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Endocrinology Vol. 140, No. 11 5149-5153
Copyright © 1999 by The Endocrine Society

ARTICLES

Prolactin Stimulates Leptin Secretion by Rat White Adipose Tissue1

Oreste Gualillo, Francisca Lago, Maria García, Carmen Menéndez, Rosa Señarís, Felipe F. Casanueva and Carlos Diéguez

Department of Physiology (F.L., M.G., R.S., C.D.) and Department of Medicine-Molecular Endocrinology Section (O.G., C.M., F.F.C.), University of Santiago de Compostela, School of Medicine, 15705 Santiago de Compostela, Spain

Address all correspondence and requests for reprints to: Prof. Carlos Diéguez, Department of Physiology, University of Santiago de Compostela, School of Medicine, Rua S. Francisco sn, 15705 Santiago de Compostela, Spain. E-mail: fscadigo{at}usc.es


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Leptin, the obese (Ob) gene product, is an adipocyte-derived satiety factor that is involved in the regulation of food intake and body weight. Leptin signals nutritional status to several other physiological systems and modulates their function. As PRL is involved in energy and lipid metabolism, this study was undertaken to investigate the role of PRL on in vivo regulation of leptin serum concentration and Ob messenger RNA expression in white adipose tissue in rats. It was found that increased serum PRL levels, obtained by pituitary graft or exogenous injected ovine PRL (oPRL, 5 mg/kg), significantly stimulate serum leptin concentration. A significant increase (P < 0.01) in serum leptin concentration was present in hyperprolactinemic animals (4.7 ± 0.4 µg/liter) in comparison to controls (1.2 ± 0.1 µg/liter and 1.09 ± 0.09 µg/liter of intact sham operated and ovariectomized rats, respectively). Similar results were obtained in oPRL-treated animals where leptin levels were 5.4 ± 0.1 µg/liter vs. 1.1 ± 0.1 µg/liter and 0.8 ± 0.08 µg/liter of intact sham operated rats and ovariectomized, respectively (P < 0.001). This stimulatory effect of PRL on serum leptin levels was significantly reduced by food deprivation (P < 0.01) where serum leptin levels were 12.5 ± 0.65 µg/liter in grafted animals vs. 3.2 ± 0.36 µg/liter of grafted animals subjected to 48 h of food deprivation. Moreover, in vivo, PRL was able to induce leptin messenger RNA levels in several areas of rat white adipose tissue. The data demonstrate that PRL acts on the adipose tissue increasing leptin synthesis and secretion, suggesting a new role for this lactogenic hormone in the regulation of food intake.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LEPTIN, the 16-kDa obese gene product, is a prevalently fat cell-derived satiety factor that is involved in the regulation of food intake and energy expenditure (1, 2) and appears to be intimately associated with body weight homeostasis (3). Recent studies have demonstrated that the Ob gene expression and circulating leptin levels are modulated in vivo by a host of factors including insulin, glucocorticoids, and cytokines (4, 5, 6). PRL is a cytokine on the basis of its homology with this peptide superfamily (7). The biological events, activated by PRL through its receptors, lead to specific patterns of gene transcription and are dependent upon the cell lineage and its stage of development. PRL influences various physiological processes; among these are the regulation of mammary gland development, initiation and maintenance of lactation, immune modulation, osmoregulation, and lipid metabolism. It has been reported that PRL can act on adipose tissue because PRL receptors rise during adipocytes differentiation and may well be involved on fetal development as well as on lipid metabolism of mature adipocytes (8, 9). Although this evidence suggested an influence of PRL on adipose tissue, the mechanisms implicated remain to be elucidated. The aim of this study was to investigate whether PRL regulates leptin synthesis and secretion by white adipose tissue in rats.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Drugs
2-Bromo-{alpha}-Ergocriptine methane sulfonate (BRC) salt was purchased from Sigma (Barcelona, Spain) (B-2134). Ketamine hydrochloride (Ketolar, Parke-Davis) was a generous gift of Dr. Ramon Castro (Galicia General Hospital, Santiago, Spain).

Serum PRL determination
Serum PRL was determined as previously described (10) by means of double antibody RIA using materials and protocols by Dr. A. F. Parlow (National Hormone and Pituitary Program of NIDDK, Baltimore, MD). All samples were assayed in duplicate within one assay and results expressed in terms of the NIDDK PRL-RP-3 standard.

Serum leptin determination
Serum leptin levels were measured by RIA as described (11) using a rat leptin RIA kit (Linco Research, Inc., St. Louis, MO). The limit of sensitivity was 0.5 µg/liter. The intra and interassay coefficient of variation for concentrations of 1.6 µg/liter and 11.6 µg/liter was 2.4% and 4.6% and 4.8% and 5.7% respectively.

Induction of hyperprolactinemia by pituitary graft
Female Sprague Dawley rats (supplied by the Animal House, University of Santiago, Spain) were used for the experiments. The body weight of the different experimental groups were as follows: intact sham: 135.6 ± 1.6 g; ovariectomized (ovx): 135.38 ± 5.2 g; ovx + graft: 135 ± 3.9 g; bromocriptine treated: 134.42 ± 2.1 g. The animals were housed at constant temperature under a fixed 12-h light, 12-h dark cycle with free access to food and water. The protocols were approved by the Ethics Committee of the University of Santiago de Compostela and experiments performed in agreement with the rules of laboratory animal care and the international law on animal experimentation.

All animals were bilaterally ovariectomized or sham operated under ketamine anesthesia (4 mg/kg). Ovariectomy was conducted to obtain a result independent from ovaric function, i.e. a group of hormones that have strong actions on ob gene expression (11, 12). Levels of estradiol were markedly decreased in ovariectomized rats (33 ± 2.8 ng/ml) in comparison to intact rats (78 ± 4.7 ng/ml; P < 0.01). One group of seven rats received two pituitary glands, obtained from two rats of the same sex and age, under the kidney capsule. The completeness of graft acceptance was determined for each animal by autopsy. No change in whole body weight was observed during the experimental period as demonstrated also by other authors in other species (13).

Pharmacological treatments
One group of seven ovx rats were treated with BRC with a dose of 2 mg/kg administered ip every 12 h, the respective control group received only the drug vehicle. Another group received ovine PRL (oPRL-21, lot AFP10692, kindly supplied by Dr. A. F. Parlow, National Hormone and Pituitary Program of NIDDK, Baltimore, MD), 12 sc injections of 5 mg/kg at 8 h intervals. Animal were killed 4 days after the surgery procedure, and whole blood was utilized for serum collection and subsequently for PRL and leptin RIA as previously described. Adipose tissue from retroperitoneal, mesenteric, and sc areas was dissected and immediately frozen in dry ice and stored at -80 C until use.

Food deprivation experiments
Female Sprague Dawley rats were sham operated or ovariectomized as described above. Two groups of ovariectomized rats were implanted with 2 pituitary gland in the kidney pocket. All the animals (two sham-intact groups, two ovx groups, and two ovx + graft groups of seven rats in each group) were housed for 48 h at constant temperature under a fixed 12-h light, 12-h dark cycle with free access to food and water. After 48 h, one group of respectively sham, ovx, and ovx + graft were food deprived for other 48 h. The feeding groups received water and food ad libitum for the same time of fasting animals. At the end of the experiment all the animals were killed between 0800 h and 1300 h. Trunk blood was collected and serum was separated by centrifugation and stored at -20 C until used for hormone measurement. The body weight of the different experimental groups at the end of the experiment were as follows: intact sham fed: 168.7 ± 0.8 g; intact sham fast: 159.4 ± 2.1 g; ovx fed: 165.1 ± 2.6 g; ovx fast: 154 ± 2.8 g; ovx + graft fed: 171.1 ± 3.3 g; ovx + graft fast:157.1 ± 3.6 g.

Statistical analysis
Data are expressed as mean ± SEM and analyzed with a computerized package for statistical analysis. Statistically significant difference was determined by Anova followed by posthoc multiple comparison test. A P value <0.05 was considered as significant.

RNA preparation and RT-PCR
Total RNA was isolated from frozen adipose tissues by Trizol-LS TM method (Life Technologies, Inc., Grand Island, NY). Tissues (about 100 mg) were homogenized using a Polytron homogenizer in 750 µl of Trizol LS reagent, and recovery of total RNA after isopropanol precipitation, was measured with a spectrophotometer (Beckman Coulter, Inc., DU62) at 260 nm. 1 microgram of total RNA was used to perform RT-PCR. Complementary DNAs (cDNAs) were synthesized using 200 U of Moloney murine leukemia reverse transcriptase (Life Technologies, Inc.) and 6 µl of dNTPs mix (10 mM of each dNTP, Promega Corp., Madison, WI), 6 µl of first strand buffer (250 mM Tris-HCl pH 8.3, 375 mM KCl, 15 mM MgCl2 Life Technologies, Inc.), 1.5 µl of 50 mM MgCl2, 0.17 µl of Random examers solution (3 µg/µl, Life Technologies, Inc.), 0.25 µl of RNase OutTM (Recombinant ribonuclease inhibitor 40 µ/µl Life Technologies, Inc.), in a total volume of 30 µl. Reaction mixtures were incubated at 37 C for 50 min and at 42 C for 15 min. The RT reaction was terminated by heating at 95 C for 5 min and subsequently quick chilled on ice. Three microliters of RT reaction were used for PCR amplification. The amplification conditions were as follows: 5 µl of PCR buffer (200 mM Tris-HCl, pH 8.4, and 500 mM KCl, Life Technologies, Inc.), 1.5 µl of 50 mM MgCl2, 4 µl of dNTPs mix, 300ng of Ob gene upstream primer 5'-TCACCCCATTCTGAGTTTTGTC-3' (+158, +178 GenBank U 48849), 300 ng of Ob gene downstream primer 5'-CGCCATCCAGGCTCTCT-3' (+360, +344, GenBank U48849, and 1.25 U of Taq DNA Polymerase (Gibco-Life Technologies, Inc.). The amplification profile was: denaturation at 94 C for 1 min, annealing at 60 C for 1 min, and extension at 72 C for 1 min. Thirty-five-cycle amplification was completed with an additional step at 72 C for 10 min. The amplification was performed in an automatic thermal cycler (Mastercycler gradient, Eppendorf). To ensure that PCR was effected in the linear amplification range, samples were taken after 15, 20, 25, 30, 35, and 40 cycles. The reaction was linear over this range for both ob (r = 0.96) and ß-actin (r = 0.96) as shown in Fig. 1Go, which is in agreement with data reported by other authors (14).



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  		Figure 1. Kinetic of amplification of the leptin target cDNA (A) and ß-actin target cDNA (B). Linear regression shows a correlation coefficient of 0.96 for both leptin and ß-actin cDNAs. There is not a significant departure from linearity.

 
To determine the relative amounts of Ob messenger RNA (mRNA) in each sample, Ob RNA was compared with the ß-actin gene. For the ß-actin gene, two specific primers span introns were used, which do not coamplify processed pseudogenes (15): forward primer (5'-TACAACTCCTTGCAGCTCC-3') and reverse primer (5'-ATCTTCATGAGGTAGTCAGTC-3'). PCR reaction generate a single 203-bp product for the ob gene and a single 626-bp product for the ß-actin gene. PCR products were separated on 2% agarose gel, stained with ethidium bromide and examined with UV light and quantitated with a Gel Doc 1000 Documentation System (Bio-Rad Laboratories, Inc. Hercules, CA).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of changes in PRL serum concentration on serum leptin levels and ob gene expression in rat white adipose tissue
As shown in Fig. 2AGo, pituitary graft induced a large increase (P < 0.001) in PRL serum levels. 51.01 ± 3.09 µg/liter vs. 11.26 ± 2.6 µg/liter and 4.95 ± 0.5 µg/liter of sham operated rats and ovariectomized rats, respectively. A significant increase in leptin serum concentration (Fig. 2BGo) was present in hyperprolactinemic animals with pituitary graft, in comparison to controls (P < 0.01).



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  		Figure 2. Effect of pituitary graft and brc treatment (4 days) on serum PRL (A) and leptin levels (B) of bilaterally ovx rats. *, P < 0.05; **, P < 0.01; ***, P < 0.001.

 
Leptin levels in grafted animals were 4.7 ± 0.4 µg/liter vs. 1.2 ± 0.1 µg/liter and 1.09 ± 0.09 µg/liter of intact sham operated and ovariectomized rats, respectively.

Ovariectomy did not produce significant differences in serum leptin levels in comparison to intact sham-operated rats. When a D2 dopamine receptor agonist such as bromocriptine was used in ovariectomized rats, an evident reduction of PRL serum levels was found after 4 days of treatment with no significant decrease of leptin serum levels in comparison to intact sham operated rats and ovariectomized rats, 0.9 ± 0.1 µg/liter and 1.0 ± 0.1 µg/liter, respectively.

As shown in Fig. 3Go, leptin mRNA expression was significantly increased in retroperitoneal, mesenteric, and sc white adipose tissue of hyperprolactinemic pituitary grafted animals after 4 days of the implant, in comparison to controls (P < 0.01 in sc and mesenteric fat tissues; P < 0.05 in retroperitoneal fat tissues).



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  		Figure 3. Effect of pituitary graft (black bars) and brc (gray bars) treatment on in vivo leptin mRNA expression of WAT areas, in comparison to control ovariectomized rats. *, P < 0.05; **, P < 0.01.

 
In contrast, no significant modifications were observed in Ob mRNA expression in the aforementioned areas of white adipose tissue of bromocriptine-treated rats.

Similar results were obtained in oPRL-treated animals, in which leptin levels were 5.4 ± 0.1 µg/liter vs. 1.1 ± 0.1 µg/liter, and 0.8 ± 0.08 µg/liter of intact sham operated rats and ovariectomized rats respectively (Fig. 4Go).



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  		Figure 4. Effect of oPRL administration (5 mg/kg sc every 8 h) on serum leptin levels of bilaterally ovx rats. ***, P < 0.001.

 
As shown in Fig. 5Go, a significant decrease of leptin levels (3.2 ± 0.36 µg/liter) was observed in food-deprived animals with pituitary graft in comparison to fed ad libitum animals (12.5 ± 1.6 µg/liter, P < 0.01). This effect was also observed in control animals (1.56 ± 0.15 µg/liter vs. 0.59 ± 0.02 µg/liter, P < 0.001 of intact sham operated feeding and intact sham food-deprived rats, respectively) as well as in ovariectomized rats (1.35 ± 0.09 µg/liter vs. 0.67 ± 0.03 µg/liter, P < 0.01 of ovx feeding animals and ovx food-deprived rats).



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  		Figure 5. Food deprivation (48 h) reverts serum leptin increase driven by pituitary graft in feeding animals. ***, P < 0.001; **, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Leptin is secreted prevalently by adipocytes, and it has been proposed to be a lipostatic factor that regulates the amount of body fat stores by mean of a closed feedback loop involving the hypothalamus (16). Several hormones regulate leptin mRNA and serum leptin levels such as insulin, glucocorticoids, and cytokines. PRL is a peptide hormone produced mainly in the anterior pituitary, but it is also synthesized in extrapituitary sites (17), and it seems to act as a cytokine, serving as a powerful immunomodulator (18, 19). Furthermore, PRL also exerts its biological action on adipose tissue, where it may play a role in preadipocyte differentiation, as well as in adipocytes metabolism (8, 9). Although only a small number of studies have been conducted on the interaction between PRL and body weight, it has been reported that sustained hyperprolactinemia in humans may be associated with a relative high rate of obesity, followed by weight loss after normalization of serum PRL levels (20, 21). On the other hand, in obesity, a pathological state associated with high leptin levels, alterations in the neuroregulation of PRL secretion have been described. Finally, an inverse relationship between leptin and PRL was reported in lactating women (22). This could be due to PRL may inhibit leptin secretion by a direct action on fat cell secretion or fat mass, leptin may inhibit in vivo human PRL secretion, or they may be independently regulated covariables. In support of the latter possibility is the finding that leptin levels were similar in lactating and nonlactating women. Data so far available do not support an inhibitory effect of leptin on PRL secretion because indirect evidence suggests that leptin may well have a stimulatory role on PRL secretion because in ob/ob mice leptin administration partially restores lactation (23). Also it has been reported that leptin increases in vitro PRL secretion (24), but no actions of PRL on leptin have been reported. To our knowledge, this is the first report providing direct evidence for a role of PRL in regulating leptin secretion in rats. This PRL-induced leptin release appears to be mediated by an increase in Ob mRNA content of the fat cells. Therefore, the higher incidence of obesity in hyperprolactinemic patients is unlikely to be mediated by a leptin deficient state. It rather supports the existence of a leptin-resistant state as that previously found in nonhyperprolactinemic obese subjects. Taking into account that food deprivation markedly impaired both PRL secretion and leptin levels (25, 26, 27), we assessed whether exogenous PRL administration was able to restore to normal leptin levels in food-deprived animals. Our data showing that leptin levels were markedly reduced in hyperprolactinemic food-deprived rats argues against a major role of PRL as the mechanism responsible for impaired leptin secretion in this experimental setting. In agreement with this date we found that in bromocriptine-treated rats leptin levels were unchanged, suggesting that reduction of PRL levels below the physiological range are not associated to changes in leptin secretion.

In any event, these data and those previously reported by others (24) indicate the existence of a reciprocal regulation of leptin and PRL. This PRL effect reported herein could open a new loop for the regulation of leptin levels in mammals.

Recent studies indicate that PRL, originally considered a reproductive hormone, also plays a role as a potent immunoregulatory hormone with proinflammatory properties (16, 17, 18). Several reports have demonstrated that in some autoimmune inflammatory diseases, such as rheumatoid arthritis and systemic lupus erithematosus, PRL levels are often elevated (28), and these pathologies are associated with modification of body mass (29, 30). Furthermore, several proinflammatory cytokines, most notably tumor necrosis {alpha} (TNF-{alpha}) and interleukin 1 (IL-1), both induced by PRL (31), produced a prompt and dose-dependent increase in serum leptin levels and leptin mRNA expression in mice adipose tissue (32), and it is possible that these factors could be involved in PRL-induced increase in leptin gene expression. The mechanism by which PRL exerts its stimulatory effect on leptin is still unclear. On a theoretical basis, it could be possible through a direct effect on PRL receptors on the adipocytes. Nevertheless, the fact that the density of PRL receptors in these cells is relatively low (8) and our own data (unpublished observations showing a lack of effect of PRL on in vitro leptin secretion) argue against this possibility. Therefore, it is likely that PRL exerts its effects through an indirect mechanism. This indirect mechanism could be probably connected to the PRL-driven induction of serum factor as well as proinflammatory cytokines as TNF-{alpha} or IL-1, notwithstanding the biochemical events that interplay between these cytokines and leptin levels regulation are not all clarified.


   Acknowledgments
 
We would like to thank Dr. A. F. Parlow (NIDDK) for kind gift of rPRL kit and oPRL. We expecially acknowledge Prof. Raffaele Di Carlo (University of Naples "Federico II") for his helpful advice and valuable discussions during the course of these investigations.


   Footnotes
 
1 This work was supported by grants from the Fondo de Investigación Sanitaria, Spanish Ministry of Health, the Xunta de Galicia and the "Pedro Barriè de la Maza" Foundation. Oreste Gualillo is a recipient of a TMR-30 Research Training Grant, Program IV Framework of RTD: Contract ERBFMBI-CT 98–3368 from the European Commission, DG XII SRD. Back

Received May 14, 1999.


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 Introduction
 Materials and Methods
 Results
 Discussion
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Identification of Functional Prolactin (PRL) Receptor Gene Expression: PRL Inhibits Lipoprotein Lipase Activity in Human White Adipose Tissue
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M. R. Garcia, M. Amstalden, S. W. Williams, R. L. Stanko, C. D. Morrison, D. H. Keisler, S. E. Nizielski, and G. L. Williams
Serum leptin and its adipose gene expression during pubertal development, the estrous cycle, and different seasons in cattle
J Anim Sci, August 1, 2002; 80(8): 2158 - 2167.
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C. A. Mastronardi, W. H. Yu, V. K. Srivastava, W. L. Dees, and S. M. McCann
Lipopolysaccharide-induced leptin release is neurally controlled
PNAS, November 20, 2001; (2001) 251543598.
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C. Ling and H. Billig
PRL Receptor-Mediated Effects in Female Mouse Adipocytes: PRL Induces Suppressors of Cytokine Signaling Expression and Suppresses Insulin-Induced Leptin Production in Adipocytes in Vitro
Endocrinology, November 1, 2001; 142(11): 4880 - 4890.
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M. Freemark, D. Fleenor, P. Driscoll, N. Binart, and P. A. Kelly
Body Weight and Fat Deposition in Prolactin Receptor-Deficient Mice
Endocrinology, February 1, 2001; 142(2): 532 - 537.
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O. Gualillo, J. E. Caminos, M. Blanco, T. Garcia-Caballero, M. Kojima, K. Kangawa, C. Dieguez, and F. F. Casanueva
Ghrelin, A Novel Placental-Derived Hormone
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M. E. Freeman, B. Kanyicska, A. Lerant, and G. Nagy
Prolactin: Structure, Function, and Regulation of Secretion
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M. d. C. García, F. F. Casanueva, C. Diéguez, and R. M. Señarís
Gestational Profile of Leptin Messenger Ribonucleic Acid (mRNA) Content in the Placenta and Adipose Tissue in the Rat, and Regulation of the mRNA Levels of the Leptin Receptor Subtypes in the Hypothalamus During Pregnancy and Lactation
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 Proc. Natl. Acad. Sci. USAHome page
C. A. Mastronardi, W. H. Yu, V. K. Srivastava, W. L. Dees, and S. M. McCann
Lipopolysaccharide-induced leptin release is neurally controlled
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[Abstract] [Full Text] [PDF]

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