Tartaglia et al. (1995) identified and cloned the leptin
receptor (OB-­R) gene in mice and humans. The human OB-­R is com-
posed of 1165 amino acids and is divided into three domains: ex-
tracellular, transmembrane and intracellular. OB-­R belongs to class
I cytokine superfamily, and there are at least six different isoforms,
named OB-­Ra, OB-­Rb, OB-­Rc, OB-­Rd, OB-­Re, OB-­Rf. The six isoforms
are divided into three categories: short (OB-Ra, OB-Rc, OB-­Rd, OB-­
Rf), long (OB-­Rb) and soluble (OB-­Re) forms (Catteau et al., 2016;
Wauman, Zabeau, & Tavernier, 2017). (Figure 1) Different OB-­R ac-
tivation conveys different biological activities of leptin. Short forms
of OB-­R are mainly distributed in the brain, lung, cerebral choroid
plexus and the brain microvascular plexus (Banks, Kastin, Huang,
Jaspan, & Maness, 1996). OB-­Ra and OB-­Rc are responsible for the
translocation of leptin, which helps leptin penetrate the cell barrier,
such as the blood–brain barrier and the placenta (Dardeno et al.,
2010; Smith & Waddell, 2003). OB-­Re is a soluble receptor lack-
ing intracellular and transmembrane segment. OB-­Re is the major
leptin binding protein in circulation and modulates leptin bioavail-
ability (Ge, Huang, Pourbahrami, & Li, 2002; Schaab & Kratzsch,
2015). OB-­Rb, which is highly expressed in the hypothalamus, is a
functional receptor that contains three highly conserved tyrosine
residues binding to the Janus kinase/signal transducer and activator
of transcription (JAK/STAT) for signal transduction (Wauman et al.,
2017).
F I G U R E   1   Six different isoforms of
leptin receptor (OB-­R). The six isoforms
of OB-­R are divided into three categories:
short (OB-­Ra, OB-­Rc, OB-­Rd, OB-­Rf), long
(OB-­Rb) and soluble (OB-Re) forms. Apart
from OB-Re, every form includes three
domains: extracellular, transmembrane and
intracellular. All leptin receptor isoforms
share the same ligand-­binding extracellular
domain. The short type receptor contains
an intracellular fragment with 30~40
amino acids while the long isoform has
an extended intracellular domain of 301
amino acids with binding sites for signal
transduction
3 | REGULATION OF LEPTIN ON MA LE
REPRODUCTIVE SYSTEM
3.1 | Puberty
The development of puberty is mainly controlled by genes and in-
fluenced by a multihormonal effect (Budak et al., 2006). Puberty is
characterised by an increase in testosterone driven by increasing
concentrations of pituitary gonadotrophins and gonadotrophin-­
releasing hormone (GnRH) in boys (El-­Eshmawy, Aal, & El Hawary,
2010). Both animal experiments and human studies have confirmed
that leptin plays an important role in the initiation of puberty. Mice
lacking leptin (ob/ob) or the leptin receptor (db/db) exhibit hypo-
gonadism and stay prepubertal (Strobel, Issad, Camoin, Ozata, &
Strosberg, 1998). Leptin administration to ob/ob mice leads to pu-
bertal development, and the same situation does not occur in db/db
mice (Donato et al., 2011). In addition, ob/ob mice demonstrated a
marked sensitivity to negative feedback of gonadotropins because
of persistent immaturity of the hypothalamic–pituitary axis, con-
sistent with a prepubertal state of high negative feedback restraint
(Elias & Purohit, 2013; Swerdloff, Batt, & Bray, 1976). In parallel
with mice, those who have mutation in leptin or leptin receptor
gene show failure of pubertal growth spurt and lack of secondary
sexual characteristics (Farooqi & O’Rahilly, 2006). Leptin treatment
can lead to elevated gonadotropin and sex hormone levels, puber-
tal development and gonadal development (Farooqi et al., 2002).
Several studies found that adolescent boys with constitutional
delay of growth and puberty had significantly lower leptin than
the normal (Bideci, Cinaz, Hasanoglu, & Tumer, 2002; El-­Eshmawy
et al., 2010; Gill, Hall, Tillmann, & Clayton, 1999). The delayed pu-
berty onset is the result of low leptin production (Elias & Purohit,
2013). However, the exact role of leptin in the initiation of puberty
is unclear. Several studies have shown that leptin levels increase
prepubertally and then decline to baseline levels after the initiation
of puberty (Mantzoros, Flier, & Rogol, 1997; Maqsood et al., 2007),
suggesting that leptin plays an important role in the initiation of
ZHANG and GONG
puberty. However, Ozata, Ozdemir, and Licinio (1999) believed that
leptin was not the primary factor of puberty initiation because they
found a delay of over 20 years in the onset of regular menstruation
in a leptin-­deficient woman. Instead, it might only play a permis-
sive role, and other metabolic and endocrine factors contributed
to the maturation of the reproductive system. Rutters et al. (2009)
found that the leptin concentrations increased significantly from
Tanner stage 1 to 2 and decreased significantly from Tanner stage
2 to 5, suggesting that leptin played a different role at different
times. Exogenous leptin accelerates puberty initiation without af-
fecting body weight, suggesting that leptin links puberty initiation
with weight and energy storage (Farooqi, 2002). Many nuclei in the
hypothalamus are involved in the regulation of leptin on puberty ini-
tiation. Donato et al. (2011) found that the development of puberty
regulated by leptin was achieved by the expression of the excitatory
neurotransmitter glutamate in ventral premammillary nucleus(PMV)
instead of Kiss1 neurons. Leptin directly activates PMV, which in
turn activates its downstream GnRH neurons (Leshan et al., 2009).
α-­melanocyte-­stimulating hormone (α-­MSH) is the major product
of proopiomelanocortin (POMC) gene in the arcuate nucleus (ARC)
(Yong, Faulkner, & Hill, 2011). Manfredilozano et al. (2016) unveiled
a novel leptin-­α-­MSH-­Kiss1-­GnRH signalling pathway which regu-
lated puberty onset and he believed thatα-­MSH was an important
downstream regulator of leptin’s effect on pubertal awakening of
the HPG axis. Venancio found that short-­term high-­fat diet could in-
crease kisspeptin expression and induce earlier puberty, which was
associated with an increase in cocaine-­and amphetamine-­regulated
transcript (CART) neurons expression in the ARC (Venancio et al.,
2017). Mammalian target of rapamycin (mTOR) is also involved in
puberty initiation by regulating the expression of Kiss1 and blocking
the mTOR pathway can disrupt normal puberty initiation time (Roa
& Tena-­Sempere, 2010; Roa et al., 2010).
3.2 | Regulation on hypothalamus–pituitary–
testis axis
A large number of studies have shown that the brain is a key posi-
tion for leptin to play a role. Leptin plays a role in multiple parts of
the brain, including arcuate nucleus (ARC), ventral medial nucleus
(VMN), paraventricular nucleus (PVN)(Van Vugt et al., 2006). Both in
vitro and in vivo, experiments have shown that leptin can stimulate
LH secretion (Yu, Kimura, Walczewska, Karanth, & McCann, 1997).
However, GnRH cells do not express leptin receptors (Skorupskaite,
George, & Anderson, 2014), suggesting that leptin may regulate the
reproductive system indirectly. It has been proposed that GnRH
neurons are affected by leptin mediated via other neuropeptides,
such as neuropeptide Y (NPY), agouti-­regulated peptide (AgRP),
proopiomelanocortin (POMC) and gama-­aminobutyric acid (GABA)
(Iqbal et al., 2001; Sullivan & Moenter, 2004). In addition, more and
more studies have shown that leptin mediates the reproductive
system by regulating kisspeptins produced by the Kiss1 gene. Both
mice and human experiments show that the lack of Kiss1 receptors
caused by genetic mutations can lead to hypogonadism (Seminara
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et al., 2003). In vivo, experiments confirm that kisspeptins can pro-
mote the release of GnRH and increase serum FSH, LH and testos-
terone (Thompson et al., 2004). Smith, Acohido, Clifton, and Steiner
(2006) found approximately 40% of the cells expressing Kiss1 in
the ARC coexpressed the leptin receptor. The mRNA of kisspeptins
in the ARC of ob/ob mice significantly reduced compared to the
wild-­type control (Quennell et al., 2011) and increased when leptin
was administered to ob/ob mice (Luque, Kineman, & Tenasempere,
2007). Furthermore, the Kiss1 cells in the ARC contain leptin-­
activated signal transduction pathways (Quennell et al., 2011).
Leptin can promote pulsed secretion of GnRH in arcuate nucleus
neurons of hypothalamus in a dose-­dependent manner (Lebrethon,
Vandersmissen, Gerard, Parent, & Bourguignon, 2000). In addition,
leptin can promote the release of LH and FSH by activation of nitric
oxide synthase and regulate the growth and differentiation of pitui-
tary cells (Iqbal, Pompolo, Considine, & Clarke, 2000; Tezuka et al.,
2002). Studies have shown that leptin is also expressed in the tes-
tis, and leptin is involved in the regulation of testis (Soyupek et al.,
2005; Zamorano et al., 1997). Leptin seems to be a direct factor
in inhibiting testicular steroidogenesis (Landry, Cloutier, & Martin,
2013). Tena-­
Sempere found that leptin could inhibit basal and
stimulated testicular testosterone secretion in vitro, and several de-
creased mRNAs of upstream elements in the steroidogenic pathway
(steroidogenic factor 1, steroidogenic acute regulatory protein and
cytochrome P450 cholesterol sidechain cleavage enzyme) might
contribute to leptin-­induced inhibition of rat testicular steroido-
genesis (Tena-­Sempere et al., 1999, 2001). Fombonne (Fombonne,
Charrier, Goddard, Moyse, & Krantic, 2007) found that leptin could
inhibit division of prepubertal Leydig cells via a cyclin D1. Leptin
inhibited testosterone secretion by interfering with the cAMP sig-
nalling and downregulating the expression of steroidogenic acute
regulatory protein (Lin et al., 2009). Landry found that high levels
of leptin downregulated STAT transcriptional activity and reduced
cAMP-­dependent steroidogenic genes. (Landry, Sormany, Haché,
Roumaud, & Martin, 2017). In addition to abundant expressions of
OB-­Rb, other isoforms such as OB-Ra, Ob-­Rf, OB-Re and OB-Rc
were also detected in prepubertal and adult testes, suggesting a
complex pattern of signalling processing (Tena-­Sempere & Barreiro,
2002). In contrast, testosterone can also inhibit leptin secretion by
acting on white fat, resulting in inverse correlation between leptin
and testosterone levels (Luukkaa et al., 1998). Overall, the mecha-
nism of leptin regulating the hypothalamus–pituitary–testis axis is
complex, involving not only stimulatory but also inhibitory effects
(Figure 2).
3.3 | Leptin and male infertility
Both leptin-­deficient genes in humans and rats exhibit a range of
reproductive system abnormalities, including decreased weights of
ventral prostate and testes, fewer sperm in the seminiferous tubules
and smaller size of Leydig cells (Elias & Purohit, 2013; Mounzih, Lu, &
Chehab, 1997). Studies have shown that leptin levels in patients with
azoospermia are higher than those with normal semen, and plasma
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F I G U R E   2   Interactions between leptin and the hypothalamic–pituitary–testicle axis. Leptin interacts with neuroendocrine axis and transmits
body metabolic signals to the reproductive system. Leptin can stimulate POMC/CART and inhibit NPY/AgRP neurons of the arcuate nucleus
which elicit anorexic signals to increase the feeling of satiety. Meanwhile, leptin can act on the hypothalamus–pituitary–testicle axis to regulate
gonadotropin secretion and spermatogenesis. POMC, proopiomelanocortin; CART, amphetamine-­regulated transcript; NPY, neuropeptide Y;
AgRP, agouti-­related peptide; ME, median eminence; GnRH, gonadotropin-­releasing hormone; LH, luteinizing hormone; FSH, follicle-­stimulating
hormone; T: testosterone; DHT, dihydrotestosterone

leptin levels are not significantly correlated with FSH and LH, suggest-
ing that leptin can act directly on the testis (Ma, Chen, Wang, Hu, &
Huang, 2011; Steinman et al., 2001; Zorn, Osredkar, Meden-­Vrtovec,
& Majdic, 2007). Ishikawa et al. (2007) investigated the relationships
between the expression of leptin in the testis and spermatogenesis
and found that leptin was expressed on germ cells and was mainly
expressed in spermatocytes, whereas OB-­R was expressed predomi-
nantly on Leydig cells. He also found that the expression rate of OB-­R
in Leydig cells was negatively correlated with the serum testosterone
concentration. Chen et al. (2009) found that the expression of leptin
and its receptor in the testis of experimental varicocele rats increased
and was negatively correlated with testicular weight, Johnsen score,
thickness of seminiferous epithelium and diameter of the seminifer-
ous tubules. Many studies have found that human seminal plasma
contains leptin, which is mainly secreted by the seminal vesicles or
prostate tissues and exists in free form (Aquila et al., 2005; Camiña
et al., 2002). Glander, Lammert, Paasch, Glasow, and Kratzsch (2002)
found that leptin level in seminal plasma was significantly higher in in-
fertility patients and showed a significantly negative correlation with
percentage and velocity of motile spermatozoa, whereas Zorn et al.
(2007) found no correlation between leptin and sperm characteris-
tics. Ma et al. (2011) thought that leptin was an important marker for
the detection of nonobstructive azoospermia. In addition to affecting
sperm motility, leptin may also be involved in regulating the physio-
logical function of spermatozoa. Jope, Lammert, Kratzsch, Paasch, and
Glander (2003) found leptin and leptin receptor expression in human
spermatozoa, and leptin receptor was closely related to the integrity
of sperm cell membrane. Aquila et al. (2005) found leptin secreted by
sperm modulated its metabolism independently by systemic leptin
and was closely related to sperm capacitation. Lampiao and du Plessis
(2008) found that leptin could trigger STAT3 signal transduction path-
way and anti-­apoptotic protein BCL-­2 to enhance sperm capacitation
index and acrosin activity. Exogenous leptin administration adversely
affects sperm count and morphology (Almabhouh et al., 2015; Haron,
D’Souza, Jaafar, Zakaria, & Singh, 2010), which can be prevented by
melatonin (Almabhouh & Singh, 2017; Almabhouh et al., 2017). These
findings indicate a pathophysiological relevance of seminal leptin in
sperm. However, Hatami-­Baroogh et al. (2010) evaluated leptin re-
ceptor expression and found that the long isoform of leptin recep-
tor was not expressed in sperm. The expression of leptin receptor at
mRNA level may be related to the contamination of other cells. In
addition, Li, Chiu, Cheung, and Yeung (2009) believed that leptin did
not exert any effects on sperm motility and capacitation/acrosome
reaction. Further study is needed to elucidate these controversial is-
sues regarding the presence, location and function of leptin receptor
in human spermatozoa.
4 | CONCLUSION
In recent years, with the progress of genetic modified mouse mod-
els and molecular biology techniques, we have a better understand-
ing of the role of leptin in reproductive neuroendocrine axis. Leptin
may play an important role in regulating the reproductive system
ZHANG and GONG
through different levels of expression and through acting on differ-
ent parts of the hypothalamus–pituitary–testis axis. Leptin interacts
with neuroendocrine axis and transmits body metabolic signals to
the reproductive system. Many mechanisms such as the effects of
leptin on testicular physiology and spermatogenesis are not yet fully
understood. An in-­depth study of leptin on male reproductive regu-
lation will help to reveal some of the mechanisms of male infertil-
ity, which is expected to provide new ideas for the diagnosis and
treatment.
CO NFLI CT OF I NTE RE ST
The authors declare that there are no conflict of interests regarding
the publication of this paper.
O RCI D
J. Zhang  http://orcid.org/0000-0001-8831-7464
REFERENCES
Almabhouh, F. A., Osman, K., Ibrahim, S. F., Gupalo, S., Gnanou, J., Ibrahim,
E., & Singh, H. J. (2017). Melatonin ameliorates the adverse effects of
leptin on sperm. Asian Journal of Andrology, 19(6), 647–654. https://doi.
org/10.1111/and.12325
Almabhouh, F. A., Osman, K., Siti Fatimah, I., Sergey, G., Gnanou, J., &
Singh, H. J. (2015). Effects of leptin on sperm count and morphology in
Sprague-­Dawley rats and their reversibility following a 6-­week recov-
ery period. Andrologia, 47(7), 751–758.
Almabhouh, F. A., & Singh, H. J. (2017). Adverse effects of leptin on histone-­
to-­protamine transition during spermatogenesis are prevented by mel-
atonin in Sprague-­Dawley rats. Andrologia, 50(1). http://onlinelibrary.
wiley.com/doi/10.1111/and.12814/full.
Aquila, S., Gentile, M., Middea, E., Catalano, S., Morelli, C., Pezzi, V., & Ando,
S. (2005). Leptin secretion by human ejaculated spermatozoa. Journal of
Clinical Endocrinology and Metabolism, 90(8), 4753–4761.
Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B., & Maness, L. M. (1996).
Leptin enters the brain by a saturable system independent of insulin.
Peptides, 17(2), 305–311.
Barash, I. A., Cheung, C. C., Weigle, D. S., Ren, H., Kabigting, E. B., Kuijper, J.
L., … Steiner, R. A. (1996). Leptin is a metabolic signal to the reproduc-
tive system. Endocrinology, 137(7), 3144–3147.
Bideci, A., Cinaz, P., Hasanoglu, A., & Tumer, L. (2002). Leptin, insulin-­like
growth factor (IGF)-­I and IGF binding protein-­3 levels in children with
constitutional delay of growth. Journal of Pediatric Endocrinology and
Metabolism, 15(1), 41–46.
Budak, E., Fernandezsanchez, M., Bellver, J., Cervero, A., Simon, C., &
Pellicer, A. (2006). Interactions of the hormones leptin, ghrelin, adi-
ponectin, resistin, and PYY3-­36 with the reproductive system. Fertility
and Sterility, 85(6), 1563–1581.
Camiña, J. P., Lage, M., Menendez, C., Graña, M., García-Devesa, J., Dieguez,
C., & Casanueva, F. F. (2002). Evidence of free leptin in human seminal
plasma. Endocrine, 17(3), 169–174.
Caprio, M., Isidori, A. M., Carta, A. R., Moretti, C., Dufau, M. L., & Fabbri, A.
(1999). Expression of functional leptin receptors in rodent Leydig cells.
Endocrinology, 140(11), 4939–4947.
Catteau, A., Caillon, H., Barrière, P., Denis, M. G., Masson, D., & Fréour, T.
(2016). Leptin and its potential interest in assisted reproduction cycles.
Human Reproduction Update, 22(3), 320–341.
|
      5 of 7
Chen, B., Guo, J. H., Lu, Y. N., Ying, X. L., Hu, K., Xiang, Z. Q., … Huang, Y.
R. (2009). Leptin and varicocele-­related spermatogenesis dysfunction:
Animal experiment and clinical study. International Journal of Andrology,
32(5), 532–541.
Cravo, R. M., Frazao, R., Perello, M., Osborne-Lawrence, S., Williams, K. W.,
Zigman, J. M., … Elias, C. F. (2013). Leptin signaling in Kiss1 neurons
arises after pubertal development. PLoS ONE, 8(3), e58698.
Dardeno, T. A., Chou, S. H., Moon, H.-S., Chamberland, J. P., Fiorenza, C. G.,
& Mantzoros, C. S. (2010). Leptin in human physiology and therapeu-
tics. Frontiers in Neuroendocrinology, 31(3), 377–393.
Donato, J. Jr, Cravo, R. M., Frazao, R., Gautron, L., Scott, M. M., Lachey, J.,
… Elias, C. F. (2011). Leptin’s effect on puberty in mice is relayed by the
ventral premammillary nucleus and does not require signaling in Kiss1
neurons. The Journal of Clinical Investigation, 121(1), 355–368.
El-Eshmawy, M. M., Aal, I. A. A., & El Hawary, A. K. (2010). Association
of ghrelin and leptin with reproductive hormones in constitutional
delay of growth and puberty. Reproductive Biology and Endocrinology,
8, 153.
Elias, C. F., & Purohit, D. (2013). Leptin signaling and circuits in puberty and
fertility. Cellular and Molecular Life Sciences, 70(5), 841–862.
Farooqi, I. S. (2002). Leptin and the onset of puberty: Insights from ro-
dent and human genetics. Seminars in Reproductive Medicine, 20(2),
139–144.
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu,
C., & O’Rahilly, S. (2002). Beneficial effects of leptin on obesity, T cell
hyporesponsiveness, and neuroendocrine/metabolic dysfunction of
human congenital leptin deficiency. The Journal of Clinical Investigation,
110(8), 1093–1103.
Farooqi, S., & O’Rahilly, S. (2006). Genetics of obesity in humans. Endocrine
Reviews, 27(7), 710–718.
Fombonne, J., Charrier, C., Goddard, I., Moyse, E., & Krantic, S. (2007).
Leptin-­mediated decrease of cyclin A2 and increase of cyclin D1 ex-
pression: Relevance for the control of prepubertal rat Leydig cell divi-
sion and differentiation. Endocrinology, 148(5), 2126–2137.
Gale, S. M., Castracane, V. D., & Mantzoros, C. S. (2004). Energy homeo-
stasis, obesity and eating disorders: Recent advances in endocrinology.
Journal of Nutrition, 134(2), 295–298.
Ge, H., Huang, L., Pourbahrami, T., & Li, C. (2002). Generation of soluble
leptin receptor by ectodomain shedding of membrane-­spanning re-
ceptors in vitro and in vivo. Journal of Biological Chemistry, 277(48),
45898–45903.
Gill, M. S., Hall, C. M., Tillmann, V., & Clayton, P. E. (1999). Constitutional
delay in growth and puberty (CDGP) is associated with hypoleptinae-
mia. Clinical Endocrinology -­Oxford, 50(6), 721–726.
Glander, H. J., Lammert, A., Paasch, U., Glasow, A., & Kratzsch, J. (2002).
Leptin exists in tubuli seminiferi and in seminal plasma. Andrologia,
34(4), 227–233.
Gonzalez, R. R., Simon, C., Caballero-Campo, P., Norman, R., Chardonnens,
D., Devoto, L., & Bischof, P. (2000). Leptin and reproduction. Human
Reproduction Update, 6(3), 290–300.
Haron, M. N., D’Souza, U. J. A., Jaafar, H., Zakaria, R., & Singh, H. J. (2010).
Exogenous leptin administration decreases sperm count and increases
the fraction of abnormal sperm in adult rats. Fertility and Sterility, 93(1),
322–324.
Hatami-Baroogh, L., Razavi, S., Zarkesh-Esfahani, H., Tavalaee, M., Tanhaei,
S., Ghaedi, K., … Nasr-Esfahani, M. H. (2010). Evaluation of the leptin re-
ceptor in human spermatozoa. Reproductive Biology and Endocrinology,
8, 17.
Henson, M. C., & Castracane, V. D. (2006). Leptin in pregnancy: An update.
Biology of Reproduction, 74(2), 218–229.
Huang, L., & Li, C. (2000). Leptin: A multifunctional hormone. Cell Research,
10(2), 81–92.
Imagawa, K., Numata, Y., Katsuura, G., Sakaguchi, I., Morita, A., Kikuoka, S.,
… Nakao, K. (1998). Structure-­function studies of human leptin. Journal
of Biological Chemistry, 273(52), 35245–35249.
 |
6 of 7       ZHANG and GONG
Iqbal, J., Pompolo, S., Considine, R. V., & Clarke, I. J. (2000). Localization of
leptin receptor-­like immunoreactivity in the corticotropes, somatotro-
pes, and gonadotropes in the ovine anterior pituitary. Endocrinology,
141(4), 1515–1520.
Iqbal, J., Pompolo, S., Murakami, T., Grouzmann, E., Sakurai, T., Meister,
B., & Clarke, I. J. (2001). Immunohistochemical characterization of
localization of long-­form leptin receptor (OB-­Rb) in neurochemically
defined cells in the ovine hypothalamus. Brain Research, 920(1–2),
55–64.
Ishikawa, T., Fujioka, H., Ishimura, T., Takenaka, A., & Fujisawa, M. (2007).
Expression of leptin and leptin receptor in the testis of fertile and infer-
tile patients. Andrologia, 39(1), 22–27.
Jope, T., Lammert, A., Kratzsch, J., Paasch, U., & Glander, H. J. (2003). Leptin
and leptin receptor in human seminal plasma and in human spermato-
zoa. International Journal of Andrology, 26(6), 335–341.
Lampiao, F., & du Plessis, S. S. (2008). Insulin and leptin enhance human
sperm motility, acrosome reaction and nitric oxide production. Asian
Journal of Andrology, 10(5), 799–807.
Landry, D., Cloutier, F., & Martin, L. J. (2013). Implications of leptin in neuro-
endocrine regulation of male reproduction. Reproductive Biology, 13(1),
1–14.
Landry, D. A., Sormany, F., Haché, J., Roumaud, P., & Martin, L. J. (2017).
Steroidogenic genes expressions are repressed by high levels of leptin
and the JAK/STAT signaling pathway in MA-­10 Leydig cells. Molecular
& Cellular Biochemistry, 433(1–2), 79–95.
Lebrethon, M. C., Vandersmissen, E., Gerard, A., Parent, A. S., &
Bourguignon, J. P. (2000). Cocaine and amphetamine-­ regulated-­
transcript peptide mediation of leptin stimulatory effect on the rat
gonadotropin-­releasing hormone pulse generator in vitro. Journal of
Neuroendocrinology, 12(5), 383–385.
Leshan, R. L., Louis, G. W., Jo, Y. H., Rhodes, C. J., Munzberg, H., & Myers,
M. G. Jr (2009). Direct innervation of GnRH neurons by metabolic-­and
sexual odorant-­sensing leptin receptor neurons in the hypothalamic ven-
tral premammillary nucleus. Journal of Neuroscience, 29(10), 3138–3147.
Li, H. W. R., Chiu, P. C. N., Cheung, M. P. L., & Yeung, W. S. B. (2009). Effect
of leptin on motility, capacitation and acrosome reaction of human
spermatozoa. International Journal of Andrology, 32(6), 687–694.
Lin, Q., Poon, S. L., Chen, J., Cheng, L., Hoyuen, B., & Leung, P. C. (2009).
Leptin interferes with 3′,5′-­cyclic adenosine monophosphate
(cAMP) signaling to inhibit steroidogenesis in human granulosa cells.
Reproductive Biology & Endocrinology, 7(1), 115.
Luque, R. M., Kineman, R. D., & Tenasempere, M. (2007). Regulation of
Hypothalamic Expression of KiSS-­1 and GPR54 Genes by Metabolic
Factors: Analyses Using Mouse Models and a Cell Line. Endocrinology,
148(10), 4601–4611.
Luukkaa, V., Pesonen, U., Huhtaniemi, I., Lehtonen, A., Tilvis, R., Tuomilehto,
J., … Huupponen, R. (1998). Inverse correlation between serum testos-
terone and leptin in men. Journal of Clinical Endocrinology & Metabolism,
83(9), 3243.
Ma, Y., Chen, B., Wang, H., Hu, K., & Huang, Y. (2011). Prediction of sperm
retrieval in men with non-­ obstructive azoospermia using artificial
neural networks: Leptin is a good assistant diagnostic marker. Human
Reproduction, 26(2), 294–298.
Manfredilozano, M., Roa, J., Ruizpino, F., Piet, R., Garciagaliano, D., Pineda,
R., … Romeroruiz, A. (2016). Defining a novel leptin–melanocortin–kiss-
peptin pathway involved in the metabolic control of puberty. Molecular
Metabolism, 5(10), 844–857.
Mantzoros, C. S., Flier, J. S., & Rogol, A. D. (1997). A longitudinal assessment
of hormonal and physical alterations during normal puberty in boys. V.
Rising leptin levels may signal the onset of puberty. Journal of Clinical
Endocrinology and Metabolism, 82(4), 1066–1070.
Maqsood, A. R., Trueman, J. A., Whatmore, A. J., Westwood, M., Price, D.
A., Hall, C. M., & Clayton, P. E. (2007). The relationship between noc-
turnal urinary leptin and gonadotrophins as children progress towards
puberty. Hormone Research, 68(5), 225–230.
Margetic, S., Gazzola, C., Pegg, G. G., & Hill, R. A. (2002). Leptin: A review of
its peripheral actions and interactions. International Journal of Obesity
and Related Metabolic Disorders, 26(11), 1407–1433.
Messinis, I. E., & Milingos, S. D. (1999). Leptin in human reproduction.
Human Reproduction Update, 5(1), 52–63.
Mounzih, K., Lu, R., & Chehab, F. F. (1997). Leptin treatment rescues the
sterility of genetically obese ob/ob Males. Endocrinology, 138(3),
1190–1193.
Ozata, M., Ozdemir, I. C., & Licinio, J. (1999). Human leptin deficiency caused
by a missense mutation: Multiple endocrine defects, decreased sympa-
thetic tone, and immune system dysfunction indicate new targets for
leptin action, greater central than peripheral resistance to the effects of
leptin, and spontaneous correction of leptin-­mediated defects. Journal
of Clinical Endocrinology and Metabolism, 84(10), 3686–3695.
Quennell, J. H., Howell, C. S., Roa, J., Augustine, R. A., Grattan, D. R., &
Anderson, G. M. (2011). Leptin deficiency and diet-­induced obesity reduce
hypothalamic kisspeptin expression in mice. Endocrinology, 152(4), 1541.
Roa, J., Garcíagaliano, D., Castellano, J. M., Gaytan, F., Pinilla, L., &
Tenasempere, M. (2010). Metabolic control of puberty onset: New play-
ers, new mechanisms. Molecular & Cellular Endocrinology, 324(1–2), 87.
Roa, J., & Tena-Sempere, M. (2010). Energy balance and puberty onset:
Emerging role of central mTOR signaling. Trends in Endocrinology &
Metabolism, 21(9), 519–528.
Rutters, F., Nieuwenhuizen, A. G., Verhoef, S. P. M., Lemmens, S. G. T.,
Vogels, N., & Westerterp-Plantenga, M. S. (2009). The relationship be-
tween leptin, gonadotropic hormones, and body composition during
puberty in a Dutch children cohort. European Journal of Endocrinology,
160(6), 973–978.
Sainz, N., Barrenetxe, J., Moreno-Aliaga, M. J., & Martinez, J. A. (2015).
Leptin resistance and diet-­induced obesity: Central and peripheral ac-
tions of leptin. Metabolism, 64(1), 35–46.
Schaab, M., & Kratzsch, J. (2015). The soluble leptin receptor. Best Practice
& Research Clinical Endocrinology & Metabolism, 29(5), 661–670.
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S.
Jr, Shagoury, J. K., … Colledge, W. H. (2003). The GPR54 gene as a regu-
lator of puberty. New England Journal of Medicine, 349(17), 1614–1627.
Skorupskaite, K., George, Jyothis. T., & Anderson, Richard. A. (2014). The
kisspeptin-­GnRH pathway in human reproductive health and disease.
Human Reproduction Update, 20(4), 485.
Smith, J. T., Acohido, B. V., Clifton, D. K., & Steiner, R. A. (2006). KiSS-­1
neurones are direct targets for leptin in the ob/ob mouse. Journal of
Neuroendocrinology, 18(4), 298–303.
Smith, J. T., & Waddell, B. J. (2003). Developmental changes in plasma leptin
and hypothalamic leptin receptor expression in the rat: Peripubertal
changes and the emergence of sex differences. Journal of Endocrinology,
176(3), 313–319.
Soyupek, S., Armagan, A., Serel, T. A., Hoscan, M. B., Perk, H., Karaoz, E.,
& Candir, O. (2005). Leptin expression in the testicular tissue of fertile
and infertile men. Archives of Andrology, 51(3), 239–246.
Steinman, N., Gamzu, R., Yogev, L., Botchan, A., Schreiber, L., & Yavetz, H.
(2001). Serum leptin concentrations are higher in azoospermic than in
normozoospermic men. Fertility and Sterility, 75(4), 821–822.
Strobel, A., Issad, T., Camoin, L., Ozata, M., & Strosberg, A. D. (1998). A
leptin missense mutation associated with hypogonadism and morbid
obesity. Nature Genetics, 18(3), 213–215.
Sullivan, S. D., & Moenter, S. M. (2004). γ-­Aminobutyric acid neurons in-
tegrate and rapidly transmit permissive and inhibitory metabolic cues
to gonadotropin-­ releasing hormone neurons. Endocrinology, 145(3),
1194–1202.
Swerdloff, R. S., Batt, R. A., & Bray, G. A. (1976). Reproductive hormonal
function in the genetically obese (ob/ob) mouse. Endocrinology, 98(6),
1359–1364.
Tartaglia, L. A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R.,
… Tepper, R. I. (1995). Identification and expression cloning of a leptin
receptor, OB-­R. Cell, 83(7), 1263–1271.
ZHANG and GONG
Tena-Sempere, M., & Barreiro, M. L. (2002). Leptin in male reproduction:
The testis paradigm. Molecular and Cellular Endocrinology, 188(1–2),
9–13.
Tena-Sempere, M., Manna, P. R., Zhang, F. P., Pinilla, L., Gonzalez, L. C.,
Dieguez, C., … Aguilar, E. (2001). Molecular mechanisms of leptin ac-
tion in adult rat testis: Potential targets for leptin-­induced inhibition of
steroidogenesis and pattern of leptin receptor messenger ribonucleic
acid expression. Journal of Endocrinology, 170(2), 413–423.
Tena-Sempere, M., Pinilla, L., Gonzalez, L. C., Dieguez, C., Casanueva, F. F.,
& Aguilar, E. (1999). Leptin inhibits testosterone secretion from adult
rat testis in vitro. Journal of Endocrinology, 161(2), 211–218.
Tezuka, M., Irahara, M., Ogura, K., Kiyokawa, M., Tamura, T., Matsuzaki, T.,
… Aono, T. (2002). Effects of leptin on gonadotropin secretion in juve-
nile female rat pituitary cells. European Journal of Endocrinology, 146(2),
261–266.
Thompson, E. L., Patterson, M., Murphy, K. G., Smith, K. L., Dhillo, W. S.,
Todd, J. F., … Bloom, S. R. (2004). Central and peripheral administration
of kisspeptin-­10 stimulates the hypothalamic-­pituitary-­gonadal axis.
Journal of Neuroendocrinology, 16(10), 850–858.
Van Vugt, D. A., Lujan, M. E., Froats, M., Krzemien, A., Couceyro, P. R., &
Reid, R. L. (2006). Effect of fasting on cocaine-­amphetamine-­regulated
transcript, neuropeptide Y, and leptin receptor expression in the non-­
human primate hypothalamus. Neuroendocrinology, 84(2), 83–93.
Venancio, J. C., Margatho, L. O., Rorato, R. C., Rosales, R. R. C., Debarba, L.
K., Coletti, R., , & Elias, L. L. K. (2017). Short-­term high-­fat diet ­increases
leptin activation of cart neurons and advances puberty in female mice.
Endocrinology, 158(11), 3929–3942.
|
      7 of 7
Wauman, J., Zabeau, L., & Tavernier, J. (2017). The leptin receptor complex:
Heavier than expected? Frontiers in Endocrinology, 8, 30.
Yong, X., Faulkner, L. D., & Hill, J. W. (2011). Cross-­talk between metabo-
lism and reproduction: The role of POMC and SF1 neurons. Frontiers in
Endocrinology, 2, 98.
Yu, W. H., Kimura, M., Walczewska, A., Karanth, S., & McCann, S. M. (1997).
Role of leptin in hypothalamic-­pituitary function. Proceedings of the
National Academy of Sciences, 94(3), 1023–1028.
Zamorano, P. L., Mahesh, V. B., De Sevilla, L. M., Chorich, L. P., Bhat, G. K., &
Brann, D. W. (1997). Expression and localization of the leptin receptor
in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology,
65(3), 223.
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J.
M. (1994). Positional cloning of the mouse obese gene and its human
homologue. Nature, 372(6505), 425–432.
Zorn, B., Osredkar, J., Meden-Vrtovec, H., & Majdic, G. (2007). Leptin lev-
els in infertile male patients are correlated with inhibin B, testosterone
and SHBG but not with sperm characteristics. International Journal of
Andrology, 30(5), 439–444.
How to cite this article: Zhang J, Gong M. Review of the role
of leptin in the regulation of male reproductive function.
Andrologia. 2018;e12965. https://doi.org/10.1111/and.12965