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Original Studies |
Departments of Laboratory Medicine and Pathology (L.J., M.E.C., B.W.S., E.K., R.V.L.), and Endocrine Research Program (B.G.B., J.L., N.E.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: R. V. Lloyd, M.D., Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota 55905. E-mail: lloyd.ricardo{at}mayo.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The cloning of the leptin receptor gene (LEPR or OB-R) (9) showed that it was highly expressed in many tissues (8, 10) and is related to the class 1 cytokine receptor superfamily (11). Various alternatively spliced short OB-R isoforms, in addition to the long form or OB-Rb, have been identified and include OB-Ra, OB-Rc, and OB-Rd, which have 34, 32, and 40 amino acid cytosolic carboxyl-termini, respectively (10). In addition, a soluble extracellular isoform, OB-Re, which lacks the transmembrane domain, has been described (11). OB-Rb, which has a full-length cytosolic domain of 302 amino acids is a STAT (signal transducer and activator of transcription)-signaling-competent receptor (12, 13, 14). The leptin receptor also oligomerizes with itself (15), but the isoforms, which lack known signaling sequence motifs, are of uncertain physiological significance.
Various lines of evidence have implicated leptin in anterior pituitary function (16, 17, 18, 19, 20, 21). Yu et al. first reported that leptin played a role in controlling hormone secretion in the anterior pituitary (16). Leptin has also been shown to stimulate nitric oxide release from the pituitary (17). Zamorano et al. showed that the OB-R was expressed in the rat anterior pituitary and hypothalamus by RT-PCR (18), whereas other workers reported that OB-R gene expression was increased by GH and/or GHRH (19). Leptin deficiency in obese individuals due to a mutation associated with a truncated leptin receptor lacking both the transmembrane and intracellular domains has been reported to lead to pituitary dysfunction and obesity (20). This observation emphasizes the important role of leptin in pituitary function. The recent localization of leptin receptor isoforms in human pituitaries by RT-PCR and in situ hybridization provided direct evidence for a functional role of leptin in the human pituitary (21, 22). Our preliminary studies detected the long form of leptin receptor (OB-Rb) in normal pituitary as well as in adenomas (21), although another study found OB-Rb only in adenomas (22).
In this report, we show that leptin is produced by normal cells and tumors in the anterior pituitary, and that there is decreased leptin protein expression in pituitary adenomas compared to that in normal pituitaries. Leptin also inhibits the proliferation of anterior pituitary tumor cells in vitro. In addition, both OB-Rb and OB-Ra are expressed by normal and neoplastic pituitary cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Formalin-fixed, paraffin-embedded tissues from 26 cases of surgically resected pituitary adenomas and 6 nonneoplastic autopsy pituitaries obtained within 6 h postmortem were used for in situ hybridization analysis and immunohistochemistry. Freshly obtained tissues from 20 cases of pituitary adenomas, 1 pituitary ACTH carcinoma with liver metastases, and 2 nonneoplastic pituitaries were used for ribonucleic acid (RNA) extraction. An additional 2 cases of pituitary gonadotroph adenomas were dissociated and used for cell culture studies. All tumors were classified by immunohistochemistry as previously reported (23, 24, 25). Some cases, including null cell and gonadotroph adenomas, were also examined by electron microscopy.
Cell culture
Pituitary adenomas were dissociated with 0.25% trypsin and plated onto 35-mm dishes coated with extracellular matrix (Accurate Surgical & Scientific Instruments Corp., Hicksville, NY) at 0.3–1 x 106 cells/dish, as previously described (23, 24). The HP75 human pituitary cell line, developed in our laboratory from a nonfunctional pituitary adenoma infected with a replication-defective recombinant human adenovirus that contains a simian virus 40 early large T antigen (24), was included in this study. Tumor cells were grown in DMEM with 2% fetal bovine serum at 37 C in a 5% CO2 atmosphere for 6 days, and the medium was changed every other day. Aliquots of cells were treated with 10-6–10-12 mol/L leptin (Eli Lilly & Co., Indianapolis, IN). To analyze the effects of leptin on pituitary hormone secretion, cell culture medium was collected for hormone and pancreastatin immunoassays after 6 days of culture, as previously described (24, 25). Cells from primary culture of gonadotroph tumors were incubated in duplicate with leptin (10-8 mol/L), and the secretion of FSH was measured on days 2 and 6 of culture by immunoassay as previously reported using 5 x 105 cells/dish (24).
Cell growth experiments
To study the effects of leptin on cell growth, the
following cell lines were used in addition to HP75 cells:
GH3 cells (a rat pituitary GH- and PRL-secreting cell line,
from American Type Culture Collection, Manassas, VA) and T
antigen-expressing mouse gonadotroph cell lines LßT2 and
T3-1 (obtained from Dr. Pamela Mellon, University of
California-San Diego, La Jolla, CA). [3H]Thymidine
incorporation was performed as previously reported (24, 26). Briefly,
cells were seeded on 35-mm plastic dishes at 0.25 x
106 cells/dish under the conditions described above. After
6 days of treatment with leptin (10-8 mol/L), the medium
was changed, and fresh medium with 5 µCi/mL
[3H]thymidine (SA, 15.0 Ci/mmol; DuPont/NEN,
Boston, MA) was added for 6 h. The cells were harvested by
trypsinization and washed three times in phosphate-buffered saline
(PBS). The cell number from each dish was counted and diluted to
106 cell/mL in PBS. Cell viability was greater than 95%
when examined by trypan blue exclusion. An aliquot of suspended cells
(100 µL) was placed into scintillation vials and lysed with 0.5
N NaOH and 1% SDS for 30 min, followed by the addition of
4.9 mL scintillation cocktail (26). Radioactivity was counted in an
LS3801 scintillation counter (Beckman Coulter, Inc., Palo
Alto, CA). Results were reported as mean counts per minute per
105 cells ± SEM. Student’s unpaired
t test and ANOVA were used for statistical analysis.
RT-PCR
Total RNA from pituitary adenomas was extracted with the TRIzol
reagent kit (Life Technologies, Inc., Gaithersburg, MD)
and used for analysis of OB, OB-R, and OB messenger RNAs (mRNAs) by
RT-PCR. The sequences of primers and hybridization probes are shown in
Table 1
. The housekeeping genes
hypoxanthine phosphoribosyl transferase (HPRT) and
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were used as internal
controls. RT-PCR was performed as previously described (24). Thirty
cycles of PCR amplification with 57 C annealing temperature were used
for OB-R, and 40 cycles with 55 C annealing temperature were used for
OB. The PCR products were analyzed by 2% agarose gel electrophoresis
with ethidium bromide staining and Southern hybridization as previously
reported (23, 24). All primers spanned introns, except for the OB-Rb
primers, which were both located in exon 20. Negative controls
consisted of omitting the RT reaction for each sample, which resulted
in no bands after RT-PCR and Southern hybridization. The PCR reactions
were shown to be within the linear range by using different volumes of
complementary DNA samples for PCR followed by Southern hybridization
and densitometric analysis.
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The human OB-R complementary DNA, a gift from Dr. Caro
(Eli Lilly & Co., Indianapolis, IN), were cloned onto
pCRII-TOPO (Invitrogen, Carlsbad, CA) and linearized with
BamHI or ApaI. Riboprobes were generated by
in vitro transcription reaction and digoxigenin 11-UTP
(Boehringer Mannheim, Indianapolis, IN) labeling with
either T7 (antisense) and SP6 (sense) RNA polymerase for OB-Rb (
338
bp) or SP6 (antisense) and T7 (sense) for OB-Ra (338 bp), according
to the manufacturer’s instruction (Promega Corp.,
Madison, WI). The labeled probes were digested with deoxyribonuclease,
extracted with phenol/chloroform, and precipitated with ethanol.
In situ hybridization signals were detected by the
antidigoxigenin AP (1:200 dilution; Boehringer Mannheim)
and nitroblue tetrazolium/5-bromo-4-chloro-3-indolyl-phosphate
system. Human hypothalamus tissue was used as a positive control, and
the sense probes were used as a negative control.
Immunohistochemistry
Frozen sections from pituitary tissues and cytospin slides from pituitary adenoma culture cells were used for immunohistochemical analysis for OB-R and leptin. Fat tissues from the abdomen and breast were used as positive controls. The anti-OB-R antibody (1:1000 dilution) was a gift from Drs. Caro and Considine (Eli Lilly & Co., and University of Indiana, Indianapolis, IN) which was raised against a peptide from amino acids 236–254 of the OB-R corresponding to the extracellular domain. This antibody did not distinguish between the long and the common isoforms and was used as previously reported (27). Antileptin antibodies consisted of a polyclonal antiserum from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA; 1:500), and a monoclonal antibody from Sigma Chemical Co. (St. Louis, MO; used at 1:250). Single and combined immunohistochemistries were performed using the avidin-biotin-peroxidase and alkaline phosphatase methods (Vector Kit, Vector Laboratories, Inc., Burlingame, CA). Antigen retrieval by microwave treatment in 0.1 mol/L citrate buffer, pH 6.0, was performed for 5 min with each sample. Colocalization studies by immunostaining with the leptin monoclonal antibody and polyclonal pituitary antibodies from the National Pituitary Agency were performed with two normal pituitaries as previously described (25). Monoclonal pituitary hormone antibodies, including dilutions and sources were: PRL (1:400) and GH (1:400), both from BioGenex Laboratories, Inc. (San Ramon, CA); and LH (1:800), FSH (1:800), TSH (1:2000), and ACTH (1:800) from DAKO Corp. (Carpinteria, CA); these were used for colocalization with polyclonal leptin. An absorption control using purified leptin (Eli Lilly & Co.) at 50 µg/mL was performed for the leptin immunostaining studies. Other negative controls consisted of substituting PBS or normal serum for the primary antibodies. Immunohistochemical staining in normal pituitaries and adenomas was evaluated independently by two persons and graded as: 0, negative; 1+, weakly positive; 2+, moderately positive; and 3+, strongly positive.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leptin expression in normal and neoplastic pituitaries was first
analyzed by RT-PCR. Fat tissues from the abdomen and the breast used as
positive controls were both positive for the 414-bp leptin transcript
(Fig. 1). Leptin mRNA was detected in
three of four ACTH tumors, one of four GH adenomas, two of four null
cell, and one of four gonadotroph adenomas. A positive amplification
signal was present in three of four normal pituitaries. The HP75
pituitary cell line was positive for leptin, whereas all PRL adenomas
(n = 4) were negative for leptin (Fig. 1).
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20–25% of pituitary cells) and in tumor cells
(Fig. 2). Leptin staining was abolished
by absorption with 50 µg/mL purified leptin (Fig. 2). Colocalization
studies with leptin and pituitary hormones showed the following types
of anterior pituitary cells producing leptin: ACTH (70% of ACTH cells
positive for leptin), GH (21% positive), LH (29% positive), FSH (33%
positive), TSH (32% positive), and folliculo-stellate cells (64%
positive), whereas very few PRL cells were positive (3%). Adipose
tissues, used as a positive control, were also positive for leptin.
Analysis of 23 pituitary adenomas and six normal pituitaries by
immunohistochemistry with the anti-leptin monoclonal antibody showed
weak (1+) immunoreactivity in 10 adenomas and moderate (2+) to strong
(3+) staining in all normal pituitaries (Table 2). Correlation of the RT-PCR results and
immunohistochemical staining of the same tumor cases showed that six
adenomas positive for leptin by RT-PCR were also positive by
immunohistochemistry. Two adenomas were negative for leptin by both
RT-PCR and immunohistochemistry, whereas one tumor was focally positive
by immunohistochemistry and was negative by RT-PCR.
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When the HP75 cell line, which expressed both OB-Rb and
OB-Ra, was analyzed for the effects of leptin on the secretion of
pancreastatin, there was a dose-dependent increase in pancreastatin
secretion, with the maximum level of secretion observed with
10-8 mol/L pancreastatin (Fig. 3). After several days of culture of
gonadotroph adenomas in the presence of 10-8 mol/L leptin,
one tumor had 50% on day 2 and 50% on day 6 increases in FSH
secretion. The second tumor showed 36% and 11% decreases in FSH
secretion on days 2 and 6, respectively. Both gonadotroph tumors showed
a 2- to 3-fold increase in pancreastatin secretion on day 6. The levels
of FSH secretion in the HP75 cell line were too low to measure.
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). The same results
were noted by counting aliquots of cells from each culture (data
not shown). Analysis of the GH3 rat pituitary cell line
showed that 10-8 mol/L leptin also significantly inhibited
GH3 cell proliferation, but leptin did not inhibit
proliferation of the T3-1 or LßT2 cell
lines (Fig. 4).
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Analysis of pituitary tissue by RT-PCR showed expression of both
OB-Ra and OB-Rb by normal and neoplastic pituitaries (Fig. 5). OB-Ra was present in all 12 tumors
and in the normal pituitary, whereas OB-Rb was present in 10 of 12
tumors and in the normal pituitary. The human hypothalamic tissues,
used as a positive control, expressed both OB-Ra and OB-Rb (data not
shown). The HP75 pituitary cell line and an ACTH carcinoma were also
positive for both isoforms (Fig. 5). The GH3,
LßT2, and T3-1 cell lines were also
positive for OB-Ra and OB-Rb, although the bands were less intense
after Southern hybridization compared to the HP75 cell lines (data not
shown).
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Analysis of tissue sections by in situ
hybridization showed that OB-Ra and OB-Rb were expressed by 26 of 26
and 22 of 26 adenomas, respectively, and in the normal pituitary (Fig. 6). Both normal pituitaries and hypothalamus were positive for OB-Ra
and OB-Rb. The sense control did not show any positive staining,
confirming the specificity of the probe (Fig. 6). The HP75 pituitary cell line was
positive for OB-Rb and OB-Ra (Fig. 6).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies of the physiological functions of leptin have shown that it is involved in other metabolic functions in addition to energy metabolism. Leptin has been shown to regulate pituitary hormone secretion in rodents in vitro and in vivo (16, 17, 18, 19, 20, 21). Leptin has a role in fertility (29), in the onset of puberty (8), and in the regulation of food intake in humans (8, 30, 31). It also has a role in the regulation of body weight, which is disrupted in pathological states such as anorexia nervosa (32).
In the present study, leptin stimulated pancreastatin secretion in cultured pituitary HP75 cells. Pancreastatin is a proteolytic product of chromogranin A that functions as a prohormone in many neuroendocrine tissues (33, 34). Studies of the rat pituitary have shown that leptin stimulates gonadotropin and PRL release from anterior pituitary cells (16). The in vivo administration of leptin to rodents leads to elevated gonadotropin levels (35). Analysis of primary cultures of two pituitary tumors showed an increase in FSH secretion in one tumor and a slight decrease in the second tumor with 10-8 mol/L leptin. Sufficient cells were not available to test a wider range of leptin concentration on FSH secretion, but our findings suggest that leptin may have variable effects on gonadotropin secretion.
Peripheral levels of leptin may also influence other pituitary hormones, as serum ACTH and cortisol have been shown to be inversely related to leptin levels in humans (36). Leptin was reported to be a stimulator of GH secretion (37). Tannenbaum et al. observed that administered leptin antiserum resulted in a decrease in spontaneous GH release (38), whereas intracerebroventricular leptin also stimulates spontaneous pulsative GH secretion and GH response to GHRH (39). Shimon et al. (22) showed that leptin stimulated GH secretion in human fetal pituitaries. The HP75 cell line is derived from a nonfunctioning pituitary tumor that produced some FSH, and it also produces significant amounts of pancreastatin in vitro, so it may serve as a model to study the role of leptin in pituitary tumor regulation.
Our study of the effect of leptin on pituitary cell proliferation also showed that high concentrations of leptin inhibit pituitary proliferation in human and rat pituitary cell lines. These findings implicate leptin in the regulation of growth and differentiation of pituitary cells. Earlier studies of the pituitaries of ob/ob mice noted that the pituitaries had normal weights and histological appearance, suggesting that leptin may not play a significant role in pituitary hyperplasia and tumor development in these mice, (39). However, another strain of mice with inbred obesity, the Japanese KK mice (GH) had larger pituitaries than their lean controls, and there was an increase in the acidophil cells in these mice (39, 40). These findings indicate that the role of leptin in pituitary tumorigenesis needs further investigation. The finding of leptin in normal human pituitary cells suggests that some pituitary adenomas may produce large amounts of leptin (leptinomas), which may be associated with specific physiological and pathological changes in patients with such tumors.
Some growth factors, such as transforming growth factor-ß1, which inhibit pituitary cell proliferation, often lead to an increase in hormone production in the pituitary (41). Glasow et al. recently showed that leptin inhibited ACTH-induced aldosterone, cortisol, and dehydroepiandosterone secretion from the adrenal cortex (42). Leptin also inhibited LH-stimulated estradiol production from cultured ovarian granulosa cells (43). These findings implicate leptin in the physiological function of different endocrine organs or endocrine target organs in which pituitary hormones have a significant regulatory effect.
Various cytokines have been shown to regulate pituitary function (44). Leptin is related to cytokines, and the leptin receptor is a member of the class I cytokine receptor superfamily, which includes receptors for interleukin-6, GH, granulocyte colony-stimulating factor, leukemia inhibitory factor, and the gp130 signaling subunit (45, 46). Several pituitary cell types, including ACTH and folliculo-stellate cells, have been shown to express IL-6, IL-2, as well as IL-2 receptors, suggesting a common overlap between the leptin receptor superfamily and anterior pituitary cell receptors (47, 48, 49). Thus, the finding of leptin colocalization in folliculo-stellate cells is similar to previous reports of interleukin expression by these cells (49). IL-1, IL-2, as well as IL-6 usually have an inhibitory effect on normal anterior pituitary cell proliferation, which is similar to the effect of leptin on HP75 and GH3 pituitary cell growth (47, 48, 49, 50, 51, 52, 53). However, some of the interleukins can also stimulate cell growth (53). For example IL-6 inhibits rat pituitary cell growth, but stimulates the growth of GH3 pituitary tumor cells (54). Taken together, these findings indicate that leptin as well as other members of the cytokine family can regulate pituitary cell proliferation, usually by inhibiting growth, raising the possibility that an escape from the suppressive effects of leptin and other inhibitory cytokines may contribute to the autonomous growth of anterior pituitary cells and tumors.
The OB-R is a single membrane-spanning receptor with various alternatively spliced isoforms (9, 10, 11, 12, 13, 14, 15). The long form of the receptor, OB-Rb, has been localized in several tissues, including the hypothalamus and pituitary (17, 19, 21, 22, 27). Our studies localizing OB-Rb as well as OB-Ra in normal and neoplastic human anterior pituitary cells (21) agree with a recent report by Shimon et al. (22) in which OB-Rb was localized in human pituitary adenomas by RT-PCR. These other investigators also localized OB-Rb in fetal, but not in adult, normal pituitaries (22). Using two different approaches, RT-PCR and in situ hybridization, we demonstrated OB-Rb in normal human pituitaries obtained within a few hours postmortem. The differences in our study and that of Shimon et al. (22) may be due to other variables, such as the postmortem interval of the pituitary tissues. The normal pituitaries used in this study were obtained within 6 h postmortem, whereas the postmortem interval was not stated in the study by Shimon et al. (22). Longer postmortem intervals could lead to degradation of OB-Rb mRNA and protein to the shorter isoforms, such as OB-Ra. In addition, another recent study with human pituitaries detected the long form splice variant in normal pituitaries and adenomas (55). The localization of OB-Rb in specific tissues depends on the methods used as well as species variation. Although an earlier investigation did not detect OB-R in the rat adrenal by RT-PCR (18), a more recent study with adrenals using laser capture microdissection was able to localize and show a functional leptin receptor in human adrenal cortical cells by RT-PCR (42). Functional leptin receptors have also been observed in the human ovary (43).
Our RT-PCR analysis detected OB-Rb in the GH3 cell line,
which was significantly inhibited from proliferating by
10-8 mol/L leptin, and in the T3-1 and
LßT2 cell lines, which were not significantly inhibited
from proliferating by leptin. Some of the observed effects of leptin on
these cell lines may be related to the relatively long doubling time of
the T3-1 and LßT2 lines compared to the
GH3 cell lines, which is shown for the control cell lines
in Fig. 4.
In conclusion, 1) leptin mRNA and protein are expressed in most normal anterior pituitary cells and in some tumors, and there is decreased leptin immunoreactivity in adenomas compared to normal pituitaries; 2) leptin stimulates pancreastatin secretion from cultured pituitary cells; 3) both OB-Rb and OB-Ra mRNAs are expressed in normal and neoplastic human pituitary tissues; and 4) leptin also inhibits the proliferation of human and rat anterior pituitary cell lines in vitro. The inhibitory effect of leptin on pituitary cell proliferation suggests that this protein plays an important role in the growth and differentiation of anterior pituitary cells.
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Acknowledgments |
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T3-1 and LßT2 cell lines, and Shuya Zhang
for technical assistance. |
Footnotes |
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Received March 16, 1999.
Revised May 4, 1999.
Accepted May 10, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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