Effect of Peripheral Kisspeptin Administration on Adiponectin, Leptin, and Resistin Secretion Under Fed and Fasting Conditions in the Adult Male Rhesus Monkey (Macaca mulatta)

Abstract

In the last few years, kisspeptin-KISS1R signaling has appeared as a major regulator of the reproductive function in several vertebrate species. However, KISS1(encoding kisspeptin) and its putative receptor, KISS1R, are expressed in several other tissues. Adipose tissue, which secretes many peptides with diverse functions in normal physiology, expresses KISS1, which is modulated by gonadal steroids as well as by body nutritional status. Similarly, KISS1Rexpression is also found in adipose tissue, but the local role of kisspeptin in adipocyte function is currently unknown. Therefore, in the present study the effects of exogenous human kisspeptin-10 (KP10) were studied on three important adipokines, namely, adiponectin, leptin, and resistin in a set of four chair-restraint habituated intact adult male rhesus monkeys under; 1) normal fed conditions, 2) 24-h fasting conditions, and 3) 48-h fasting conditions. Plasma resistin and leptin levels decreased (p<0.01), whereas adiponectin levels increased (p<0.05) in fasted monkeys. Kisspeptin administration significantly increased (p<0.05) mean plasma adiponectin levels under fed and 24-h fasting conditions as compared to pretreatment or vehicle-treatment levels. A stimulatory effect was also observed on the 48-h fasting stimulated plasma adiponectin levels, but it lacked statistical significance. In contrast, no effect of kisspeptin was observed on mean plasma leptin and resistin levels. Thus, the present study demonstrated a stimulatory effect of peripheral kisspeptin administration on the plasma adiponectin levels under fed and 24-h fasting conditions in the adult male rhesus monkey. These findings, therefore, assign a novel role to kisspeptin, a regulator of adipocyte function in higher primate.

Full text

Animals, Clinical570
Wahab F et al. Kisspeptin Eff ect on Adipokines Release … Horm Metab Res 2010; 42: 570 – 574
received 24.07.2009
accepted 09.03.2010
Bibliography
DOI http://dx.doi.org/
10.1055/s-0030-1252016
Published online:
May 5, 2010
Horm Metab Res 2010;
42: 570 – 574
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 0018-5043
Correspondence
Dr. M. Shahab
Reproductive Neuroendo-
crinology Laboratory
Department of Animal Sciences
Faculty of Biological Sciences
Quaid-i-Azam University
45320 Islamabad
Pakistan
Tel.: + 92 / 51 / 9064 30 14
Fax: + 92 / 51 / 2601 176
Shahab@qau.edu.pk
Key words
● ▶ fasting
● ▶ kisspeptin
● ▶ GPR54
● ▶ adiponectin
● ▶ leptin
● ▶ resistin
● ▶ monkey
Eff ect of Peripheral Kisspeptin Administration on
Adiponectin, Leptin, and Resistin Secretion Under
Fed and Fasting Conditions in the Adult Male Rhesus
Monkey ( Macaca mulatta )
of the HPG axis through an alteration of the
hypothalamic kisspeptin-Kiss1r signaling [6, 13,
14, 17] .
Kiss1 and Kiss1r are also expressed in many
peripheral tissues, including adipose [18 – 22] .
Adipose tissue is the source of a number of bioac-
tive peptides, known as adipokines, which par-
ticipate in a variety of functions [23] . Adiponectin,
leptin, and resistin are adipokines that play an
important role in the regulation of energy home-
ostasis and metabolism. Leptin acts as a satiety
factor and its systemic concentration is in pro-
portion with body fat mass. Adiponectin is the
most abundant adipokine in the circulation. Adi-
ponectin, unlike leptin, is negatively correlated
with body fat mass. Adiponectin augments insu-
lin sensitivity while leptin and resistin decrease
it [24] . These adipokines also impact on the
reproductive axis. Leptin enhances, whereas adi-
ponectin decreases, the output of key reproduc-
Introduction
▼
KISS1 (encoding kisspeptin) and KISS1R (encod-
ing the receptor of kisspeptin) are necessary for
normal reproductive function [1, 2] . Many verte-
brate species attain fertility when the expression of
the hypothalamic Kiss1 gene increases at the time
of the pubertal awakening of the hypothalamic-
pituitary-gonadal (HPG) axis [3 – 6] . Mutations in
KISS1R cause hypogonadotropic hypogonadism in
humans [1, 2] and an activating mutation of
KISS1R causes precocious puberty [7] . Both Kiss1r
and Kiss1 knock out mice also have impaired
reproductive ability [8 – 10] . Adequate kisspep-
tinergic drive to GnRH neurons is necessary for
maintaining fertility in adulthood [11, 12] . Envi-
ronmental and metabolic factors can aff ect the
expression of hypothalamic Kiss1 [6, 13 – 16] .
Body energy reserves and seasonal variations
have been documented to modulate functioning
Authors F. Wahab , R. Bano , S. Jabeen , S. Irfan , M. Shahab
Affi liation Laboratory of Reproductive Neuroendocrinology, Department of Animal Sciences, Faculty of Biological Sciences,
Quaid-i-Azam University, Islamabad, Pakistan
Abstract
▼
In the last few years, kisspeptin-KISS1R signaling
has appeared as a major regulator of the repro-
ductive function in several vertebrate species.
However, KISS1 (encoding kisspeptin) and its
putative receptor, KISS1R , are expressed in sev-
eral other tissues. Adipose tissue, which secretes
many peptides with diverse functions in normal
physiology, expresses Kiss1 , which is modulated
by gonadal steroids as well as by body nutritional
status. Similarly, Kiss1r expression is also found
in adipose tissue, but the local role of kisspep-
tin in adipocyte function is currently unknown.
Therefore, in the present study the eff ects of
exogenous human kisspeptin-10 (KP10) were
studied on three important adipokines, namely,
adiponectin, leptin, and resistin in a set of four
chair-restraint habituated intact adult male rhe-
sus monkeys under; 1) normal fed conditions,
2) 24-h fasting conditions, and 3) 48-h fast-
ing conditions. Plasma resistin and leptin levels
decreased (p < 0.01), whereas adiponectin levels
increased (p < 0.05) in fasted monkeys. Kisspeptin
administration signifi cantly increased (p < 0.05)
mean plasma adiponectin levels under fed and
24-h fasting conditions as compared to pre-
treatment or vehicle-treatment levels. A stimu-
latory eff ect was also observed on the 48-h
fasting stimulated plasma adiponectin levels,
but it lacked statistical signifi cance. In contrast,
no eff ect of kisspeptin was observed on mean
plasma leptin and resistin levels. Thus, the
present study demonstrated a stimulatory eff ect
of peripheral kisspeptin administration on the
plasma adiponectin levels under fed and 24-h
fasting conditions in the adult male rhesus mon-
key. These fi ndings, therefore, assign a novel role
to kisspeptin, a regulator of adipocyte function in
higher primate.

Animals, Clinical 571
Wahab F et al. Kisspeptin Eff ect on Adipokines Release … Horm Metab Res 2010; 42: 570 – 574
tive hormones [23, 25 – 28] . The role of resistin on the reproductive
axis is less understood.
The release of adipokines from adipose tissue is dictated by
many factors. Adipose tissue expresses numerous receptors that
allow it to respond aff erent signals from endocrine hormones as
well as the central nervous system (CNS). Adipose tissue
expresses Kiss1 and Kiss1r [22] , but the specifi c role of kisspeptin
signaling in the physiology of this tissue is currently unknown.
Therefore, the aim of the present study was to examine the eff ect
of peripheral administration of exogenous kisspeptin on the
basal plasma levels of adiponectin, leptin, and resistin in the
adult male rhesus monkey.
Energy imbalance is characterized by a number of changes in the
plasma concentrations of adipokines [23, 24, 29 – 32] . Short-term
fasting reduces plasma levels of resistin and leptin while increas-
ing the plasma levels of adiponectin [29, 32, 33] . Fasting also
changes the expression of Kiss1 [22] ; therefore, we hypothesized
that fasting conditions may cause alterations in the response of
adipokines to kisspeptin. Therefore, the second aim of the
present study was to look for any alteration in the response of
adipokines (adiponectin, leptin, and resistin) to a kisspeptin
challenge during short-term fasting (24- and 48-h fasting) con-
ditions.
Materials and Methods
▼
Animals
Four adult intact male rhesus macaques ( Macaca mulatta ), 6 –
8 kg in weight (6 – 9 years old) were used in the present study.
The animals were housed in individual cages, in the same room,
under temperature (25 ± 2 ° C) and light-controlled (lights on,
0600 – 1 800 h) conditions in the Department ’ s primate facility.
The animals were fed daily with fresh fruits / vegetables (0900 –
0930 h) and standard monkey food at 1 300 – 1 330 h, with free
excess to tap water. Entry into the primate room was restricted
to the animal caretakers and personnel involved in the research
work. The animals were habituated to chair restraint eight weeks
prior to commencement of the experiments. Each animal was
restrained on the chair for four hours daily. Animals were also
trained to take their food and water while chair restrained. For
the ease of fi xing or removing from the chair, animals were
sedated by administering ketamine hydrochloride (Ketlar,
Astarapin, Germany 3 – 5 mg / kg BW) intramuscularly. All animal
studies were approved by the Departmental Committee for Care
and Use of Laboratory Animals.
Venous catheterization
Under ketamine (10 mg / kg BW, i.m.) anesthesia, a tefl on cannula
was inserted in the saphenous vein. The free end of the cannula
(Vasocan Branule, 0.8 mm / 22 G O.D, B. Braun Melsungen AG, Bel-
gium) was linked to a syringe by a butterfl y tube (Length 300 mm,
volume 0.29 ml, 20 GX3 / 4 ” , JMS, Singapore). This conduit was
used for sequential withdrawal of blood samples and i. v. admin-
istration of kisspeptin-10 (KP10). Experiments were initiated
when the animals had fully recovered from sedation.
Pharmacological agents
Ketamine and heparin (Rotexmedica, Trittau, Germany) were
purchased from the local supplier. Human KP10 (amino acids
112 – 121) was purchased from the local agent of the Calbiochem
(La Jolla, CA, USA). Working solutions of KP10 were made in nor-
mal saline (0.9 % NaCl). The eff ectiveness of the peripheral KP10
was ascertained by a prominent stimulation of the plasma testo-
sterone levels after administration (data not shown).
Blood sampling
Sequential blood samples (2 ml) were obtained at – 60 min,
– 30 min, and immediately before i. v. bolus administration of
vehicle or KP10 at time 0, and sampling continued for 3 h after
the injection at 30-min intervals. Samples were collected in
heparinized syringes, and an equal amount of heparinized (5 IU /
ml) normal saline was administered, following withdrawal of
each sample. Blood sampling was conducted between 1 100 –
1 500 h. Blood samples were centrifuged at 3 000 rpm for 10 min
at 4 ° C, and the plasma was separated and stored at – 20 ° C until
hormone analysis.
Studies of the eff ects of KP were conducted during a period of 35
days (March – April 2008) on 6 diff erent days. The treatments
were given in the following order: 1) vehicle (normal saline,
1 ml) in normal fed conditions; 2) Human KP10 (50 μ g / animal
diluted in 1 ml normal saline) in 48-h fasting conditions; 3) KP10
in normal fed conditions; 4) vehicle in 48-h fasting conditions;
5) KP10 in 24-h fasting conditions; 6) vehicle in 24-h fasting
conditions.
Analysis of hormones
Changes in plasma adiponectin, leptin, and resistin levels were
monitored using specifi c ELISA kits (AssayMax Human ELISA;
Assaypro 41 Triad south drive St. Charles, MO, USA) following the
instructions of the manufacturer. The limit of the adiponectin
assay was 0.2 ng / ml; the intra- and inter-assay coeffi cients of
variation were below 8 % . The sensitivity of the leptin assay
was < 150 pg / ml; the intra- and inter-assay coeffi cients of varia-
tion were below 6 % . The minimum detectable limit of resistin
assay was < 100 pg / ml, and the intra- and inter-assay coeffi cients
of variation were below 6 % .
Statistical analysis
Hormonal concentrations after administration of KP10 and vehi-
cle were compared by repeated measures ANOVA, and one-way
ANOVA followed by Dunnett ’ s multiple comparisons test. Statis-
tical comparisons of mean plasma levels of adiponectin, leptin,
and resistin under fasting and fed conditions, and for mean pre-
and post-treatment adiponectin, leptin, and resistin levels were
also made by paired student ’ s t -tests. All data are presented as
mean ( ± SEM). Statistical signifi cance was set at p < 0.05.
Results
▼
Basal plasma levels of adiponectin, leptin, and resistin
under fed and fasting conditions
The basal plasma concentrations of adiponectin, leptin, and
resistin during a 1 h period before vehicle administration under
fed and fasting (24- and 48-h) conditions in adult male monkeys
are shown in ● ▶ Fig. 1 . Short-term fasting either for 24- or 48-h
signifi cantly decreased (p < 0.01) mean basal levels of leptin and
resistin. In contrast, fasting (24- and 48-h) led to a signifi cant
increase (p < 0.05) in the basal levels of adiponectin.

Animals, Clinical572
Wahab F et al. Kisspeptin Eff ect on Adipokines Release … Horm Metab Res 2010; 42: 570 – 574
Eff ect of KP10 on adiponectin secretion under fed and
fasting conditions
Mean plasma adiponectin levels 60 min before and 180 min after
vehicle and KP10 administration in fed and fasted adult male
monkeys are shown in ● ▶ Fig. 2 and Table 1 . Comparison of mean
pre- and post-treatment levels showed that vehicle did not aff ect
mean plasma adiponectin levels under both fed and fasting con-
ditions. KP10 administration increased (p < 0.05) plasma levels
of adiponectin under fed conditions. KP10 administration also
increased adiponectin levels in both 24- and 48-h fasting condi-
tions, but statistical signifi cance (p < 0.05) was observed only for
the increase in 24-h fasting conditions.
Eff ect of KP10 on leptin secretion under fed and fasting
conditions
Comparison of mean plasma leptin levels for 60 min before and
180 min after vehicle and KP10 administration under fed and
fasting conditions in the adult male rhesus monkeys are shown
in ● ▶ Fig. 3 . Administration of both vehicle and KP10 had no sig-
nifi cant eff ect on the leptin secretion in both fed and fasted
monkeys.
Eff ect of KP10 on resistin secretion under fed and
fasting conditions
Comparison of mean plasma resistin levels 60 min before and
180 min after vehicle and KP10 administration under fed and
fasting conditions in the adult male rhesus monkeys are shown
in ● ▶ Fig. 4 . Administration of both vehicle and KP10 had no sig-
nifi cant eff ect on the resistin secretion in both fed and fasted
monkeys.
Discussion
▼
Recently, it has been shown that the hypothalamic Kiss1 expres-
sion can be modifi ed by leptin [26] . This observation suggests
that kisspeptin secreting neurons may serve as a possible link
between metabolism and reproduction. Currently, there is no
clear evidence whether kisspeptin, in turn, can aff ect secretion
of leptin or other adipokine hormones. However, the possible
action of kisspeptin in secretion of these hormones is suggested
by the observation that Kiss1r is expressed in the adipose tissue
[22] . Therefore, we report the eff ect of the peripheral adminis-
tration of KP10 on the secretion of three adipokines, namely,
leptin, adiponectin, and resistin secretion. Our results demon-
strate that exogenous KP10 administration did not alter mean
basal plasma leptin and resistin concentrations. In contrast,
KP10 administration caused stimulation of plasma adiponectin
under both fed and fasting (24-h and 48-h) conditions. The fi nd-
ing that peripheral administration of kisspeptin to an adult male
monkey elicits a robust release of adiponectin suggests that
kisspeptin has a role in secretion of this adipokine.
The nature of the eff ect of kisspeptin administration on adi-
ponectin is not established. As Kiss1 and Kiss1r are expressed in
adipose tissue [22] , a physiological role for kisspeptin in this tis-
sue cannot be excluded. It is also not clear whether the action of
kisspeptin on the adiponectin release is endocrine / paracrine or
autocrine. Circulating levels of kisspeptin have been noted in
both peripubertal and adults subjects [34 – 36] . However, studies
of modulation of plasma kisspeptin levels in a variety of meta-
bolic conditions or correlation between plasma kisspeptin and
0
Adiponectin ResistinLeptin
10
20
30
40
Hormones
ng/ml, µg/ml
Fed 24-h fas ting 48-h fas ting
**
**
**
**
Fig. 1 Comparison of overall mean ( ± SEM) basal plasma adiponectin
( μ g / ml), leptin (ng / ml), and resistin (ng / ml) concentrations in a 1 h period
in normal fed, 24- and 48-h fasted adult male rhesus monkeys (n = 4).
Fasting resulted in a signifi cant reduction in mean plasma leptin and
resistin levels ( * p < 0.01) while it signifi cantly ( * * p < 0.05) increased
plasma adiponectin levels (n = 4).
0
10
20
30
40
50
Fed 24-h fasting 48-h fasting
Conditions
*
*
Mean Plasma Adiponectin (µg/ml)
Pre-KP10 Post-V Post-KP10
Fig. 2 Comparison of mean ( ± SEM) plasma adiponectin concentrations
in the 60 min pre- and 180 min post-KP10 / vehicle treatment periods in
fed, 24- and 48-h fasted adult male monkeys (n = 4). KP10 administration
(50 μ g) signifi cantly increased ( * p < 0.05) mean adiponectin in fed as well
as in 24-h fasted monkeys as compared to vehicle- and pre-treatments
levels (n = 4).
Table 1 Changes in mean ( ± SEM) plasma adiponectin concentrations ( μ g / ml) during 1 h before and 3 h after KP10 administration under normal fed, 24-, and
48-h fasting conditions in the adult male rhesus monkeys (n = 4)
Pre-KP10 Post-KP10
Conditions − 60 min − 30 min 0 min 30 min 60 min 90 min 120 min 150 min 180 min
Fed 11.3 ± 1.2 11.26 ± 1.3 12.77 ± 2.1 19.10 ± 0.6 * 24.8 ± 1.2 * 24.35 ± 1.5 * 23.71 ± 2.5 * 19.58 ± 1.1 * 18.34 ± 1.3 *
24-h fasting 16.2 ± 1.4 19.1 ± 1.1 18.4 ± 1.6 23.4 ± 1.4 26.7 ± 1.7 * 31.1 ± 1.8 * 28.7 ± 1.7 * 26.4 ± 1.5 * 23.1 ± 1.6
48-h fasting 28.41 ± 3.9 24.99 ± 4.4 23.53 ± 4.3 41.77 ± 9.8 36.75 ± 6.5 36.70 ± 4.1 36.20 ± 4.5 34.22 ± 3.7 35.2 ± 3.3
* Repeated measures ANOVA, and one-way ANOVA followed by post hoc Dunnett’s test showed that kisspeptin administration signifi cantly ( * p < 0.05) increased plasma
adiponectin levels under fed and 24-h fasting conditions as compared to pretreatment (0, − 30, and − 60) or vehicle-treatment levels

Animals, Clinical 573
Wahab F et al. Kisspeptin Eff ect on Adipokines Release … Horm Metab Res 2010; 42: 570 – 574
adipocyte hormones have not been done. On the other hand,
because Kiss1 and Kiss1r have been detected in adipose tissue
[22] , a paracrine / autocrine action is also possible. As fasting has
been shown to increase Kiss1 mRNA (and hence kisspeptin) lev-
els in rat adipose tissue [22] , our fi ndings suggest that locally
produced kisspeptin under fasting conditions could contribute
to the increase in circulating adiponectin levels observed in this
state.
The physiological importance of the kisspeptin eff ect on adi-
ponectin is not clear. Some preliminary studies in rats have indi-
cated an inhibitory eff ect of adiponectin on LH and T release
[27, 28] . Adiponectin receptors are expressed in the rat hypotha-
lamus, pituitary, and testis [27, 28, 37, 38] suggesting a possible
direct action of adiponectin on key reproductive hormones. Our
fi ndings appear to suggest a novel inhibitory infl uence of
kisspeptin on the reproductive hormones secretion, which is
mediated by adiponectin and enacted only under certain energy
defi cient conditions. As adiponectin is able to cross blood-brain
barrier and its receptors are present in the hypothalamus
[37, 38] , it is possible that adiponectin may act as a feedback sig-
nal for hypothalamic Kiss1 system.
The reasons for the lack of an eff ect of kisspeptin on leptin and
resistin secretion in the present study are not clear. The dose of
KP10 employed may be too low to aff ect leptin and resistin
release, but this possibility is less likely as the same dose stimu-
lated plasma adiponectin levels. Therefore, it is possible that
kisspeptin may not aff ect the basal secretion of leptin and resis-
tin in monkeys. Fasting led to a decrease in the basal secretion of
these hormones, and kisspeptin had no eff ect on fasting leptin
and resistin secretion. A previous study has shown that kisspep-
tin administration does not aff ect basal secretion of insulin,
another metabolic hormone, but rather modulates glucose-
stimulated insulin secretion [21] . Further studies, therefore, will
be important to check for any eff ect of kisspeptin on the stimu-
lated secretion of these hormones.
In summary, we have described the eff ect of exogenous periph-
eral administration of kisspeptin on the release of three adipo-
kines, namely, adiponectin, leptin, and resistin. Our data have
demonstrated, for the fi rst time, that exogenous peripheral
administration of kisspeptin has no eff ect on leptin and resistin
secretion, but acts as potent stimulator of adiponectin release in
the adult male rhesus monkey under both fed and fasting condi-
tions. Our fi ndings, therefore, assign a novel role to kisspeptin, as
a regulator of adipocyte secretory function in higher primates.
Acknowledgements
▼
The work presented here was funded by Higher Education
Commission, Islamabad, Pakistan. Fazal Wahab is an indigenous
Ph.D. fellow of HEC. The authors are greatly indebted to
Dr. Stephanie Seminara for critically reviewing the manuscript.
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