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D Maiter

Publications and source records attributed to D Maiter.

16 recordsLinked to original sources
PubMed1992

Differential regulation by growth hormone (GH) of insulin-like growth factor I and GH receptor/binding protein gene expression in rat liver.

We have reported that female hypophysectomized (hypox) rats replaced with T4 and cortisone and treated for 7 days with GH injections (4 x 12.5 micrograms/day) had significantly greater growth and increase in serum insulin-like growth factor-I (IGF-I) than did hypox rats continuously infused with GH (50 and 250 micrograms/day), whereas GH binding to liver membranes was increased only by infusion. We now report the effects of hypophysectomy, T4 and cortisone replacement, and the aforementioned continuous vs. intermittent GH treatment on liver IGF-I and GH receptor (GHR)/binding protein (GHBP) gene expression in female rats. Concentrations of IGF-I peptide were measured in acid-extracted sera and liver tissues. Total GH binding to liver membranes was determined in MgCl2-treated homogenates and serum GH binding activity was assessed by gel filtration of serum incubated with 125I-bovine GH. The abundance of messenger RNA (mRNA) transcripts encoding IGF-I, the GHR, and the GHBP was quantified by Northern hybridization analysis of liver poly(A)+ RNA. Hypophysectomy in female animals decreased serum IGF-I and liver IGF-I mRNA concentrations by 95% and 87%, respectively, serum GHBP activity, and total liver GH binding by 50% (P less than 0.001 compared with intact controls), and liver GHR and GHBP mRNA abundance by 30-35% (P less than 0.05 vs. controls). These changes were not reversed by T4 and cortisone treatment. Repeated injections of GH produced a 13-fold increase in liver IGF-I peptide and a 5-fold increase in liver IGF-I mRNA concentrations (vs. saline-treated hypox rats), whereas continuous GH infusions induced only 7-fold and 2-fold increases in IGF-I peptide and mRNA, respectively. Serum GHBP activity was not changed in the GH-injected animals, but rose 2- to 3-fold in the GH-infused rats, an increase similar to that reported for their liver GH binding sites. No major change in liver concentrations of GHR and GHBP mRNAs was seen after repeated GH injections. Differential regulation of the two GHR/GHBP gene products was observed after continuous infusion of GH, with a net 60-70% increase in liver GHBP mRNA abundance contrasting with no apparent change in the GHR mRNA transcript. These results indicate that pulsatile GH administration is more effective than continuous GH infusion in stimulating liver IGF-I gene expression, and this effect is not mediated by an increase in GHR mRNA or protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of Variance↗
PubMed1991

Neonatal treatment with monosodium glutamate: effects of prolonged growth hormone (GH)-releasing hormone deficiency on pulsatile GH secretion and growth in female rats.

Administration of monosodium glutamate (MSG) to neonatal rodents produces permanent lesions of hypothalamic arcuate neurons that secrete GH-releasing hormone (GHRH). The present study was intended to determine the consequences of GHRH deficiency on the pulsatile GH secretory pattern and growth in MSG-treated female rats and to compare these effects with those observed in male littermates. Male and female rats were injected with MSG [4 mg/g body wt (BW), sc] or saline (controls) on days 2, 4, 6, 8, and 10 after birth. Immunoreactive GHRH concentrations were decreased in the hypothalamus (by 60%) and in the median eminence (by 95%) of adult male and female MSG-treated rats. In contrast, somatostatin concentrations were unaffected. BW and linear growth were severely impaired in male MSG-treated rats, but in MSG-lesioned females BW was not different from controls, and the attenuation of longitudinal growth was less severe and the obesity more pronounced than in males. These sex differences occurred despite similar reductions (by 55%) in serum insulin-like growth factor I concentrations in male and female MSG-treated rats. MSG treatment also produced decreases in pituitary wt and GH content (by 60%), independent of sex. Pulsatile GH secretion was studied by serial blood sampling of chronically cannulated, freely moving rats. Plasma GH patterns were analyzed by the PULSAR program. Compared to controls, treatment with MSG led to a marked inhibition (by 90%) of GH secretion in both sexes. Significant reductions in GH pulse amplitude (-95%) and pulse duration (-62%) were observed in males, whereas pulse amplitude (-85%), pulse frequency (-67%), and baseline GH concentrations (-80%) were markedly reduced in females. The GH responses to an iv bolus injection of rat GHRH (1 microgram/rat) was severely blunted in both male and female MSG-treated rats. This study demonstrates that GHRH deficiency in female rats results in a marked inhibition of GH pulses, as in males, but also causes severe and sex-specific reductions in GH basal secretion and pulse frequency. These observations suggest that hypothalamic GHRH secretion in female rats is more continuous than in males and is a determinant of the elevated interpulse secretion of GH. Moreover, body wt and linear growth are less severely affected by arcuate lesions in female animals, compared to males. These sex-related differences in growth rates may result in part from the tendency of female MSG-lesioned rats to become more obese than males, and the development of obesity, in turn, may antagonize the factors that tend to slow linear growth.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Failure of insulin-like growth factor-I (IGF-I) infusion to promote growth in protein-restricted rats despite normalization of serum IGF-I concentrations.

Dietary protein restriction in young rats induces GH resistance characterized by growth arrest and low serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether the low serum IGF-I concentrations are responsible for the stunted growth, we infused 4-week-old protein-restricted rats with recombinant human IGF-I (300 micrograms/day) or rat GH (200 micrograms/100 g body wt/day) by osmotic minipump for 1 week. Despite the normalization of serum IGF-I concentrations by IGF-I infusion, carcass growth was not stimulated. In contrast, growth of the spleen and kidney was enhanced (+45% and +28%, respectively). Serum IGF-binding protein 3 (IGFBP-3), the principal carrier of IGF-I in the serum at this age, is decreased by 34% in protein-restricted animals and restored to normal by IGF-I infusion. Contrary to the selective effects of IGF-I on growth of protein-restricted rats, well nourished hypophysectomized rats infused with 150 micrograms/day recombinant human IGF-I showed a significant growth response, including carcass and organ growth and normalization of IGFBP-3 values. These responses indicate that our IGF-I preparation and mode of delivery were effective. We conclude that: 1) dietary protein restriction causes organ-specific resistance to the growth-promoting properties of exogenous IGF-I; 2) IGF-I mediates the stimulatory effects of growth hormone on IGFBP-3 synthesis; and 3) the absence of carcass growth in the presence of normal serum IGF-I concentrations during infusion of IGF-I suggests that the growth arrest that accompanies protein restriction is mediated in part by resistance to IGF-I.

Animals↗
PubMed1991

Sexually dimorphic expression of the growth hormone-releasing hormone gene is not mediated by circulating gonadal hormones in the adult rat.

The sexual dimorphism characterizing GH secretion in the rat is thought to be related to differences in the hypothalamic synthesis and release of the GH-regulating peptides, GH-releasing hormone (GHRH), and somatostatin. Therefore, the influence of gender and sex steroid hormones on hypothalamic expression of the GHRH gene in adult rats were examined. GHRH messenger RNA (mRNA) levels were measured in individual rat hypothalami by Northern hybridization analysis using a 32P-labeled complementary DNA encoding rat GHRH. Destruction of hypothalamic GHRH neurons by neonatal treatment with monosodium glutamate caused similar 3-fold reductions in the levels of GHRH mRNA in adult male and female animals. In three separate experiments, hypothalamic GHRH mRNA concentrations in male rats were 2- to 3-fold greater than in randomly cycling females (four or five rats per group; P less than 0.01). In spite of the greater abundance of GHRH mRNA abundance in the male rat hypothalamus, circulating gonadal steroids lacked the ability to modulate GHRH gene expression in adult animals, since neither gonadectomy nor pharmacological sex steroid replacement changed GHRH mRNA levels in the hypothalamus of male and female adult rats. Furthermore, GHRH mRNA concentrations in female rats were similar during the proestrus, estrus, and diestrus phase of the estrous cycle. Also, GH inhibited hypothalamic GHRH gene expression in a sex-specific manner. Exposure to high levels of GH secreted by the MtTW15 tumor for 4 weeks reduced GHRH mRNA concentrations 7-fold in male rats (P less than 0.001) but only 2-fold in females (P less than 0.05). These studies demonstrate that GHRH gene expression in the rat hypothalamus is sexually dimorphic. Basal mRNA levels are greater in male rats, and expression in male hypothalami is more sensitive to feedback inhibition by GH than expression in females. There is no evidence for regulation of GHRH mRNA levels by either testosterone or estrogen in adult rats. These gender differences in GHRH gene expression likely contribute to the generation of a sex-specific pattern of GH secretion.

Animals↗
PubMed1991

Evidence that pretranslational and translational defects decrease serum insulin-like growth factor-I concentrations during dietary protein restriction.

Dietary protein restriction causes GH resistance and decreases serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether pretranslational or translational defects are involved in the decline of serum IGF-I concentrations during protein restriction, we measured hepatic IGF-I mRNA abundance together with the serum IGF-I peptide response to exogenous GH after 1 week of protein restriction (5% casein in diet; P5) in hypophysectomized rats. We compared these responses with those of hypophysectomized rats fed a protein-sufficient diet (15% casein in diet; P15) and given exogenous GH. A single injection of rat GH (200 micrograms/100 g BW) produced a comparable IGF-I mRNA increment in both groups (at 6 h, 7.8 +/- 1.1 arbitrary units in P5 vs. 8.2 +/- 1.1 in P15), but failed to raise serum IGF-I normally in the P5 group (at 6 h, 90 +/- 15 ng/ml in P5 vs. 216 +/- 63 in P15; P less than 0.01). The post-GH decline of the 7.5-kilobase (kb) IGF-I mRNA abundance was faster in P5 than in P15 animals. In another experiment in intact rats subjected to protein restriction, injections of pharmacological doses of rat GH (400 micrograms/100 g BW.day) for 1 week restored liver IGF-I mRNA abundance to normal without normalization of serum IGF-I (403 +/- 91 vs. 713 +/- 53 ng/ml; P less than 0.01). Our data suggest that 1) the machinery involved in the transcription of the liver IGF-I gene is intact in protein-restricted rats, because these animals retain the ability to muster normal IGF-I mRNA responses to high doses of exogenous GH; 2) the stability of the 7.5-kb IGF-I mRNA is probably decreased by the protein restriction, as suggested by the faster decline of the 7.5-kb transcript in P5 than in P15 hypophysectomized rats; and 3) the discrepancy between normal liver IGF-I mRNA abundance and low serum and liver IGF-I peptide concentrations suggests that translational stalling of the IGF-I mRNAs or increased serum IGF-I clearance is involved in the low serum IGF-I concentrations during dietary protein restriction.

Animals↗
PubMed1990

Influence of thyroid hormone on the concentration of galanin in the rat brain and pituitary.

Galanin (GAL) is a 29-amino acid peptide implicated in neuroendocrine regulation of prolactin, growth hormone and thyrotropin in the rat. GAL-like immunoreactivity and GAL messenger RNA (mRNA) are present in the anterior pituitary (AP) and hypothalamus and the expression of GAL mRNA has been shown to be modulated by peripheral gonadal steroid hormones. In view of possible interactions between members of the steroid/thyroid hormone receptor family and recent data suggesting an effect of GAL on thyrotropin secretion, we investigated the possible influence of thyroid status on GAL concentrations in the hypothalamus and AP of the male rat. Three weeks after the surgical removal of the thyroid gland from male rats, the concentrations of GAL in the median eminence (ME) and AP were reduced 54 and 65%, respectively. Similarly, GAL concentrations were decreased 39% in the ME and 69% in the AP of animals rendered hypothyroid by treatment with propylthiouracil (PTU). The effects of PTU treatment in both regions were reversed by daily T4 injections (50 micrograms/kg). The effects of PTU in the ME were reversed after 2 weeks of T4 treatment, whereas 3 weeks of replacement therapy were required to restore GAL concentrations in the AP. However, T4 treatment of intact control animals did not influence GAL concentrations. This study demonstrates that the presence of thyroid hormones is required for the maintenance of physiological concentrations of GAL in the hypothalamus and AP of the rat. These data also suggest that GAL may be involved in the negative feedback regulation of the hypothalamohypophysial-thyroid axis.

Animals↗
PubMed1990

[Diabetes, malnutrition and growth retardation].

We investigated the cellular mechanisms responsible for growth hormone (GH) resistance in diabetes and malnutrition in the rat. In insulin-dependent diabetes, a post-receptor defect participates in GH resistance. During fasting, there is a loss of liver GH binding sites. Dietary protein restriction causes a post-receptor defect. This defect can be attributed to the combined effects of decreased liver IGF-I mRNA content and impaired message translation.

Animals↗
PubMed1989

Reduction of serum insulin-like growth factor-I by dietary protein restriction is age dependent.

We have determined if dietary protein restriction for 1 wk has differential effects on growth, serum IGF-I, and liver growth hormone receptors at various stages of development. Female Wistar rats were fed a low (5%) protein diet for 7 d at 3, 4, 6, 8, and 12 wk of age, whereas controls were maintained on a normal (15%) protein diet. Body wt gain was impaired in the groups fed the low protein diet, despite normal energy intake, and the effect was attenuated with age. Liver cell number (DNA content) was reduced by low protein feeding in the 3-, 4-, and 6-wk age groups (p less than 0.01), but not in the older animals. Protein restriction caused a dramatic decrease in serum IGF-I in the younger animals (90 and 82% reduction versus normal fed age-matched controls, at 3 and 4 wk, respectively; p less than 0.001), and this effect was progressively attenuated with increasing age (49, 40, and 25% reductions of serum IGF-I at 6, 8, and 12 wk, respectively). Changes in serum IGF-I correlated with those of liver cell number (r = 0.80; p less than 0.001). Total and free liver growth hormone receptors were slightly decreased in the low protein diet groups at 4 (p less than 0.05) and 6 wk (total: p less than 0.001; free: p less than 0.01) but not in the other age groups. The occurrence of profound diet induced reductions in IGF-I without proportional reductions in liver GH receptors suggest that the apparent GH resistance occurs at a postreceptor level.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1989

Dietary protein restriction decreases insulin-like growth factor I independent of insulin and liver growth hormone binding.

To determine the role of hypoinsulinemia and liver somatogenic (GH) receptors in growth retardation and decreased serum insulin-like growth factor I (IGF-I) levels during protein restriction, we have used a rat model where the effects of a low protein intake on body weight (BW), serum IGF-I concentration, and liver GH binding could be evaluated in the presence of low or high insulin concentrations. Two days after being made diabetic with streptozotocin (60 mg/kg BW), 6-week-old female rats (nine per group) were begun on a low (5%) or normal (15%) protein diet, without or with insulin supplementation (3 U lente daily). Nondiabetic rats fed both diets were used as controls (nine per group). In the nondiabetic animals, 7 days of protein restriction reduced BW gain by 50% (P less than 0.001), serum insulin by 44% (P less than 0.025), and serum IGF-I concentrations by 28% (P less than 0.001) without significantly changing liver GH binding. By day 9, BW was decreased in the diabetic animals by 12%, serum insulin by 80%, serum IGF-I by 55%, and liver GH binding by 62%; these effects were similar in the 5% and 15% protein-fed rats (P less than 0.001 vs. the corresponding controls). In the diabetes fed the normal diet, insulin treatment restored BW gain, serum IGF-I, and liver GH binding to normal values. In contrast, in the diabetics fed a protein-restricted diet and treated with insulin, BW gain and serum IGF-I concentrations remained low, similar to those in the malnourished controls. This diet-induced growth attenuation was observed despite high circulating insulin (2-3 times normal values), appropriate glucose control (63 +/- 9 mg/dl), and near restoration of liver GH binding. We conclude that while both protein restriction and diabetes attenuate growth and reduce IGF-I concentrations, the effects of protein restriction are independent of the effects of insulin and probably act by alteration of postreceptor mechanisms.

Animals↗
PubMed1988

Acute down-regulation of the somatogenic receptors in rat liver by a single injection of growth hormone.

Prolonged continuous administration of GH induces somatogenic receptors in rat liver. However, because GH secretion is pulsatile and the effect of acute changes in serum GH concentrations on liver GH receptors is unknown, we measured total (MgCl2-treated homogenates) and free (water-treated homogenates) GH-binding sites in the livers of hypophysectomized (hypox) rats killed between 1 and 24 h after a single sc injection of rat GH (100 micrograms/100 g BW; n = 29). Control hypox rats (n = 10) were studied immediately or 3 h after injection of vehicle. GH injection caused profound decreases in both total and free liver GH receptors, but these changes followed different kinetic patterns. Free receptors declined rapidly (to 17% of control), reaching a nadir at the same time (1 h) as the maximal GH concentration in serum. These free receptors then increased, returning to normal 12 h after GH injection. In contrast, total GH receptors were slightly increased at 1 h, decreased to their minimal value at 6 h (53% of control), and returned to normal at 12 h. Serum immunoreactive somatomedin-C/insulin-like growth factor I concentrations peaked 12 h after GH injection. Total and free liver GH receptors were quantitated in hypox rats that had been injected 3 h previously with doses of rat GH from 2.5-500 micrograms/100 g BW or with vehicle. Both total and free binding sites decreased in a dose-dependent manner; the maximal responses were 40% and 90% below control values, respectively. Half-maximal reductions in GH binding were achieved when 10 micrograms GH/100 g BW were given. These data suggest that a surge of GH in serum leads to a time- and dose-dependent down-regulation of the liver somatogenic binding sites and are consistent with ligand-induced internalization and degradation of the receptor.

Animals↗
PubMed1988

Different effects of intermittent and continuous growth hormone (GH) administration on serum somatomedin-C/insulin-like growth factor I and liver GH receptors in hypophysectomized rats.

To determine if the pattern of GH delivery is important for the regulation of serum somatomedin-C/insulin-like growth factor I (Sm-C/IGF-I) and liver somatogenic receptors, we have measured serum Sm-C/IGF-I concentrations and free (H2O-treated homogenates) and total (MgCl2-treated homogenates) liver GH-binding sites in hypophysectomized rats treated for 7 days with rat GH (rGH), given either continuously by osmotic minipumps (50 and 250 micrograms/day) or intermittently (four sc injections of 12.5 micrograms/day). At a daily dose of 50 micrograms, intermittent rGH produced greater weight gain [+29.7 +/- 0.8 g (mean +/- SE)] than continuous GH infusion (23.3 +/- 2.0 g; P less than 0.01). Likewise, the serum Sm-C/IGF-I concentration rose more with intermittent (0.33 +/- 0.1 U/ml) than with continuous delivery (0.17 +/- 0.01 U/ml; P less than 0.01). The serum Sm-C/IGF-I level achieved with repeated GH injections was even greater than that after continuous delivery of a 5-fold higher GH dose (250 micrograms/day; 0.27 +/- 0.02 U/ml; P less than 0.05). Continuous infusions of 50 and 250 micrograms rGH/day increased the number of liver total GH receptors by 2.5-fold over that of controls. In contrast, frequent GH injections did not affect GH binding, and the serum Sm-C/IGF-I concentration did not correlate with liver GH-binding sites in the GH-injected rats (r = 0.189; P = NS). Induction of hepatic PRL receptors was 10-fold higher when GH was given continuously than when it was given intermittently. The close correlation observed between GH- and PRL-binding sites in all GH-treated rats (r = 0.955; P less than 0.001) suggests that their regulation may be linked. These data suggest that the regulatory mechanism controlling Sm-C/IGF-I production and growth might be different from those that regulate GH receptor concentrations, with GH pulses being crucial for the maximal stimulation of Sm-C/IGF and growth, but continuous exposure to GH being required for up-regulation of liver GH receptors.

Animals↗
PubMed1988

Decreased serum insulin-like growth factor I response to growth hormone in hypophysectomized rats fed a low protein diet: evidence for a postreceptor defect.

In protein-calorie malnutrition, serum IGF-I concentrations are low despite high GH. This GH resistance might be due to a reduced number of liver GH binding sites as suggested by studies performed in fasted rats that were refed a low protein diet. To determine whether a postreceptor defect in GH action might also contribute to the GH resistance, we measured the number and the affinity constant of the liver GH binding sites and the serum IGF-I responses to injections of recombinant bGH in hypophysectomized female rats, fed a standard (15% protein) diet (N = 25) or a low (5%) protein diet (N = 25) for 8 days. There were no significant differences in the liver GH binding capacities between the 15% and the 5% protein-fed rats, whether expressed as pmol per liver (20.6 +/- 3.5 vs 14.4 +/- 1.3; mean +/- SEM; P less than 0.2; N = 5, respectively), pmol per mg DNA (1.08 +/- 0.16 vs 0.84 +/- 0.07; P less than 0.4) or fmol per mg of protein (28.98 +/- 5.04 vs 30.26 +/- 2.00; P greater than 0.5). Likewise, the affinity constants of the GH binding sites of the 15% and the 5% protein-fed rats were not significantly different (0.78 +/- 0.05 vs 0.78 +/- 0.07 x 10(9) l/mol; P greater than 0.5). Despite these non-significant reductions in liver GH binding sites, the IGF-I responses 24 h after sc injections of increasing doses of bovine GH were blunted in the rats fed the 5% protein diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Early changes in serum concentrations of somatomedin-C induced by dietary protein deprivation in rats: contributions of growth hormone receptor and post-receptor defects.

To define the mechanism(s) for the decrease of somatomedin concentrations in acute protein malnutrition, we have assessed the relationships between serum immunoreactive somatomedin-C/insulin-like growth factor-I (Sm-C/IGF-I), serum immunoreactive GH and total (MgCl2-treated homogenates) as well as free (water-treated homogenates) liver somatogenic (GH) binding sites in growing rats fed a 5% protein diet for 12 or 24 h and given an s.c. injection(s) of rat GH (rGH) or saline. Control rats were fed a 15% protein diet and injected with rGH or saline. After 12 and 24 h of protein restriction, body weight was 6.9 and 8.2% below controls respectively (P less than 0.001), while Sm-C/IGF-I concentrations were reduced by 58 and 66% respectively (P less than 0.001 vs controls). Serum GH concentrations were not affected by the low protein intake. Furthermore, injection(s) of 50-100 micrograms rGH failed to raise serum Sm-C/IGF-I concentrations in the protein-deficient animals. The number of total and free GH-binding sites was modestly (15-20%) decreased at 12 and 24 h in the protein-restricted rats. Serum Sm-C/IGF-I concentrations correlated weakly with free and total binding sites (r = 0.48 and 0.38 respectively). Affinity constants of GH-binding sites were not changed by protein restriction. The profound reduction in Sm-C/IGF-I concentrations within a few hours of beginning protein restriction, and the discordance between this reduction and the small decline in somatogenic binding sites, suggests that, in addition to GH receptor loss, a postreceptor defect may participate in the GH resistance occurring in the early stages of protein deficiency.

Animals↗