The aging suppressor klotho: a potential regulator of growth hormone secretion

2014 ◽  
Vol 307 (3) ◽  
pp. E326-E334 ◽  
Author(s):  
Shiri Shahmoon ◽  
Hadara Rubinfeld ◽  
Ido Wolf ◽  
Zvi R. Cohen ◽  
Moshe Hadani ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Secretory Granules ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Negative Regulator ◽  
Prolonged Treatment ◽  
Mrna Levels ◽  
Gh Secretion ◽  
Positive Regulator ◽  
Igf I

Klotho is a transmembranal protein highly expressed in the kidneys, choroid plexus, and anterior pituitary. Klotho can also be cleaved and shed and acts as a circulating hormone. Klotho-deficient mice ( kl/kl mice) develop a phenotype resembling early aging. Several lines of evidence suggest a role for klotho in the regulation of growth hormone (GH) secretion. The kl/kl mice are smaller compared with their wild-type counterparts, and their somatotropes show reduced numbers of secretory granules. Moreover, klotho is a potent inhibitor of the IGF-I pathway, a negative regulator of GH secretion. Therefore, we hypothesized that klotho may enhance GH secretion. The effect of klotho on GH secretion was examined in GH3 rat somatotrophs, cultured rat pituitaries, and cultured human GH-secreting adenomas. In all three models, klotho treatment increased GH secretion. Prolonged treatment of mice with intraperitoneal klotho injections increased mRNA levels of IGF-I and IGF-I-binding protein-3 mRNA in the liver, reflecting increased serum GH levels. In accord with its ability to inhibit the IGF-I pathway, klotho partially restored the inhibitory effect of IGF-I on GH secretion. Klotho is known to be a positive regulator of basic bFGF signaling. We studied rat pituitaries and human adenoma cultures and noted that bFGF increased GH secretion and stimulated ERK1/2 phosphorylation. Both effects were augmented following treatment with klotho. Taken together, our data indicate for the first time that klotho is a positive regulator of GH secretion and suggest the IGF-I and bFGF pathways as potential mediators of this effect.

Effect of actively immunizing sheep against growth hormone-releasing hormone or somatostatin on spontaneous pulsatile and neostigmine-induced growth hormone secretion

1995 ◽  
Vol 144 (1) ◽  
pp. 83-90 ◽  
Author(s):  
E Magnan ◽  
L Mazzocchi ◽  
M Cataldi ◽  
V Guillaume ◽  
A Dutour ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Physiological Role ◽  
Gh Secretion ◽  
Igf I ◽  
Plasma Gh ◽  
Hypophysial Portal

Abstract The physiological role of endogenous circulating GHreleasing hormone (GHRH) and somatostatin (SRIH) on spontaneous pulsatile and neostigmine-induced secretion of GH was investigated in adult rams actively immunized against each neuropeptide. All animals developed antibodies at concentrations sufficient for immunoneutralization of GHRH and SRIH levels in hypophysial portal blood. In the anti GHRH group, plasma GH levels were very low; the amplitude of GH pulses was strikingly reduced, although their number was unchanged. No stimulation of GH release was observed after neostigmine administration. The reduction of GH secretion was associated with a decreased body weight and a significant reduction in plasma IGF-I concentration. In the antiSRIH group, no changes in basal and pulsatile GH secretion or the GH response to neostigmine were observed as compared to controls. Body weight was not significantly altered and plasma IGF-I levels were reduced in these animals. These results suggest that in sheep, circulating SRIH (in the systemic and hypophysial portal vasculature) does not play a significant role in pulsatile and neostigmine-induced secretion of GH. The mechanisms of its influence on body weight and production of IGF-I remain to be determined. Journal of Endocrinology (1995) 144, 83–90

Negative feedback of insulin-like growth factor-I on growth hormone secretion by porcine pituitary cells

1995 ◽  
Vol 75 (1) ◽  
pp. 57-61 ◽  
Author(s):  
C. Farmer ◽  
H. Lapierre
Keyword(s):  
Growth Hormone ◽  
Negative Feedback ◽  
Culture Media ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Late Gestation ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Age Related ◽  
Igf I

Pituitaries from female Yorkshire pig fetuses (90 d, n = 26; 110 d, n = 17) and 6-mo-old pigs (n = 5) were enzymatically dispersed, plated, and cultured for 47 h. The cells were then rinsed and incubated for 22 h with testing media containing 0, 50, 100, 200, 300 or 400 ng mL−1 of IGF-I. Half of the wells from each concentration of IGF-I were then incubated for an additional 3 h with concentrations of IGF-I similar to those in the previous incubation, while the other half also had GRF added to the testing media to reach a final concentration of 10−8 M. Culture media were then collected from all the wells, were frozen, and later assayed for GH. Irrespective of whether GRF was present, IGF-I decreased pituitary secretion of GH (P < 0.001). A significant negative response to IGF-I was already present at the dose of 50 ng mL−1 (P < 0.0001). However, the extent of the GH response to IGF-I seen in pigs of various ages differed depending on whether GRF was present. The present results therefore establish that IGF-I does exert a negative feedback on pituitary GH secretion in swine and that the age-related changes in this feedback are dependent on the presence of GRF. In swine, it appears that high circulating concentrations of GH in late-gestation fetuses are not a result of a lesser sensitivity of the somatotroph to the inhibitory actions of IGF-I. Key words: Pig, cell culture, pituitary, IGF-I, growth hormone, age

scholarly journals Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

2011 ◽  
Vol 301 (4) ◽  
pp. R1143-R1152 ◽  
Author(s):  
Johannes D. Veldhuis ◽  
Cyril Y. Bowers
Keyword(s):  
Body Mass Index ◽  
Growth Hormone ◽  
Body Mass ◽  
Negative Feedback ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Gh Secretion ◽  
Model Free ◽  
Preclinical Investigation ◽  
Igf I

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E2 (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E2/T administration potentiated both pulsatile ( P = 0.006) and entropic ( P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode ( P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass ( P = 0.005). The composite of gender, body mass index, E2, IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

Suppression of hyperinsulinemia restores growth hormone secretion and metabolism in obese mice

2021 ◽  
Author(s):  
Zhengxiang Huang ◽  
Xuehan Lu ◽  
Lili Huang ◽  
Yang Chen ◽  
Chunhong Zhang ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Energy Metabolism ◽  
Energy Expenditure ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Metabolic Effects ◽  
Prolonged Treatment ◽  
Gh Secretion ◽  
Normal Chow ◽  
High Insulin

The well-balanced secretion between insulin and growth hormone (GH) is essential in regulating substrate metabolism, energy metabolism and body composition. High insulin and low GH levels are often observed in obesity, contributing to reduced energy expenditure and further fat accumulation. Although suppression of hyperinsulinemia is proposed as a treatment for obesity, changes in GH secretion and energy metabolism following this treatment are not thoroughly studied. This leaves unexplained observations, such as unchanged lean mass following insulin reduction. In this study, high-fat diet-induced obese (DIO) and normal chow-fed lean mice on a C57BL/6J background were treated for 7 weeks with diazoxide (1250 mg/kg in food), a KATP channel opener that suppressed insulin secretion. Diazoxide treatment for 10 days was sufficient to increase pulsatile GH secretion in DIO mice before any significant body weight change. The restored insulin-GH balance in DIO mice was followed by improvement in substrate and energy metabolism in a prolonged treatment period (4-6 weeks), including reduced fat mass, increased lipid oxidation and energy expenditure, as well as improved insulin sensitivity and metabolic flexibility. These metabolic benefits occurred along with the changes in the expression level of genes regulated by the insulin-GH balance. When applying diazoxide to normal chow-fed normoinsulinemic lean mice, none of the above metabolic effects was observed, suggesting that the metabolic changes following diazoxide treatment were mediated through the suppression of hyperinsulinemia. These results suggest that suppression of hyperinsulinemia by diazoxide restores GH secretion and improved substrate and energy metabolism in DIO mice.

Serum α-klotho levels are not informative for the evaluation of growth hormone secretion in short children

2017 ◽  
Vol 30 (10) ◽  
Author(s):  
Cristina Meazza ◽  
Heba H. Elsedfy ◽  
Randa I. Khalaf ◽  
Fiorenzo Lupi ◽  
Sara Pagani ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transmembrane Protein ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Serum Levels ◽  
Tolerance Test ◽  
Gh Secretion ◽  
Short Children ◽  
Egyptian Children ◽  
Igf I

AbstractBackground:α-Klotho is a transmembrane protein that can be cleaved and act as a circulating hormone (s-klotho). s-Klotho serum levels seem to reflect growth hormone (GH) secretory status. We investigated the role of s-klotho as a reliable marker of GH secretion in short children and the factors influencing its secretion.Methods:We enrolled 40 short Egyptian children (20 GH deficiency [GHD] and 20 idiopathic short stature [ISS]). They underwent a pegvisomant-primed insulin tolerance test (ITT) and were accordingly reclassified as 16 GHD and 24 ISS. The samples obtained before and 3 days after pegvisomant administration, prior to the ITT, were used for assaying insulin-like growth factor (IGF)-I and s-klotho.Results:IGF-I and s-klotho serum levels were not significantly different (p=0.059 and p=0.212, respectively) between GHD and ISS. After pegvisomant, a significant reduction in IGF-I and s-klotho levels was found in both groups. s-Klotho significantly correlated only with IGF-I levels in both groups.Conclusions:s-Klotho mainly reflects the IGF-I status and cannot be considered a reliable biomarker for GH secretion in children.

Effects of repetitive administration of growth hormone-releasing hormone on growth hormone secretion, insulin-like growth factor I, and bone metabolism in postmenopausal women

1989 ◽  
Vol 120 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Paul Franchimont ◽  
Didier Urbain-Choffray ◽  
Pierre Lambelin ◽  
Marie-Anne Fontaine ◽  
Gerard Frangin ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Bone Metabolism ◽  
Postmenopausal Women ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Significant Rise ◽  
Maximum Peak ◽  
Gh Secretion ◽  
Age Related ◽  
Igf I

Abstract. This study sought to determine whether GH response to synthetic GHRH was impaired in 13 postmenopausal (55-71 years) as compared with that in 8 eugonadal women and whether IGF-I and bone metabolism were consequently depressed. Thereafter, the effects of daily iv injections of 80 μg GHRH-44 for 8 days were studied in the same postmenopausal group. In addition to significantly higher basal IGF-I and osteocalcin levels (P< 0.005) in eugonadal as compared with the postmenopausal women, the administration of one GHRH-44 injection resulted in significantly higher 120-min postinjection GH maximum peak and cumulative responses in the former group as well (P< 0.005). Highly significant correlations were observed between 17β-estradiol plasma levels and either GH maximum peak or cumulative responses to GHRH-44 when both groups were pooled together, but not when considered independently. In postmenopausal women, a correlation was found between both age and duration of menopause and GH responses. Repeated GHRH-44 injections in postmenopausal women induced a significant increase in GH response (P< 0.001) as well as in IGF-I levels from day 4 to 8. No phospho-calcium parameters were modified except for a significant rise in osteocalcin from day 2 to 8. These data indicate an age-related loss of sensitivity of somatotrope cells to GHRH-44 in postmenopausal women, partly corrected by repeated daily GHRH-44 injections. As a consequence of the GHRH-induced increase in GH secretion, IGF-I was also enhanced and may be responsible for a stimulatory effect on bone formation, as shown by the osteocalcin increase, uncoupled from bone resorption.

Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans

2002 ◽  
Vol 283 (5) ◽  
pp. E1008-E1015 ◽  
Author(s):  
Craig A. Jaffe ◽  
D. Kim Turgeon ◽  
Kenneth Lown ◽  
Roberta Demott-Friberg ◽  
Paul B. Watkins
Keyword(s):  
Gender Differences ◽  
Growth Hormone ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Treatment Protocol ◽  
Metabolic Effects ◽  
Gh Secretion ◽  
Igf I ◽  
Daily Dose ◽  
Igfbp 3

The importance of gender-specific growth hormone (GH) secretion pattern in the regulation of growth and metabolism has been demonstrated clearly in rodents. We recently showed that GH secretion in humans is also sexually dimorphic. Whether GH secretion pattern regulates the metabolic effects of GH in humans is largely unknown. To address this question, we administered the same daily intravenous dose of GH (0.5 mg · m−2 · day−1) for 8 days in different patterns to nine GH-deficient adults. Each subject was studied on four occasions: protocol 1 (no treatment), protocol 2 (80% daily dose at 0100 and 10% daily dose at 0900 and 1700), protocol 3 (8 equal boluses every 3 h), and protocol 4 (continuous GH infusion). The effects of GH pattern on serum IGF-I, IGF-binding protein (IGFBP)-3, osteocalcin, and urine deoxypyridinoline were measured. Hepatic CYP1A2 and CYP3A4 activities were assessed by the caffeine and erythromycin breath tests, respectively. Protocols 3 and 4 were the most effective in increasing serum IGF-I and IGFBP-3, whereas protocols administering pulsatile GH had the greatest effects on markers of bone formation and resorption. All GH treatments decreased CYP1A2 activity, and the effect was greatest for pulsatile GH. Pulsatile GH decreased, whereas continuous GH infusion increased, CYP3A4 activity. These data demonstrate that GH pulse pattern is an independent parameter of GH action in humans. Gender differences in drug metabolism and, potentially, gender differences in growth rate may be explained by sex-specific GH secretion patterns.

Restoration of juvenile baseline growth hormone secretion with preservation of the ultradian growth hormone rhythm by continuous delivery of growth hormone-releasing factor

1992 ◽  
Vol 135 (2) ◽  
pp. 371-382 ◽  
Author(s):  
R. Vasilatos-Younken ◽  
P. H. Tsao ◽  
D. N. Foster ◽  
D. L. Smiley ◽  
H. Bryant ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Weight ◽  
Bone Growth ◽  
Hormone Secretion ◽  
Plasma Concentrations ◽  
Growth Hormone Secretion ◽  
High Dose ◽  
Mrna Levels ◽  
Epiphyseal Growth Plate ◽  
Gh Secretion

ABSTRACT The ability of continuously delivered GH-releasing factor (GRF) to enhance GH secretion while maintaining the normal ultradian GH rhythm was investigated. Synthetic human GH-releasing factor (hGRF(1–44)NH2) was continuously infused for 4 days by means of i.v. catheters to 11-week-old broiler chickens. At this age, overall endogenous GH secretion is low, and baseline GH is barely detectable. Six birds per treatment received vehicle (control), 0·324 mg hGRF(1–44)NH2/kg body weight per day (low dose) or 3·24 mg hGRF(1–44)NH2/kg body weight per day (high dose). After 4 days of GRF conditioning, concurrent with continued GRF infusion, serial blood samples were removed via atrial catheters at 15-min intervals for 6 h and GH plasma profiles determined. High dose GRF significantly increased GH plasma concentrations over tenfold compared with controls; however, most of this increase reflected an increase in basal GH, which was reinstated to juvenile baseline levels. Augmentation of pulse amplitude above this increased baseline was not proportionately as high, and failed to reach juvenile levels. The ultradian rhythm of GH was not altered by continuous GRF administration. Both low and high dose GRF treatments resulted in significant enlargement of the anterior pituitary gland. Total pituitary GH mRNA levels, although elevated over twofold by GRF treatment, were not significantly different from controls. Measures of plasma GH magnitude (overall and baseline mean, and peak amplitude) were significantly correlated with pituitary GH mRNA for control birds, but were not correlated for GRF treatments. Feed intake was markedly depressed (33%) on the high dose GRF treatment, in conjunction with total inhibition of body weight gain over the 4-day period of administration. Longitudinal bone growth and width of the epiphyseal growth plate were also significantly reduced by high dose GRF treatment, probably reflecting the reduced level of nutrient intake, despite high circulating concentrations of GH. Journal of Endocrinology (1992) 135, 371–382

scholarly journals Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

2021 ◽  
pp. 1-24
Author(s):  
Jan M. Wit ◽  
Sjoerd D. Joustra ◽  
Monique Losekoot ◽  
Hermine A. van Duyvenvoorde ◽  
Christiaan de Bruin
Keyword(s):  
Growth Hormone ◽  
Differential Diagnosis ◽  
Growth Hormone Secretion ◽  
Normal Growth ◽  
Stimulation Test ◽  
Healthy Children ◽  
Genetic Causes ◽  
Gh Secretion ◽  
Igf I

The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of <i>GH1</i> or <i>GHSR</i>) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to <i>GH1</i> variants) but less on the role of <i>GHSR</i> variants. Several genetic causes of (partial) GHI are known (<i>GHR</i>, <i>STAT5B</i>, <i>STAT3</i>, <i>IGF1</i>, <i>IGFALS</i> defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.

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