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Brain Research 887 (2000) 426–431
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Short communication

Stimulation of prolactin secretion by chronic, but not acute,
administration of leptin in the rat
¨ b , Toshihiro Suda a
Hajime Watanobe a , *, Helgi B. Schioth
b

a
Third Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036 -8562, Japan
Department of Neuroscience, Uppsala University, BMC, Box 593, SE 751 24 Uppsala, and Melacure Therapeutics, Uppsala, Sweden

Accepted 12 September 2000

Abstract
Leptin, the product of obese (ob) gene, has been reported to affect the secretion of all six anterior pituitary hormones, but data are
especially scarce regarding the interplay between leptin and prolactin (PRL). Thus, in this study we examined and compared in vivo the
effects of acute and chronic administrations of recombinant mouse leptin on PRL secretion in male rats. Normally-fed and 3-day-fasted

rats received an intraperitoneal bolus injection of leptin [1.0 mg / kg body weight (BW)] or vehicle only. The leptin treatment was without
effect on plasma PRL levels up to 5 h postadministration. Food deprivation for 3 days significantly decreased both PRL and leptin levels.
This decrease in plasma PRL was prevented by a 3-day constant infusion of 75 mg / kg BW/ day of leptin, which maintained plasma leptin
levels similar to those of normally-fed rats. The administration of three times the higher dose of leptin (225 mg / kg BW/ day) to fasted rats
led to further increases in both PRL and leptin in the plasma. Thus, a dose-dependent stimulatory effect of chronic leptin treatment on
PRL secretion was indicated. This study demonstrates that chronic, but not acute, administration of leptin stimulates PRL secretion in the
rat.  2000 Elsevier Science B.V. All rights reserved.
Theme: Endocrine and autonomic regulation
Topic: Neuroendocrine regulation: other
Keywords: Leptin; Prolactin; Acute hyperleptinemia; Chronic hyperleptinemia

The obese gene product, leptin, is a hormone produced
by adipocytes which plays a key role in the regulation of
food intake and energy expenditure [4,13,23,40]. Besides
its well known role in body weight homeostasis, leptin has
recently been shown to play a significant role in the
regulation of neuroendocrine function. Increasing evidence
suggests that leptin may affect the secretion of all six
anterior pituitary hormones. Of these, gonadotropins and
growth hormone have thus far been studied in more detail

than the other pituitary hormones from the viewpoint of
their interaction with leptin (for review, see Ref. [5]).
On the other hand, regarding the interplay between
leptin and prolactin (PRL), relevant data are especially
scarce. A stimulatory effect of leptin on PRL secretion
may be indirectly suggested from the evidence that leptin
partially restores lactation in the ob / ob mouse [6], a strain
*Corresponding author. Fax: 181-172-32-6846.
E-mail address: watanobe@infoaomori.ne.jp (H. Watanobe).

which does not produce leptin. There exist a few studies
which reported a direct stimulatory effect of leptin or its
fragment of PRL secretion in vivo [10] and in vitro [39],
but conflicting in vivo [14] and in vitro [33] data have also
been reported. We have also found that an intracerebroventricular (icv) administration of anti-leptin antisera significantly delayed the onset of preovulatory PRL surge,
and icv and systemic treatments of leptin to fasted rats
resumed the hormonal surge to normality [20,35,37].
In spite of these preexisting studies, it still remains to be
elucidated whether leptin can acutely affect PRL secretion
in vivo, and also whether acute and chronic administrations of leptin exert differential effects on PRL release.

Thus, in the present study we examined and compared the
effects of acute and chronic administrations of leptin to
freely-moving male rats in order to better understand a
possible physiological role of the adipocyte-derived hormone in regulating PRL secretion in the rat.
Animals: Adult male rats of the Wistar Strain [body

0006-8993 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0006-8993( 00 )03019-5

H. Watanobe et al. / Brain Research 887 (2000) 426 – 431

weight (BW), 240–250 g] were used. They were housed at
constant room temperature and humidity under a 12-h
light–dark cycle (light on at 08:00 h and off at 20:00 h).
Food and water were available ad libitum, unless otherwise
indicated.
Acute leptin treatment: For this experiment, two groups
were prepared, i.e. normally-fed and 3-day-fasted rats. The
latter group had started fasting 72 h before the injection of
leptin as described below. Two days prior to the experiment, all animals were implanted with a jugular vein

catheter filled with heparin solution under light ether
anesthesia. At about 08:00 h on the day of the experiment,
an extension tube for blood sampling was connected to the
jugular vein catheter. After leaving the animals undisturbed for about 4 h, the experiment was started at
approximately 12:00 h. Throughout the experimental
period, they were kept under a conscious, freely-moving
condition without apparent stress. Recombinant mouse
(rm) leptin (1.0 mg / kg BW) dissolved in vehicle [0.01 M
phosphate-buffered saline (PBS)], or the vehicle only, was
administered intraperitoneally (ip) as a bolus injection.
Two separate groups from both normally-fed and 3-dayfasted rats were given rm leptin or vehicle, respectively.
Blood samples (400 ml) were collected 30 min before,
immediately before, and thereafter at 30-min intervals up
to 300 min after the injection. To prevent anemia and also
the loss of circulating plasma volume, red blood cells were
resuspended in 0.9% NaCl and returned to the animals
after each blood collection. The blood was immediately
placed in EDTA-2Na (2.5 mg / ml blood)-containing tubes,
centrifuged, and the plasma was kept frozen at 2208C until
assayed for PRL and leptin.

Chronic leptin treatment: For this experiment, four
groups were prepared, i.e. normally-fed, fasted (3 days),
fasted1rm leptin (75 mg / kg BW/ day), and fasted1rm
leptin (225 mg / kg BW/ day) rats. The administration of rm
leptin was performed utilizing Alzet osmotic minipumps
(model 2001) which can deliver 24 ml / day for up to 7 days
(Alzet, Palo Alto, CA). The minipumps were filled with
0.01 M PBS (vehicle) containing rm leptin which was
adjusted for a daily delivery of 75 or 225 mg / kg BW.
Normally-fed and fasted groups were treated with the same
type of minipump which was loaded with the vehicle only.
The minipump, one for each animal, was implanted
subcutaneously in the back under light ether anesthesia 72
h before sacrifice. The dosage of 75 mg / kg BW/ day of rm
leptin was chosen based on our previous report that 100
mg / kg BW/ day of rm leptin endowed fasted adult female
rats with physiological levels of plasma leptin up to at least
72 h postadministration [37]. In consideration of the
reports by us [36] and others [9] that male rats have
significantly lower levels of plasma leptin than females, in

this study we adopted the dose of 75 mg / kg BW/ day of rm
leptin expecting it to produce a physiological level of
plasma leptin in fasted male rats. Thus, the three times
higher dosage of rm leptin (225 mg / kg BW/ day) was

427

chosen in order to achieve a supraphysiological concentration of plasma leptin. For the purpose of determining the
temporal change in plasma leptin levels in the four groups
after implanting the minipump, tail blood (300 ml) was
collected for leptin assay immediately before and 12, 24,
and 48 h after the implantation. Seventy-two hours after
the minipump implantation, animals were sacrificed by
rapid decapitation, and trunk blood was collected to
measure both leptin and PRL. All these blood samples
were collected into tubes containing EDTA-2Na (2.5 mg /
ml blood), and their subsequent treatment was done in the
same manner as described above.
Assays: PRL levels in plasma were measured by RIA
using the reagents kindly donated by Dr. A.F. Parlow

(NIDDK). Rat PRL-RP-3 was used as the standard, and
the sensitivity of the assay was 0.8 ng / ml. Plasma leptin
levels were determined by the rat leptin RIA kit produced
by Linco Research (St. Louis, MO). In this kit, rm leptin
crossreacts with the rat counterpart at 100%. It was
reported by the manufacturer that the sensitivity of the rat
leptin RIA system is 0.5 ng / ml. However, we found in our
preliminary study that the use as the standard of the
recombinant rat leptin produced by R&D Systems, Inc.
(Minneapolis, MN, USA) yields a better sensitivity of the
assay. Thus, in our leptin assay we used as the standard the
R&D Systems’ rat leptin in place of a standard preparation
supplied in the kit. Sensitivity of leptin in our modified
assay system was 0.3 ng / ml. For both PRL and leptin,
samples from individual rats were analyzed within the
same assay. Both the intra- and interassay coefficients of
variation were less than 10% in the two assays.
Statistical analyses: Results were expressed as the
mean6S.E.M. One-way or two-way ANOVA followed by
Scheffe’s post-hoc test was used to analyze the data, as

appropriate. Differences were considered significant if P
was smaller than 0.05.
Fig. 1 shows the effects of ip administration of rm leptin
(1.0 mg / kg BW) or vehicle only on plasma leptin and
PRL levels in normally-fed and 3-day-fasted rats. Vehicle
alone was without effect on plasma leptin concentrations in
both normally-fed and fasted groups during the entire
period of observation (normally-fed group, 1.360.2|
1.560.3 ng / ml; fasted group, 0.360.1|0.460.1 ng / ml).
As expected, ip administration of rm leptin produced a
marked elevation of plasma leptin in both normally-fed
and fasted groups. In both groups, plasma leptin reached
its peak 30 min postadministration (normally-fed group,
12406165 ng / ml; fasted group, 12906182 ng / ml) and
gradually declined thereafter [Fig. 1(a)]. Fig. 1(b) shows
the temporal change in PRL levels in the same plasma
samples in which leptin was measured. The ip administration of vehicle alone did not significantly affect plasma
PRL levels in both normally-fed and fasted groups during
the entire period of observation. This lack of effect on PRL
secretion was also true for the leptin treatment, which

however caused the above-mentioned robust rise in plasma

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H. Watanobe et al. / Brain Research 887 (2000) 426 – 431

Fig. 2. Temporal profile of plasma leptin in normally-fed, fasted, and
leptin-supplemented fasted male rats up to 72 h after commencement of
the respective treatments. The number of rats examined was 7–9 per
group. s—s, normally fed1PBS; n—n, fasted1PBS; d—d, fasted1
leptin (75 mg / kg BW/ day); m—m, fasted1leptin (225 mg / kg BW/ day).
w, P,0.01 vs. the remaining three groups. 1, P,0.05 vs. normally
fed1PBS and fasted1leptin (75 mg / kg BW/ day) groups. For further
details, see text.

Fig. 1. Temporal profiles of plasma leptin and PRL after ip administration of rm leptin (1.0 mg / kg BW) or vehicle only in normally-fed and
3-day-fasted male rats. The number of rats examined was 7–8 per group.
s—s, normally fed (vehicle); d—d, normally-fed (leptin); n—n,
fasted (vehicle); m—m, fasted (leptin). In this and the following figures,
where standard errors are not shown, they were smaller than the symbols.

For further details, see text.

leptin. Plasma PRL levels in both the vehicle- and leptintreated normally-fed groups were significantly (P,0.05)
higher than those in the two fasted groups between 230
and 300 min.
Fig. 2 shows the temporal profile of plasma leptin levels
in normally fed, fasted, and leptin-supplemented fasted
groups up to 72 h after commencement of the respective
treatments. In normally fed1PBS group, leptin levels
remained stable between 0 and 72 h without any significant
change. In fasted1PBS group, plasma leptin started to
decrease as early as 12 h after commencing fast, and then
gradually declined over time. Thus, fasted1PBS group had
significantly (P,0.05) lower levels of plasma leptin than

normally fed1PBS group at the timepoints of 24, 48, and
72 h. The supplementation of 75 mg / kg BW/ day of rm
leptin to fasted rats restored plasma leptin to such levels
which were slightly higher than but statistically indistinguishable from those in normally-fed1PBS group. The
administration of three times the higher dose of rm leptin

(225 mg / kg BW/ day) to fasted rats produced about three
times (P,0.01) the normal level of plasma leptin as early
as 12 h postadministration and a consistently higher level
(about 4.5 times the normal, P,0.01) from 24 h onward.
Fig. 3 shows plasma levels of leptin and PRL in
normally-fed, fasted, and leptin-supplemented fasted
groups determined 72 h after commencing the respective
treatments. Both leptin and PRL levels in the plasma were
significantly (P,0.05) lower in fasted1PBS group than in
normally fed1PBS group, but these fasting-induced
changes were completely reverted to normal by supplementing 75 mg / kg BW/ day of rm leptin. The administration of three times the higher dose of rm leptin (225 mg / kg
BW/ day) to fasted rats led to further increases in both
leptin and PRL concentrations, which exceeded the levels
of normally fed1PBS group by 4.3 and 2.3 times (P,0.05
for both), respectively.
In the first part of this study, we examined the effect of
ip bolus administration of rm leptin on PRL secretion in
conscious, freely-moving male rats. The experiment was
done under both normally-fed and 3-day fasted conditions,
because we assumed that the metabolic status of the
animal, i.e. the background levels of plasma leptin, might
modulate plasma PRL response to leptin. However, the

H. Watanobe et al. / Brain Research 887 (2000) 426 – 431

Fig. 3. Plasma levels of leptin and PRL in normally-fed, fasted, and
leptin-supplemented fasted male rats determined 72 h after commencement of the respective treatments. The number of rats examined was 7–9
per group. w, P,0.05 vs. the remaining three groups. 1, P,0.05 vs.
normally fed (NF)1PBS and fasted1leptin (75 mg / kg BW/ day) groups.
For further details, see text.

results were that the acute administration of leptin was
without effect on PRL secretion in both normally-fed and
fasted rats, despite the fact that plasma leptin levels
attained 30–60 min after injecting the rm leptin (1.0
mg / kg BW) were about 1,000 times higher than the
concentration in normally-fed male rats. These results
strongly suggest that PRL secretion may not be modified
by acute hyperleptinemia in the rat.
It was reported by Yu et al. [39] that leptin was able to
significantly stimulate PRL release in vitro from the
anterior pituitary of male rats after a 3-h incubation.
However, this effect was observed only at extremely high
concentrations of leptin such as 10 27 –10 25 M, which are
10 3 –10 5 times higher than the circulating level of leptin in
normally-fed male rats (about 10 210 M). Furthermore,

429

Tena-Sempere et al. [33] reported that 10 27 M of leptin
did not modulate PRL release from incubated anterior
pituitaries of fasted male rats within 2 h. It was recently
reported by Gonzalez et al. [10] that an icv administration
of mouse leptin-(116–130), an active fragment of the
native molecule [11], caused a significant rise in serum
PRL levels in food-deprived male rats. However, we feel
that this study of Gonzalez et al. [10] contains two
problems which may preclude us from accepting it as the
first undisputed demonstration for leptin’s PRL-releasing
activity in vivo. Firstly, the authors used a fragment of
mouse leptin instead of the mature protein. Although
leptin-(116–130) has been shown to act in a similar
manner to the native protein on both food intake and body
weight in ob / ob mice [11], it was also reported that the
expression of the normal biological activity of leptin
requires amino acid residues proximal to position 106 and
also sites between residues 106–140 [24]. Moreover, it
was recently reported that the effect of leptin-(116–130)
on body weight homeostasis is not mediated by its binding
to the long form of the leptin receptor, the receptor isoform
which is predominantly expressed in the hypothalamus
[12]. Thus, the data derived from using the leptin fragment
may not necessarily represent all the biological actions of
the mature leptin molecule. Secondly, as the authors
themselves also stated, the icv dose (15 mg) of leptin(116–130) which they administered appears to be fairly
large, even pharmacological. In our previous studies in
which the native leptin molecule was given into the rat
cerebroventricle, the dose we chose was 0.15–0.3 nmol on
a molar basis [20,35]. With this dose, we observed
normalization or a fairly good recovery of prevulatory
luteinizing hormone and PRL surges in fasted female rats
[20,35]. In the study of Gonzalez et al. [10], they administered icv 9.61 nmol of the leptin fragment, which, on a
molar basis, is 32–64 times larger than the dose (0.15|0.3
nmol) which we have previously given via the same route
[20,35]. Thus, the data obtained from using this pharmacological dose of leptin fragment must await further evaluation for their physiological meaning. At any rate, our own
data in the present study do not favor a PRL-releasing
action of acute hyperleptinemia.
In the second part of this study, we investigated whether
chronic leptin treatment affects PRL secretion. The observation that fasting for 3 days significantly lowered
plasma PRL levels, is in agreement with the preexisting
literature [2,3,7,30,38]. Moreover, as a novel finding we
found that a 3-day constant infusion of leptin to fasted rats
at such a dose (75 mg / kg BW/ day) which maintained
plasma leptin levels similar to those of normally fed rats,
reverted plasma PRL levels to normal. Furthermore, the
3-day infusion of three times the larger dose (225 mg / kg
BW/ day) of leptin led to a further elevation of plasma
PRL as well as leptin. These results demonstrate a dosedependent stimulation of PRL secretion by chronic leptin
treatment in the rat.

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H. Watanobe et al. / Brain Research 887 (2000) 426 – 431

The elevation of PRL levels by chronic leptin infusion
implies that hyperleptinemic subjects may have hyperprolactinemia. It has been reported that obesity per se is
not usually associated with increased PRL concentrations
[25]. However, in a large population study, a weak, but
significant, correlation was revealed between serum PRL
levels and body weight [34]. In addition, it was also
reported that regularly menstruating women who attained a
sizable amount of weight gain over a short period of time,
had significantly higher levels of serum PRL than the
controls [8]. Thus, it is possible that hyperleptinemia,
which accompanies obesity and weight gain, leads to
hyperprolactinemia also in humans.
An important question which reasonably emerges from
the present data is the neuroendocrine mechanism whereby
leptin stimulates PRL secretion. As already discussed
above, it is unlikely that leptin directly stimulates PRL
release from the pituitary at least at the concentrations
which we produced in the plasma by constant leptin
infusion. Thus, a probable site where leptin may primarily
act to cause a series of events which eventually culminate
in stimulated PRL release, is the hypothalamus. A decrease
in the secretion of PRL-releasing factors, e.g. dopamine
[1], or an increased release of PRL-releasing factors, such
as thyrotropin-releasing hormone and vasoactive intestinal
peptide [1], may play an intermediary role. However,
because of the following reasons, we speculate it more
likely that several peptides which originate in the hypothalamic arcuate nucleus [18] may play a primary role in
causing the leptin-stimulated PRL secretion. It is well
established that the arcuate nucleus is such a site in the
hypothalamus that shows the most abundant expression of
the leptin receptor [21,26]. The arcuate nucleus contains a
high density of neurons that produce neuropeptide Y
(NPY), a-melanocyte stimulating hormone (a-MSH), bendorphin (b-END), agouti-related protein, and several
other appetite-regulating factors [18]. Both a-MSH and
b-END are the products of the proopiomelanocortin
(POMC) gene [31]. It has been reported that the expression of the NPY and POMC genes in the arcuate nucleus is
inhibited [27,32] or stimulated [28] by leptin, respectively.
Although NPY does not seem to play a significant role in
the physiological regulation of PRL secretion [17], both
a-MSH [15,16,22] and b-END [19,29] are considered as
exerting an excitatory input on PRL release. Thus, it is
conceivable that leptin’s stimulatory action on PRL secretion is mediated by these POMC gene products. We
recently obtained data suggesting that of the two POMCderived peptides, only a-MSH, but not b-END, may play a
role in mediating the leptin stimulation of PRL secretion in
the rat. We found that repeated icv administrations of
neutralizing antibody against a-MSH, but not that against
b-END, significantly lowered plasma PRL levels which
were elevated by chronic leptin infusion (H. Watanobe and
¨
H.B. Schioth,
unpublished observations). Recent studies
reported that a-MSH acts as a mammotrope-priming agent

by rendering these cells much more responsive to physiologically relevant PRL secretagogues [16,22]. This concept
may not disagree with our present data that only the
chronic, but not acute, administration of leptin was able to
stimulate PRL secretion. We speculate so, because the
mammotrope may need to be exposed to a-MSH for a
sustained, but not a brief, period of time in order for
a-MSH to manifest its mammotrope-priming action.
In summary, in this study we demonstrated that chronic,
but not acute, administration of leptin stimulates PRL
secretion in male rats. PRL seems to be another pituitary
hormone which is regulated by the adipocyte-derived
hormone.

Acknowledgements
We wish to thank the National Hormone and Pituitary
Program of NIDDK and Dr. A.F. Parlow for the generous
donation of leptin and reagents for rat PRL RIA. We are
also grateful to Dr. H. Kodama (Exploratory Research
Laboratories, Fujisawa Pharmaceutical Co. Ltd., Tsukuba,
Ibaraki, Japan) for the measurement of leptin.

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