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Proceedings of the Society for Experimental Biology and Medicine 224:152-158 (2000)
© 2000 Society for Experimental Biology and Medicine

Original Article

The Possible Role of Prolactin in the Circadian Rhythm of Leptin Secretion in Male Rats

C. A. Mastronardi*, A. Walczewska*,2, W. H. Yu*, S. Karanth*, A. F. Parlow{dagger} and S. M. McCann*,1


* Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808–4124; and
{dagger} Harbor-UCLA Medical Center, Torrance, California 90502–2004


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In humans there is a circadian rhythm of leptin concentrations in plasma with a minimum in the early morning and a maximum in the middle of the night. By taking blood samples from adult male rats every 3 hr for 24 hr, we determined that a circadian rhythm of plasma leptin concentrations also occurs in the rat with a peak at 0130h and a minimum at 0730h. To determine if this rhythm is controlled by nocturnally released hormones, we evaluated the effect of hormones known to be released at night in humans, some of which are also known to be released at night in rats. In humans, prolactin (PRL), growth hormone (GH), and melatonin are known to be released at night, and adrenocorticotropic hormone (ACTH) release is inhibited. In these experiments, conscious rats were injected intravenously with 0.5 ml diluent or the substance to be evaluated just after removal of the first blood sample (0.3 ml), and additional blood samples (0.3 ml) were drawn every 10 min thereafter for 2 hr. The injection of highly purified sheep PRL (500 µg) produced a rapid increase in plasma leptin that persisted for the duration of the experiment. Lower doses were ineffective. To determine the effect of blockade of PRL secretion on leptin secretion, {alpha} bromoergocryptine (1.5 mg), a dopamine-2-receptor agonist that rapidly inhibits PRL release, was injected. It produced a rapid decline in plasma leptin within 10 min, and the decline persisted for 120 min. The minimal effective dose of GH to lower plasma leptin was 1 mg/rat. Insulin-like growth factor (IGF-1) (10 µg), but not IGF-2 (10 µg), also significantly decreased plasma leptin. Melatonin, known to be nocturnally released in humans and rats, was injected at a dose of 1 mg/rat during daytime (1100h) or nighttime (2300h). It did not alter leptin release significantly. Dexamethasone (DEX), a potent glucocorticoid, was ineffective at a 0.1-mg dose but produced a delayed, significant increase in leptin, manifest 100–120 min after injection of a 1 mg dose. Since glucocorticoids decrease at night in humans at the time of the maximum plasma concentrations of leptin, we hypothesize that this increase in leptin from a relatively high dose of DEX would mimic the response to the release of corticosterone following stress in the rat and that glucocorticoids are not responsible for the circadian rhythm of leptin concentration. Therefore, we conclude that an increase in PRL secretion during the night may be responsible, at least in part, for the nocturnal elevation of leptin concentrations observed in rats and humans.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Leptin is secreted from fat cells in all mammalian species studied so far. It appears to be an important hormone in the control of body weight by inhibiting food intake and altering metabolism (1-3). An increasing body of evidence indicates that leptin is a potent stimulator of the secretion of gonadotropins and may play a role in the induction of puberty (4-6).

Leptin is secreted from the adipocytes in a circadian rhythm in humans with a nadir at 0800–0900h followed by a gradual rise to reach a peak between 0 and 0200h (7, 8). At this time plasma leptin concentrations remain on a plateau for 1–2 hr and then decline to the morning nadir. It is obvious that synchronization of the release of leptin from the billion or more adipocytes in the body requires a central control mechanism. This mechanism could be neural via innervation of the fat cells or hormonally induced by a circadian rhythm of hormone release. In humans, a number of hormones that are particularly secreted at night may be responsible for this nocturnal elevation of plasma leptin concentrations. Among these possibilities would be the pineal hormone, melatonin, and the anterior pituitary hormones, prolactin (PRL) and/or growth hormone (GH), that are also secreted nocturnally and probably play a physiological role in repairing the damage from the stress of the previous day (9, 10).

The circadian rhythm of leptin release has not been established in the rat. Consequently, we initiated studies in adult male rats to determine if such a rhythm existed and to evaluate the possible role of pituitary hormones in the control of leptin secretion. Highly purified sheep PRL increased plasma leptin concentrations within 10 min of its intravenous injection. On the other hand, blockade of PRL release by injection of {alpha} bromoergocryptine (bromocryptine) (9) had the reverse effect. Thus, PRL is a candidate pituitary hormone to mediate the nocturnal elevation of leptin that occurs in humans and rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals.
Adult male rats (350–400 g) of the Holtzman strain (Harlan, Sprague Dawley, Inc., Madison, WI) were employed. Upon arrival, the animals were allowed to acclimatize for 2 weeks and were housed two per cage in a room with controlled temperature (23°–25°C) and lighting (lights on from 0700 to 1900 hr). A standard pellet diet and tap water were available ad libitum.

Determination of the Circadian Rhythm of Leptin.
In this experiment, animals were removed from the vivarium and decapitated immediately in another room, where trunk blood was then collected. A group of eight rats were removed from the animal room every 3 hr. It took 3 min for transport to the experimental room. The rats were then immediately decapitated in sequence, so that the last one was decapitated by 12 min from the time of removal from the vivarium. Therefore, the time from removal of rats from the animal room to decapitation varied from 3 to 12 min.

Drugs.
All the drugs were freshly prepared on the same day of the experiment. Highly purified GH and highly purified PRL were provided by Dr. A.F. Parlow (National Hormone and Pituitary Program, Harbor-UCLA Medical Center, Los Angeles, CA). GH was dissolved in 0.01 M NaHCO3 and thereafter taken up to the final concentration in saline. PRL was dissolved at a concentration of 2.5 mg/ml in 0.03 M NaHCO3 in 0.15 M NaCl (pH 10.8), with gentle agitation. After solubilization was effected, the pH was lowered to 8.5 by drop-wise addition of 2N HCl. Melatonin was purchased from Sigma (St. Louis, MO) and dissolved in ethanol (ETOH) at a concentration of 100 mg/ml, and thereafter it was diluted in saline to the final concentration. The final concentration of ethanol was 1.9%. Dexamethasone was bought from Sigma and dissolved in saline. (+)-Bromocriptine methasulfonate was purchased from Research Biochemicals International (RBI) (Natick, MA). It was dissolved in ETOH at a concentration of 16 mg/ml, and thereafter it was diluted in saline to the final concentration. The final concentration of ethanol was 18.75%. Insulin-like growth factor (IGF-1) and IGF-2 were purchased from Peninsula Laboratories, Inc. (Belmont, CA) and dissolved in saline.

Repeated Blood Sampling.
One day before blood sampling, the rats were anesthetized by intraperitoneal injection of 0.35 ml of ketamine/acepromazine/xylazine(90 + 2 + 6 mg/kg, respectively). Then, a Silastic catheter was introduced into the right external jugular vein and advanced to the right atrium according to the technique of Harms and Ojeda (11).

After the operation, the rats were housed singly in cages overnight in the experimental room. One hour before the experiment, between 0800 and 0900h, polyethylene tubing filled with 0.9% NaCl (saline) containing 500 IU/ml of heparin was connected to the jugular catheter, and 0.5 ml of heparin 500 IU/ml were injected. Immediately after collection of the initial 0.3-ml blood sample (Time 0), the test hormone dissolved in 0.5 ml saline or the saline diluent was injected intravenously over a period of 30 sec, and blood samples (0.3 ml) were collected subsequently every 10 min for 2 hr. Each time, the volume of blood withdrawn was replaced by an equal volume of saline containing heparin (50 IU/ml). Blood was centrifuged (1300g) for 15 min, and plasma was stored at –20°C until radioimmunoassay for leptin. Rat leptin kits were purchased from Linco Research, Inc. (St. Charles, MO). These assays have been shown to be specific for rat leptin and give comparable values for plasma leptin concentrations. The interassay and intra-assay variation was 2.5% and 2.7%, respectively.

Statistical Analysis.
Statistical differences between two means were calculated by Student's t test. The regression of leptin concentrations versus time and area under the curve was calculated using the Prism program. In some experiments, changes in leptin from the initial value obtained at Time 0 were calculated, and the significance of changes from the initial value ({Delta} leptin) was determined by the paired t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The Circadian Rhythm of Plasma Leptin in the Rat.
In this experiment, blood samples were obtained from groups of animals every 3 hr for 24 hr, and plasma leptin was determined. Values were relatively low in the morning of the first day and at a minimum at 1330h. They rose from this time to a peak at night at 0130h (Fig. 1)Go. The regression calculated between these times was significant statistically (P = 0.016). After reaching the maximal levels at 0130h, values declined to reach a minimum at 0730h, and this regression was also significant (P = 0.010). The value at 0730h was significantly less than the concentration of plasma leptin at 0130h (P < 0.01).



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  		Figure 1.   The circadian variation of plasma leptin concentrations in male rats. In this and subsequent figures, values are mean ± SEM. (n = 8 rats for each time point). The peak values at 0130h were highly significantly greater than the minimum at 0730h on the following morning with a significant negative regression during this time interval (P < 0.01). During the first day, values rose with a significant positive regression (P < 0.02) to reach the peak at 0130h.

 
The Effects of Various Hormones on Plasma Leptin Values.
In the first experiment, control animals were injected intravenously with 0.5 ml saline, and blood samples (0.3 ml) were removed every 10 min for 2 hr. There was a gradual increase in plasma leptin concentrations that reached significance (P < 0.05) by 120 min (Fig. 2)Go. The lower doses of sheep PRL (100 and 250 µg) had no significant effect on the plasma levels of leptin compared with those of the saline-injected rats (data not shown); however, the highest concentration (500 µg) produced a significant increase in leptin concentrations within 10 min delta ({Delta}) PRL. Values remained elevated for the remainder of the 2-hr sampling period (Fig. 2)Go. Similar results were obtained in a second experiment with this dose of PRL (data not shown).



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  		Figure 2.   The effect of 500 µg of highly purified sheep prolactin on plasma leptin concentrations. The change ({Delta}) of plasma leptin concentrations when compared with the initial values at various times following injection of this dose of prolactin or the saline diluent is illustrated. *P < 0.05, **P < 0.01, ***P < 0.001 versus controls at a particular time. The values compared with 0 time were compared in the controls across time, and mean plasma leptin concentration at 120 min was significantly higher than that at the initial sampling (P < 0.05). Initial plasma leptin concentration in controls (2.1 ± 0.3) was similar to that of rats that were injected with prolactin (1.8 ± 0.2).

 
Since PRL increased plasma leptin concentrations, it was of interest to determine the effect of inhibition of PRL release with the dopamine D-2 receptor agonist, bromocryptine (7). Bromocryptine (1.5 mg/rat) produced a significant decrease (P < 0.01) in plasma leptin concentrations within 10 min, and values continued to decline to reach a minimum at 110 min (Fig. 3)Go, whereas there was no change in the control saline-injected rats. Leptin concentration and the area under the curve of leptin were significantly less than in the control rats during the period from 0 to 90 min (P < 0.05).



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  		Figure 3.   The effect of bromocryptine (1.5 mg/rat) on plasma leptin concentrations. There was no significant change throughout the experiment in control animals; however, values in bromocryptine-injected animals decreased significantly at 10 min (P < 0.01) and then slowly declined progressively to reach a minimum at 90 min. There was a significant lowering of the area under the curve of plasma leptin during the period from 0 to 90 min (P < 0.05) below the area under the curve of the control animals.

 
Since GH is also secreted at night in humans and therefore is a candidate to cause the nocturnal rise in leptin, we evaluated doses of highly purified ovine GH equivalent to those used for PRL. Neither 0.1 mg nor 0.5 mg GH (data not shown) altered plasma leptin significantly, but GH (1.0 mg) decreased leptin linearly from 0 to 40 min (P < 0.05) (Fig. 4)Go. Since GH induces the release of IGF-1, we evaluated the effect of both IGF-1 and -2. IGF-1 (10 µg) (P < 0.05) but not IGF-2 at the same dose lowered plasma leptin levels significantly at 100 min after injection, and the area under the curve of plasma leptin in IGF-1–injected rats was significantly less than that of controls from 60 to 120 min (P < 0.05) (Fig. 5)Go.



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  		Figure 4.   The effect of GH (1 mg/rat) on plasma leptin concentrations. There was no significant decrease in plasma leptin values in GH-injected animals compared with those of the controls at individual time points; however, the negative regression between 0 and 40 min in GH-injected rats was significantly greater than that of controls (P < 0.05).

 


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  		Figure 5.   The effect of IGF-1 (10 µg/rat) on plasma leptin concentrations. A significant decline occurred in plasma leptin that reached a maximum at 60 min in the control animals (P < 0.05) and a significant negative regression of plasma leptin values in control and IGF-1–injected rats during this period (P < 0.01). The decline was similar in the IGF-injected animals; however, values remained low over the 60–120-min period, and during this time the area under the curve of plasma leptin in the IGF-1–injected animals was significantly less than that of the controls (P < 0.05).

 
Another hormone, which is released at night in both rat and human, is melatonin. Consequently, we tested the effect of melatonin (1 mg/rat) on plasma leptin concentrations during the day (11:00 AM) and at night (11:00 PM). Instead of increasing plasma leptin as would be expected if it were to have a role in the nocturnal elevation of leptin, the hormone produced a variable lowering of leptin levels at night (Fig. 6)Go which was not significant and had no effect on leptin release in late morning (data not shown).



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  		Figure 6.   The effect of melatonin (1 mg/rat) on plasma leptin at night (2300h). Although the mean values of leptin were lower in the melatonin-injected animals throughout the time period of the experiment, there was no significant effect when measured in terms of mean values and the difference between the values in controls and melatonin-injected animals or even the area under the curve of plasma leptin in melatonin-injected rats.

 
To determine the possible role of ACTH-induced release of glucocorticoids in the control of leptin release, the synthetic glucocorticoid, dexamethasone, was injected at a dose of 0.1 mg. This dose was ineffective to alter plasma leptin values from those of the control saline–injected animals (data not shown). However, when the dose of dexamethasone was increased by a factor of 10–1.0 mg, a delayed, highly significant increase (P < 0.01) in plasma leptin concentrations occurred at 100, 110, and 120 min (P < 0.01) (Fig. 7)Go. Also, the area under the curve between 90 and 120 min was significantly greater than that of controls (P < 0.05).



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  		Figure 7.   The effect of dexamethasone (1 mg/rat) on plasma leptin concentrations. Plasma leptin concentrations rose from a minimum at 70 min to reach a peak at 120 min. There was no effect of the control injections on leptin concentrations throughout the experiment. Values from 100 to 120 min were significantly higher than those in the controls. Single cross = P < 0.05; double cross = P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Removing single samples of blood from rats every 3 hr throughout 24 hr, revealed a circadian rhythm of leptin release in the rat analogous to that found in humans. This increase at the peak value was significant as revealed by a positive regression from the time of low values (1330h) to the peak at 0130h, and a significant negative regression to the minimum in the morning at 0730h. The scale of the rhythm was less than that seen in humans (7, 8). This may be a species difference or possibly a stress-related factor associated with removal of the animals from their cage just prior to sacrifice. This might rapidly elevate plasma leptin above basal values, thereby masking the circadian rhythm. Since stress releases PRL, and we have observed a rapid elevation in leptin by injection of PRL, stress-induced PRL release may rapidly elevate plasma leptin dampening the rhythm. Indeed, when we attempted to measure the circadian rhythm of PRL by removing several animals in sequence from the animal room and sacrificing them, we found that the initial animal removed from its cage had undetectable PRL and animals removed later had elevated prolactin so we could not determine the circadian rhythm of PRL, probably because of the interference by stress. Stress also causes a rapid release of ACTH that acts on the adrenal cortex to elevate plasma corticosterone, the predominant glucocorticoid in the rat. Since the synthetic glucocorticoid, dexamethasone, only produced a delayed elevation in plasma leptin concentrations, we believe that ACTH release occasioned by transferring the rats would not affect the leptin values obtained.

The occurrence of a circadian rhythm of leptin release suggests central neural or hormonal control of leptin secretion. In search of a hormonal control by nocturnally released hormones, we tested the effect of a number of hormones known to be released at night. One of these is prolactin, which is known to be released at night in man (9). However, a nocturnal elevation of PRL release in rats has not been established as indicated above. Prolactin at a minimal effective dose of 500 µg/rat produced a highly significant and rapid increase in plasma leptin concentrations that was maintained for the 2 hr duration of sampling. Since the values did not diverge further from those in the saline-injected controls with time, it would appear that the increase in the rate of leptin release from the fat cells induced by prolactin remained more or less constant during the 2-hr sampling period after the initial stimulation of release; otherwise, if leptin secretion were decreased or increased, there should have been a lesser or further divergence, respectively, from the values in the controls.

PRL presumably acts on its receptors on the adipocytes to stimulate a rapid release of leptin from these cells. The rapidity of the release within 10 min of injection of PRL suggests that leptin is released from secretory granules after their exocytosis. PRL receptors have been localized to cells of the immune system, but to our knowledge, have not been reported on fat cells (12).

If PRL is responsible for the elevation of leptin that occurs at night, then blockade of PRL secretion should have the reverse effect and lower plasma leptin concentrations. Indeed, blockade of PRL secretion with the D2-dopamine receptor agonist, bromocryptine (9), produced a rapid and long-lasting lowering of plasma leptin concentrations. The results are consistent with the hypothesis that PRL secreted at night in humans may mediate the nocturnal increase in leptin concentrations that occurs in both normal men (7) and women (8) and, as demonstrated here, in male rats. In humans, plasma PRL concentrations peak around 0130h at the time of the peak in plasma leptin, but then reach a second peak higher than the first at 0530h (10). During the time from 0130 to 0530h, plasma leptin levels are declining toward their nadir at 0800h. The fact the leptin is declining during the time that PRL is rising to its second nocturnal peak indicates that other factors are responsible for the decline in plasma leptin during this time. Since plasma ACTH and cortisol are increasing from 0530 to 0830h, and plasma cortisol is inversely related to leptin levels at night in humans (7, 8), cortisol could be a factor in the decline of leptin at this time in humans; however, dexamethasone, a potent glucocorticoid only increased leptin at a high dose in the rat.

The gradual increase in plasma leptin concentrations in the control, saline-injected animals over the 2-hr sampling period in the first experiments may be the result of the stress of repeated blood sampling that caused PRL release since PRL is released by stress in the rat (13). Since PRL stimulated leptin release, the stress-induced secretion of PRL may account for this gradual increase in leptin concentrations. In subsequent experiments, no significant effect of the procedure and injection of saline was observed, perhaps because with greater experience the procedures did not cause so much disturbance to the animals.

Although a fairly high dose (0.1 mg) of dexamethasone, which would probably mimic the concentrations of glucocorticoids that are present in mild stress conditions in the rat, was not effective to elevate leptin concentrations, a 10-times higher concentration (1 mg) that is almost certainly a pharmacological concentration of the glucocorticoid, did have a significant effect to stimulate release of leptin 100–120 min after injection. This is consistent with earlier results indicating that high doses of dexamethasone can increase leptin release in humans in vivo (14, 15) and in rats and humans in vitro (16, 17).

Since plasma ACTH and cortisol levels decline at night in a mirror image of the elevation of plasma leptin at night in humans, it is unlikely that ACTH mediates the nocturnal increase in leptin release that occurs in humans (7, 8) and rats. Therefore, we conclude that although glucocorticoids at high concentrations that might occur in stress situations can increase leptin, glucocorticoids are not responsible for the nocturnal elevation in plasma leptin.

GH secretion is increased at night in humans (9, 10). A nocturnal elevation of GH in rats was not demonstrated in rats that were repeatedly bled throughout 24 hr. Instead, large pulses were observed every 3 hr throughout the 24 hr (18). Since nocturnal GH levels were increased in rats bled under similar conditions to those employed in the present experiment (19), GH is another candidate to cause the increase in plasma leptin that occurs at night. Therefore, we evaluated the effect of highly purified sheep GH on plasma leptin levels. There was no effect of GH to increase leptin at a dose equimolar to that effective for PRL. Indeed, there was a small, significant decrease in plasma leptin following injection of the highest dose of GH. Many of the actions of GH are mediated by IGF-1. Therefore, it was possible that the GH might have a delayed action mediated by IGF-1. On testing both IGF-1 and IGF-2, we found that only IGF-1 induced a small, delayed but significant decline in leptin, indicating that neither GH or IGFs are likely to be responsible for the nocturnal elevation in leptin that occurs in humans and rats. Nocturnal secretion of melatonin might also be involved in the nocturnal leptin release from the adipocytes since there is a dramatic nocturnal secretion of melatonin in both man (9, 10) and rats (20). Therefore, we thought that melatonin was a logical candidate to mediate nocturnal leptin release. However, instead of increasing leptin, a high dose of melatonin injected at night (1 mg) lowered leptin, but the change was not significant. During the day it had no effect.

What is the function of this elevated secretion of leptin at night? We can only speculate, but other studies have clearly shown that leptin plays an important role in modulating reproduction by actions on the hypothalamic-pituitary unit (4-6, 21). Indeed, in the ovariectomized, estrogen-primed rat, it can stimulate a release of LH mainly brought about by LHRH release (21, 22); however, a possible action at the pituitary level was not completely ruled out in these studies since the hormone is also as active as LHRH itself to release FSH and LH from the pituitary gland (21). The pulsatile character of LH release changes late at night in women in the proliferative phase of the menstrual cycle (8). As the plasma leptin concentrations reached their nocturnal maximum, the pulsatile release of LH changed from frequent small pulses to infrequent large pulses. These large pulses of LH may stimulate additional estrogen secretion from the ovarian follicles that eventually induces the preovulatory surge of LH (8).

A paper recently appeared in which the circadian rhythm of leptin release was independently determined in rats (23). The results were similar to those reported here, but the magnitude of the variation was less. The authors found that when the animals were only offered food, from 1100 to 1500h, the circadian rhythm of leptin release was abolished, except for an earlier increase 4 hr after removal of food. They believe that nocturnal feeding by the rats is the cause of the nocturnal elevation of leptin since it could be moved forward by restrictive feeding, such that it occurred 4 hr after cessation of feeding. Even if nocturnal feeding behavior in rats is responsible for nocturnal elevation of leptin, it must be caused by central neural or hormonal signals to the adipocytes. We hypothesize that it is caused by hypothalamic stimulation of prolactin release.

In patients with anorexia nervosa, the dramatic decline in fat stores in the adipocytes leads to a deficient secretion of leptin (24). This deficiency may cause the reversion of gonadotropin secretion to the prepubertal pattern with resultant loss of menstrual cycles in these patients. Refeeding with consequent replenishment of fat stores leads to return of the normal pulsatile and diurnal secretion of leptin that may cause the return of the normal pattern of pulsatile gonadotrophin secretion, ovulation, and resumption of normal menstrual cycles (25).


   Footnotes
 
This work was supported by NIH Grant MH51853.

1 To whom requests for reprints should be addressed at Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808–4124. E-mail: mccannsm{at}mhs.pbrc.edu Back

2 Present affiliation: Institute of Physiology and Biochemistry, Department of Physiology, Medical University of Lodz, 90–131 Lindleya 3, Poland. Back


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication August 18, 1999. Accepted for publication February 10, 2000.




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