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Temporal Relationship Between the Sexually Dimorphic Spontaneous GH Secretory Profiles and Hepatic STAT5 Activity

Departments of Pediatrics and Neurology and Neurosurgery (G.S.T., W.G.), McGill University, and the Neuropeptide Physiology Laboratory, McGill University-Montréal Children’s Hospital Research Institute, Montréal, Québec H3H 1P3, Canada; and Division of Cell and Molecular Biology (H.K.C., D.J.W.), Department of Biology, Boston University, Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Dr. Gloria S. Tannenbaum, Neuropeptide Physiology Laboratory, McGill University-Montreal Children’s Hospital Research Institute, 2300 Tupper Street, Montréal, Québec H3H 1P3, Canada; E-mail: gloria.tannenbaum{at}mcgill.ca, or to Dr. David J. Waxman,

	Abstract

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STAT5 transduces transcriptional responses to GH in liver and other tissues and is proposed to mediate the sexually dimorphic effects of plasma GH secretory profiles on rodent liver gene expression. Previous studies have suggested that STAT5 undergoes repeated activation in direct response to successive GH pulses in adult male rats, with STAT5 activation being desensitized in females by their more persistent pattern of GH exposure. These findings, however, were based on in vitro studies or single blood samples analyzed for GH in vivo. In view of the highly pulsatile nature of rat GH secretion, we presently examined these hypotheses by concurrent monitoring of spontaneous GH secretory profiles and hepatic STAT5 activity in conscious, free-moving adult male and female rats. Rats were killed at times associated with spontaneous peaks or troughs of the GH rhythm; livers were removed and analyzed for STAT5 DNA-binding activity. In males, liver STAT5 activity was highest during the initial phase (15–60 min) of a GH secretory episode (mean ± SE relative STAT5 activity = 86.5 ± 11.4; plasma GH = 146.7 ± 22.4 ng/ml) and was significantly lower (P < 0.01) during the downswing of a pulse, 45–75 min after the GH peak (STAT5 = 26.1 ± 1.7; GH = 33.3 ± 13.1 ng/ml), consistent with a time-dependent down-regulation of GH signaling to STAT5. The lowest STAT5 activity was observed during the subsequent GH trough period (STAT5 = 3.6 ± 1.1; GH = 2.6 ± 0.1 ng/ml). In females, liver STAT5 activity was significantly lower (P < 0.05) than peak male levels during the initial phase of a GH secretory burst (STAT5 = 35.1 ± 15.9; GH = 68.1 ± 31.6 ng/ml) although similar to that of males during a plasma GH nadir (STAT5 = 11.0 ± 2.6; GH = 8.4 ± 2.2 ng/ml). We conclude that: 1) liver STAT5 is repeatedly activated by successive, spontaneous GH secretory episodes in intact adult male rats at approximately 3- to 3.5-h intervals; 2) time-dependent down-regulation of GH signaling to hepatic STAT5 in vivo begins by 45 min after GH peak stimulation; and 3) the lower level of liver STAT5 activation seen in adult female rats, compared with males, is a consequence of the sex-dependent differences in GH secretory patterns that characterize these animals (i.e. lower-amplitude GH pulses and lack of prolonged interpulse nadir of GH in the feminine, compared with masculine profile).

	Introduction

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THE SECRETION OF GH from the pituitary gland is characterized by multiple episodic bursts. There is, however, a marked sex difference in the pattern of GH secretion in most mammalian species, including humans [see (1, 2) for review]. Particularly in the rat, the male GH secretory profile is characterized by high-amplitude GH bursts at regular 3- to 4-h intervals, separated by a prolonged (1–1.5 h) period of mostly undetectable plasma GH levels (3). In contrast, the female rat exhibits irregular, more frequent, lower-amplitude GH pulses superimposed on an elevated GH baseline (4, 5). These distinct sex differences in the temporal patterns of GH release are of biological significance because they evoke remarkable male-female differences in body growth (6, 7), liver enzyme expression (8, 9), and GH intracellular signaling pathways (10).

Many members of the cytochrome P450 (CYP) superfamily, which encode monooxygenases active in the hydroxylation of endogenous steroids and foreign chemicals, are expressed in liver in a sex-specific manner in response to the sexually dimorphic pattern of pituitary GH secretion (11, 12, 13). STAT5b, a signal transducer and activator of transcription protein that mediates transcriptional responses to a variety of cytokines, growth factors, and hormones in liver and other tissues (14, 15, 16), has been proposed to mediate the sexually dimorphic effects of plasma GH secretory profiles on liver gene expression in rodents (10). This proposal is in part based on the finding that male plasma GH pulses activate liver STAT5b to a substantially higher level than that seen in females (10) and is strongly supported by the phenotypic characteristics of male STAT5b knockout mice, which include the loss of expression of multiple male-specific, GH-regulated liver genes including CYPs (17, 18, 19, 20). The strong correlation between rat liver nuclear STAT5 activity (primarily in the form of STAT5b) and the presence of significant GH levels in plasma at the time of liver removal (21) further suggested that STAT5 undergoes repeated activation by tyrosine phosphorylation in direct response to successive GH pulses in male rats. By contrast, the activation of liver STAT5 by plasma GH stimulation in female rats is considerably weaker and is proposed to be a consequence of down-regulation of STAT5 activation by the more persistent exposure to GH that occurs in females (22).

The earlier experiments leading to the proposal that liver STAT5 signaling is directly responsive to the temporal pattern of plasma GH stimulation, described above, were based on in vitro studies or single blood samples of GH obtained at the time of liver excision. In view of the highly pulsatile nature of GH secretion in the rat, a more direct test of these hypotheses requires an examination of the temporal relationship between the spontaneously occurring GH pulses and liver STAT5 activity in individual male and female rats. In the present study, we addressed this question by concurrently monitoring spontaneous GH secretory profiles and hepatic STAT5 activity in conscious free-moving adult male and female rats under normal physiological conditions.

	Materials and Methods

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Animals and experimental procedures
Adult male (250–375 g) and female (230–250 g) Sprague-Dawley rats were purchased from Charles River Canada (St. Constant, Québec, Canada) and individually housed in an isolated room under a rigidly controlled 12-h light, 12-h dark cycle (lights on: 0600–1800 h) in a temperature- (22 ± 1 C) and humidity-controlled environment. Purina rat chow (Ralston Purina, St. Louis, MO) and tap water were available ad libitum. Chronic intracardiac venous cannulas were implanted under sodium pentobarbital (50 mg/kg, ip) anesthesia using a previously described technique (3). After surgery, the rats were placed directly in isolation test chambers with food and H₂O freely available until body weight returned to preoperative levels (usually within 5–7 d).

On the day of the experiment, blood samples (0.3 ml) were withdrawn every 15 min starting at 0800 h until the rats were killed by decapitation at either 1100 h or 1300 h. These times were chosen because they correspond to typical peak and trough periods of GH secretion, respectively, in male rats maintained under the above photoperiodic conditions, as previously established in this laboratory (3, 23). All blood samples were immediately centrifuged, and the plasma was separated and stored at -20 C for subsequent assay of GH. To avoid hemodynamic disturbance, the red blood cells were resuspended in normal saline and returned to the animal after removal of the next blood sample. At death, the livers were immediately removed, frozen in isopentane at -40 C, and stored at -80 C until analysis of STAT5 activity. All animal-based procedures were approved by the McGill University Animal Care Committee.

Preparation of whole-liver homogenates
Approximately 200–400 mg of frozen rat liver tissue was homogenized at 4 C in a Dounce tissue grinder (10 strokes) in 2 ml of ice-cold homogenization buffer (10 mM Tris, pH 7.6, l mM EDTA, 250 mM sucrose) containing a mixture of protease inhibitors and phosphatase inhibitors (22). Samples were centrifuged at 9000 rpm for 20 min at 4 C in a Sorvall RC-5C centrifuge. Supernatants were aliquoted, snap-frozen in liquid nitrogen, and stored at -80 C. Little or no STAT5 DNA-binding activity was present in the pellet fraction.

EMSA analysis
STAT5 DNA binding was measured by EMSA using a double-stranded DNA probe corresponding to the STAT5/mammary gland factor response element of the rat ß-casein promoter, 5'-GGA-CTT-CTT-GGA-ATT-AAG-GGA-3' (sense strand, nucleotides -101 to -80). The sense strand was end labeled with ³²P using T₄ polynucleotide kinase, annealed to the antisense strand, and then purified on a BioSpin 30 chromatography column. Whole-liver homogenates (30 µg) were assayed for EMSA activity as described (22). EMSA gels were dried and exposed to PhosphorImager plates for 1–3 d. Radioactive band intensities were quantitated and analyzed on a PhosphorImager (Molecular Dynamics, Inc., Sunnyvale, CA) using ImageQuant software. Background PhosphorImager values (typically corresponding to 2–5% of a maximal male liver STAT5 signal) were determined based on the average of 2–4 blank regions from each gel and were subtracted from all samples on the gel to yield net activity values. Values are expressed as a percentage of a standard high STAT5 activity male rat liver sample or the average of several such male rat liver samples. The high STAT5 activity male rat liver reference samples used for quantitation of STAT5 DNA-binding activity in the present study were the same standards used in our two previous studies (21, 22).

Hormone assays
Plasma GH concentrations were measured in duplicate by double-antibody RIA using materials supplied by the NIDDK Hormone Distribution Program (Bethesda, MD). The averaged plasma GH values are reported in terms of the rat GH reference preparation rGH RP-2. The standard curve was linear between 0.62 and 320 ng/ml; the least detectable concentration of plasma GH under the conditions used was 1.2 ng/ml. The intraassay and interassay coefficients of variation were 7.7% and 10.7%, respectively, for duplicate samples of pooled plasma containing a mean GH concentration of 60.7 ng/ml.

Statistical analyses
ANOVA, followed by unpaired t tests, were used for statistical comparisons between experimental groups. The Pearson product-moment correlation coefficient was used to evaluate the degree of relation between plasma GH concentrations and hepatic STAT5 activity levels. Results are expressed as mean ± SE. P< 0.05 was considered significant.

	Results

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Temporal relationship between GH secretory pattern and hepatic STAT5 DNA-binding activity in adult male rats
Figure 1 illustrates spontaneous plasma GH profiles of six individual adult male rats killed during various phases of the GH rhythm; their corresponding liver STAT5 DNA-binding activities are shown in Fig. 2. The typical pulsatile pattern of GH secretion characteristic of the male rat (3) was evident in all animals, with major episodes of GH release occurring at 3- to 4-h intervals (mean ± SE GH pulse amplitude: 211 ± 3.9 ng/ml); in the intervening trough periods lasting approximately 1.5 h, plasma GH levels were mostly undetectable (<1.2 ng/ml) (Fig. 1, A–C). Liver STAT5 DNA-binding activity (Fig. 2) was highest during the initial phase of a GH secretory episode (15–60 min after pulse initiation) (Fig. 1, rats J1, J10; also see rats T10 and T11, Fig. 2). By contrast, livers of animals killed during a GH trough period (90–120 min after the GH peak) exhibited an extremely weak STAT5 signal (rats T16, J4 and T17). Intermediate liver STAT5 activity was observed in rats killed during the downswing of a GH pulse (45–75 min after the GH peak; rats T15, J6 and J9; Figs. 1 and 2).

View larger version (24K): [in this window] [in a new window]   Figure 1. Individual representative plasma GH profiles of adult male rats killed during either the upswing (A) or downswing (B) of a GH secretory episode or during a GH trough period (C). Arrows indicate the time the rats were killed and liver excision for STAT5 activity analysis.

View larger version (53K): [in this window] [in a new window]   Figure 2. STAT5 DNA-binding activity assayed in livers of individual adult male rats whose GH secretory profiles are shown in Fig. 1. EMSAs were carried out using whole-liver homogenates prepared from individual livers as described in Materials and Methods. Also included are four additional liver samples, whose GH secretory profiles are not shown in Fig. 1 (lanes 3, 4, 7, and 10). The signal shown for sample T11 (lane 4) is representative of the active male liver STAT5 standard (=103% of the male standard).

View larger version (22K): [in this window] [in a new window]   Figure 3. Mean plasma GH profiles and mean relative hepatic STAT5 activity levels (percent of maximal male response) in male rats during various phases of the GH rhythm. STAT5 activity was highest during the initial phase (15–60 min) of a GH secretory episode (A) and was lowest during the GH trough period (C). Intermediate STAT5 activity was observed during the downswing of a pulse, 60 min after the GH peak (B). Values are the mean ± SE. Arrows indicate time the rats were killed and liver excision. The number of animals in each group is shown in parentheses. a, P < 0.01 vs. GH pulse upswing; b, P < 0.001 vs. GH pulse upswing and downswing

View larger version (22K): [in this window] [in a new window]   Figure 4. Individual representative plasma GH profiles of adult female rats killed during either the time of a GH peak (A–C) or during the GH baseline period (D–F). Arrows indicate the time the rats were killed and liver excision.

View larger version (54K): [in this window] [in a new window]   Figure 5. STAT5 DNA-binding activity assayed in livers of the individual adult female rats whose GH secretory profiles are shown in Fig. 4. EMSA assays were carried out using whole-liver homogenates prepared from individual livers as described in Materials and Methods. Also included are four additional liver samples, whose GH secretory profiles are not shown in Fig. 4 (lanes 3, 4, 7, and 8).

View larger version (26K): [in this window] [in a new window]   Figure 6. Mean plasma GH profiles and relative hepatic STAT5 activity in female rats. Liver STAT5 activity levels (percent of maximal male response) in females were lower than peak male levels during the initial phase of a GH secretory burst (A) although similar to those of males during a plasma GH nadir (B). Values are the mean ± SE. Arrows indicate the times the rats were killed. The number of animals in each group is shown in parentheses.

	Discussion

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The sexual dimorphism of GH secretory patterns, discovered more than two decades ago in the rat and subsequently observed in other mammalian species, including humans, is an important determinant of a number of physiological responses to GH, including pubertal body growth rate and liver gene expression. Earlier studies aimed at defining the distinct signaling elements in male and female plasma GH patterns recognized by the liver, a major target of GH action, suggested that the time interval between plasma GH pulses is a key feature, with a minimum GH off-time required to elicit a male liver response (24). Elucidation of the molecular events and intracellular signals that underlie this response has been advanced by the discovery that the transcription factor STAT5b, which can be activated by a variety of cytokines and growth factors, including GH, is not only more strongly activated by GH in the livers of male, compared with female rats (10), but is essential for the sexually dimorphic effects of GH as well (17). Liver STAT5b activity in individual male rats is strongly correlated with the presence of significant levels of GH in blood based on single blood samples obtained at the time of liver excision, leading to the hypothesis that STAT5b may be directly activated by each succeeding plasma GH pulse, such that pulsatile plasma GH induces a pulsatile STAT5 signal (10, 21). The present study tests this hypothesis in a rigorous fashion by concurrent monitoring of spontaneous GH secretory profiles and hepatic STAT5 activity in conscious, free-moving adult rats.

The results reported here provide strong evidence that, in male rats under physiological conditions, each incoming male GH pulse, occurring approximately 3–3.5 h after the preceding GH secretory episode, strongly stimulates the activation of STAT5 (primarily STAT5b) in liver tissue. Liver STAT5 activity, which was highest during the initial phase (15–60 min) of a GH secretory episode, was found to be down-regulated as a function of time after the onset of GH pulse stimulation, such that by the conclusion of the secretory burst (typically 90–120 min after its peak), little or no STAT5 activity was detectable (Fig. 3C). This finding accounts for our earlier observation of very low liver STAT5 activity in male rats killed when plasma GH levels are less than 3.7 ng/ml (21), which is presently shown to correspond to a GH trough period. The time dependence of the down-regulation of liver STAT5 signaling, evidenced by the intermediate STAT5 activity measured in rats sampled during the GH pulse downswing (45–75 min after GH peak stimulation), is consistent with the observation in cultured liver cells that the activation of GH receptor-JAK2 signaling by GH induces a series of events that culminate in the down-regulation and termination of receptor-dependent signaling to STAT5b (25). These signal termination events begin by approximately 45 min after the initial GH stimulus and are dependent on protein synthesis and proteosome activity (25, 26, 27). These two requirements appear to reflect the involvement of suppressor of cytokine signaling (SOCS and CIS) proteins (28), which are rapidly synthesized following the initial GH stimulatory event and can inhibit GH receptor-JAK2 signaling by multiple mechanisms (29, 30), including a proteosome-dependent degradation mechanism (31). Other studies point to the additional involvement of specific protein tyrosine phosphatases, such as SHP-1 and PTP-1B in the termination of STAT5 signaling (32, 33, 34).

Liver STAT5 activation in adult female rats and in male rats administered an exogenous female-like pattern of GH stimulation is substantially lower than in untreated males (22). This low female liver STAT5 activity was proposed to reflect a down-regulation of GH receptor-JAK2 signaling, as indicated by the down-regulation of signaling that is observed in vivo upon continuous infusion of GH (10, 22) or in cultured liver cells treated with GH continuously for less than or equal to 2–3 h (26, 27). The present observation that liver STAT5 activity in female rats is significantly lower than peak male levels, even during the initial phase of a GH secretory burst, and similar to that observed in males during the downswing of a GH pulse, provides strong support for this proposal. Liver STAT5 activity in female rats sampled during a plasma GH nadir was 3-fold higher than the corresponding male GH trough period STAT5 activity, consistent with studies showing STAT5 signaling to be low, but not absent, in liver cells treated with GH continuously (35). The female plasma GH pattern thus desensitizes hepatic STAT5 signaling only partially. The low STAT5 signal seen in liver cells treated with GH continuously is maintained only so long as GH continues to be present in the culture medium, reflecting a need to continuously reactivate signaling to STAT5, presumably in the form of newly formed active GH receptor-JAK2 signaling complexes (26). The physiological significance of the low-level STAT5 signal induced by GH in female liver is uncertain but may include some of the body growth effects of GH and activation of a subset of female-expressed CYPs (19) or other liver-expressed genes.

STAT5b is activated by a specific phosphorylation of tyrosine residue 699, which induces dimerization, nuclear translocation, and DNA binding of the transcriptionally active STAT. GH-activated STAT5b (35) as well as cytokine-activated STAT1 (36) cycle back to the cytoplasm, where they are reutilized rather than degraded at the conclusion of a hormone/cytokine stimulatory event. Consequently, the strong positive correlation between the plasma GH profile and the activation status of liver STAT5 seen in male rats in the present study provides strong evidence that STAT5 actively and repeatedly shuttles approximately every 3–3.5 h from the cytoplasm into the nucleus and then back out to the cytoplasm, in direct response to each successive GH secretory burst—a key determinant being the long period of low or no plasma GH in the masculine profile, which permits the resensitization of GH receptor signaling (24) by JAK-STAT cascades. The pulsatility of the extracellular GH stimulus thus generates a pulsatile, intracellular STAT5 signal leading to the nucleus. Whether this pulsatile signal stimulates a pulsatile transcriptional response of STAT5 target genes remains to be established.

	Acknowledgments

 
We thank Brigitte Moreau and Geneviève Parent for excellent technical assistance, Christopher Wiwi for assistance in carrying out EMSA analyses, Julie Temko and Mary Penwarden for manuscript preparation, and the National Hormone and Peptide Program, NIDDK, and Dr. A. F. Parlow for the generous provision of rat GH RIA materials.

	Footnotes

 
This work was supported by Grant MT-15440 (to G.S.T.) from the Medical Research Council of Canada and by NIH Grant DK-33765 (to D.J.W.). G.S.T. holds a Chercheur de Carrière Award from the Fonds de la Recherche en Santé du Québec.

Abbreviations: CYP, Cytochrome P450; STAT5, a signal transducer and activator of transcription protein that mediates transcriptional responses to a variety of cytokines.

Received June 8, 2001.

Accepted for publication July 18, 2001.

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