scholarly journals Effect of Growth Hormone and Calorie Restriction on the Expression of Antioxidant Enzymes in the Liver and Kidney of Growth Hormone Receptor Knockout Mice

2017 ◽  
Vol 2 (2) ◽  
pp. 136-141
Author(s):  
Khalid A Al-Regaiey
Keyword(s):  
Growth Hormone ◽  
Antioxidant Enzymes ◽  
Defense Mechanisms ◽  
Growth Hormone Receptor ◽  
Oxidative Stress Marker ◽  
Gh Receptor ◽  
Liver And Kidney ◽  
Ad Libitum ◽  
Gpx Activity ◽  
Gh Resistance

Caloric restriction (CR) can delay aging and prolong life span and these actions may be related to reduced oxidative damage. Mice with disrupted growth hormone (GH) receptor/binding protein knockout (GHRKO) live significantly longer than their normal siblings. Therefore, it is of interest to examine the effects of chronic CR on hepatic and renal antioxidant enzymes as well as lipid peroxidation (LP) as an oxidative stress marker in GHRKO mice. Female GHRKO and normal mice were either fed ad libitum (AL) or subjected to 30% CR starting at 2 months of age and examined at the age of 9 months. In the liver, catalase (CAT) activity was significantly increased in GHRKO-AL as compared to normal control -AL animals. CR reduced CAT activity in both GHRKO and normal phenotypes. Cu/Zn superoxide dismutase (SOD1) activity was also higher in GHRKO-AL as compared to normal-AL mice. However, CR reduced SOD1 activity in GHRKO mutants. Glutathione peroxidase (GPx) activity was significantly decreased in GHRKO-AL mice and further reduced in GHRKO-CR group of animals. CR significantly increased LP in GHRKOs while its activity was not altered in GHRKO-AL group of mice. In the kidney, CAT activity was lower in GHRKO-AL as compared to normal-AL, however CR did not induce any significant effect in both phenotypes. Similarly, SOD1 levels were significantly lower in GHRKO than in normal mice. GPx expression was higher in GHRKO-AL as compared to control-AL. CR reduced GPx activity in GHRKO mice but increased it in controls as compared to their AL counterparts. There was no difference in LP expression between GHRKO-AL and normal-AL mice. However, CR significantly increased its levels in both phenotypes. Although these findings do not support the hypothesis that CR would increase the capacity of ROS defense mechanisms in GHRKO mice by increasing antioxidant enzymes levels, they do agree with some of the reported effects of CR on their expression. We suspect that GH resistance and CR may affect aging by different mechanisms and if CR delays aging in GHRKO animals it is not due to changes in the activity of antioxidant enzymes.

Alterations in growth hormone receptor abundance regulate growth hormone signaling in murine obstructive cholestasis

2005 ◽  
Vol 288 (5) ◽  
pp. G986-G993 ◽  
Author(s):  
Matthew A. Held ◽  
Wilfredo Cosme-Blanco ◽  
Lisa M. Difedele ◽  
Erin L. Bonkowski ◽  
Ram K. Menon ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Fat Free Mass ◽  
Cholestatic Liver Disease ◽  
Duct Ligation ◽  
Obstructive Cholestasis ◽  
Igf I ◽  
Ad Libitum ◽  
Gh Resistance

Children with cholestatic liver diseases, in particular biliary atresia, may develop an acquired growth hormone (GH) resistance. This is characterized by normal GH secretion, reduced liver GH receptor (GHR) abundance, and reduced circulating insulin-like growth factor I (IGF-I). Consequences include linear growth failure, reduced muscle mass, and increased perioperative morbidity and mortality. However, the molecular basis for altered GH signaling in liver and skeletal muscle in cholestatic liver disease is not known. We hypothesized that reduced IGF-I expression in obstructive cholestasis would be associated with downregulation of the GHR and impaired phosphorylation of signal transducers and activators of transcription (STAT5). Body composition was determined in C57BL/6J male mice after bile duct ligation (BDL) relative to pair-fed (PF) and ad libitum-fed controls. GHR, STAT5, Sp3, and IGF-I expression and/or DNA binding were assessed using immunoblots, electrophoretic mobility shift assays, and/or real time RT-PCR. Fat-free mass was reduced in PF mice relative to ad libitum-fed controls. BDL led to a further reduction in fat mass and fat-free mass relative to PF controls. TNF-α was increased in liver and skeletal muscle of BDL mice. This was associated with reduced GH-dependent STAT5 activation and IGF-I RNA expression. GHR expression was reduced in BDL mice; in liver, this was associated with reduced Sp3 binding to a GHR gene promoter cis element. Wasting in murine obstructive cholestasis is due to combined effects of reduced caloric intake and biliary obstruction. GH resistance due to downregulation of GHR expression may be attributed primarily to the obstructive cholestasis; therapies that specifically increase GHR expression may restore GH signaling in this setting.

scholarly journals The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

1998 ◽  
Vol 21 (1) ◽  
pp. 61-72 ◽  
Author(s):  
N Esposito ◽  
J Wojcik ◽  
J Chomilier ◽  
JF Martini ◽  
PA Kelly ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Human Growth ◽  
Receptor Protein ◽  
Wild Type ◽  
Gh Receptor ◽  
293 Cells ◽  
Expression And Activity ◽  
Gh Resistance

In two patients with growth hormone (GH) insensitivity syndrome (Laron syndrome), in whom the GH receptor is able to bind the hormone, the D152H mutation was identified, and lack of dimerization was proposed to explain GH resistance in these patients. To examine further the consequences of the substitution of conserved aspartate 152 on the function of the GH receptor (GHR), we reproduced the mutation in vitro on the full length GH receptor cDNA from man and rat. Effects of the mutation on expression and activity of the GHR were analyzed in 293 cells transfected with wild-type and mutant GHR cDNAs. Mutant human receptor protein was expressed at a lower level than wild-type receptor and its activity was reduced: GH-dependent signal transducer and activator of transcription 5 (Stat5)-mediated transactivation of a reporter gene was lower in 293 cells transfected with mutant GHR cDNA than in transfected cells expressing a comparable level of wild-type GHR. The membrane-bound form of the mutant and of the wild-type human GHR were able to homodimerize, as suggested by the size of the complexes detected in cross-linking experiments with 125I-human (h) GH, and also by the activity in the functional test. With the soluble GHR resulting from proteolysis of the wild-type membrane form, no dimeric complexes could be detected. However, when a soluble receptor lacking the transmembrane and cytoplasmic domains of the receptor was expressed, wild-type and not mutant GH binding protein (GHBP) was able to form dimers in the presence of hGH. The amino acid substitution has no effect on either expression or function of the rat receptor. Structural modeling of D152H soluble human and rat GHR (GHBP) supports the species-specific functional consequences of the mutation. Evaluation of the functional importance of the mutation strongly suggests that impairment in expression and activity of the mutant receptor, rather than complete lack of dimerization, explains the GH resistance of the patients.

The interrelationship between and the regulation of hepatic growth hormone receptors and circulating GH binding protein in the pig

1992 ◽  
Vol 126 (2) ◽  
pp. 155-161 ◽  
Author(s):  
Geoffrey R Ambler ◽  
Bernhard H Breier ◽  
Andrzej Surus ◽  
Hugh T Blair ◽  
Stuart N McCutcheon ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Hormone Receptor ◽  
Hormone Receptors ◽  
Binding Capacity ◽  
Binding Protein ◽  
Somatic Growth ◽  
Gh Receptor ◽  
Age Related ◽  
Igf I ◽  
Serum Gh

We evaluated the interrelationship between, and regulation of, the hepatic growth hormone receptor and serum GH binding protein (GH BP) in pigs treated with recombinant porcine growth hormone (rpGH). Infant and pubertal male pigs (N = 5 per group) received either rpGH 0.15 mg/kg daily or diluent intramuscularly for 12 days. Somatic growth, serum IGF-I and GH BP and [125I]bovine GH (bGH) binding to MgCl2-treated hepatic membrane homogenates were examined. Marked age-related increases were seen in serum GH BP (p<0.001) and [125I]bGH binding to hepatic membranes (p<0.001). GH BP was increased in rpGH treated animals (p = 0.03), from 13.8±1.2 (mean±1 x sem) (controls) to 17.8±2.0% in infants, and from 35.2±2.6 (controls) to 41.8±3.4% in pubertal animals. [125I]bGH binding to hepatic membranes was also increased by rpGH treatment (p<0.05), from 7.0±1.6 (controls) to 15.4±3.6% in infants and from 53.7±7.1 (controls) to 65.1±11.8% in pubertal animals. No significant interaction between age and treatment was seen. Overall, serum GH BP correlated significantly with [125I]bGH membrane capacity (r=0.82, p<0.001), with a correlation of r= 0.83 in the infant animals but no significant correlation in the pubertal animals considered alone (r=0.13). Serum IGF-I correlated significantly with serum GH BP (r=0.93, p<0.001) and [125]bGH membrane binding capacity (r = 0.91, p< 0.001). These observations suggest that serum GH BP levels reflect major changes of hepatic GH receptor status. In addition, the present study demonstrates that the hepatic GH receptor can be induced by GH in the infant pig, despite a developmentally low GH receptor population at this age, suggesting potential efficacy of GH at earlier ages than generally considered.

Mechanism of signaling by growth hormone receptor

1996 ◽  
Vol 76 (4) ◽  
pp. 1089-1107 ◽  
Author(s):  
L. S. Argetsinger ◽  
C. Carter-Su
Keyword(s):  
Growth Hormone ◽  
Protein Kinase ◽  
Growth Hormone Receptor ◽  
Second Messengers ◽  
Current Model ◽  
Mitogen Activated Protein Kinase ◽  
Gh Receptor ◽  
Insulin Receptor Substrates ◽  
Mitogen Activated Protein ◽  
Control Body

Growth hormone (GH) has long been known to stimulate linear growth and regulate metabolism. The cellular mechanism by which GH elicits these effects has only recently begun to be understood. This review provides an overview of a current model of GH signaling. Briefly, binding of GH to GH receptor induces receptor dimerization and activation of the tyrosine kinase JAK2. Tyrosyl phosphorylation of GH receptor and JAK2 recruits and activates signaling molecules such as Stat transcription factors, SHC, and insulin receptor substrates 1 and 2 that lead to the release of second messengers such as diacylglycerol, calcium, and nitric oxide and the activation of enzymes such as mitogen-activated protein kinase, protein kinase C, phospholipase A2, and phosphatidylinositol 3'-kinase. These pathways regulate cellular function including gene transcription, metabolite transport, and enzymatic activity that result in the ability of GH to control body growth and metabolism.

scholarly journals Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

2000 ◽  
Vol 167 (2) ◽  
pp. 295-303 ◽  
Author(s):  
JW van Neck ◽  
NF Dits ◽  
V Cingel ◽  
IA Hoppenbrouwers ◽  
SL Drop ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Binding Protein ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Gh Receptor ◽  
Igf I ◽  
Igfbp 3

The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1.25, 2.5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2.5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups. In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

Growth Hormone Receptor Antagonist Therapy in Acromegalic Patients Resistant to Somatostatin Analogs*

2000 ◽  
Vol 85 (8) ◽  
pp. 2958-2961 ◽  
Author(s):  
Vivien S. Herman-Bonert ◽  
Kenneth Zib ◽  
John A. Scarlett ◽  
Shlomo Melmed
Keyword(s):  
Growth Hormone ◽  
Receptor Antagonist ◽  
Growth Hormone Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Growth Hormone Secretion ◽  
Primary Therapy ◽  
Gh Receptor ◽  
Gh Receptor Antagonist ◽  
Octreotide Therapy

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant—three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10–20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.

scholarly journals The Effect of ZJXG Decoction on The Serum Level of Growth Hormone and The Expression of GH Receptor in Callus

2019 ◽  
Vol 12 ◽  
pp. 2320-2330
Author(s):  
Zhen Zhou ◽  
Guanxi Wang ◽  
Zhaogang Liu ◽  
Yunliang Guo
Keyword(s):  
Growth Hormone ◽  
Serum Level ◽  
Growth Hormone Receptor ◽  
Femur Fracture ◽  
Healing Process ◽  
Enzyme Linked Immunosorbent Assay ◽  
Middle Point ◽  
X Ray ◽  
Gh Receptor ◽  
Hematoxylin Eosin

The aim of experiment was to investigate the effects of Zhuangjin XuGu decoction (ZJXG decoction) on growth hormone (GH) serum and GH receptor (GHR) expression in callus. The femur fracture animal models were generated in 72 Wistar rats by cutting femur transversely at the middle point. The rats models were administered orally ZJXG decoction for 28 days. Anatomy, X-ray and hematoxylin- eosin (HE) staining were used to observe the healing process in rats. The expression of growth hormone receptor (GHR) in fibroblasts and osteoblasts in callus was evaluated by immunohistochemical assay (IHC). The serum level of GH was passed by enzyme linked immunosorbent assay (ELISA). Anatomy, X-ray and H-E staining indicated that the fibrous callus at the fracture-end increased and the fibrous granular tissue changed gradually to fibrous, cartilaginous and osseous callus. IHC and ELISA showed that after 28 days of ZJXG Decoction treatment, that GH in the fibroblasts and osteoblasts of callus and their serum level increased significantly. These results suggested that ZJXG decoction could enhance the fracture healing by enhancing GH activity and promoting the expression of GHR in the fibroblasts and osteoblasts of callus in rats.

Interleukin-6 inhibits hepatic growth hormone signaling via upregulation of Cis and Socs-3

2003 ◽  
Vol 284 (4) ◽  
pp. G646-G654 ◽  
Author(s):  
Lee A. Denson ◽  
Matthew A. Held ◽  
Ram K. Menon ◽  
Stuart J. Frank ◽  
Albert F. Parlow ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Inflammatory Diseases ◽  
Cytokine Signaling ◽  
Hormone Signaling ◽  
Tnf Receptor ◽  
Gh Receptor ◽  
Ghr Gene ◽  
Tnf Α ◽  
Socs Protein ◽  
Gh Resistance

Cytokines may cause an acquired growth hormone (GH) resistance in patients with inflammatory diseases. Anabolic effects of GH are mediated through activation of STAT5 transcription factors. We have reported that TNF-α suppresses hepatic GH receptor (GHR) gene expression, whereas the cytokine-inducible SH2-containing protein 1 (Cis)/suppressors of cytokine signaling ( Socs) genes are upregulated by TNF-α and IL-6 and inhibit GH activation of STAT5. However, the relative importance of these mechanisms in inflammatory GH resistance was not known. We hypothesized that IL-6 would prevent GH activation of STAT5 and that this would involve Cis/Socs protein upregulation. GH ± LPS was administered to TNF receptor 1 (TNFR1) or IL-6 null mice and wild-type (WT) controls. STAT5, STAT3, GHR, Socs 1–3, and Cis phosphorylation and abundance were assessed by using immunoblots, EMSA, and/or real time RT-PCR. TNF-α and IL-6 abundance were assessed by using ELISA. GH activated STAT5 in WT and TNFR1 or IL-6 null mice. LPS pretreatment prevented STAT5 activation in WT and TNFR1 null mice; however, STAT5 activation was preserved in IL-6 null mice. GHR abundance did not change with LPS administration. Inhibition of STAT5 activation by LPS was temporally associated with phosphorylation of STAT3 and upregulation of Cis and Socs-3 protein in WT and TNFR1 null mice; STAT3, Cis, and Socs-3 were not induced in IL-6 null mice. IL-6 inhibits hepatic GH signaling by upregulating Cis and Socs-3, which may involve activation of STAT3. Therapies that block IL-6 may enhance GH signaling in inflammatory diseases.

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