Endotoxin attenuates growth hormone-induced hepatic insulin-like growth factor I expression by inhibiting JAK2/STAT5 signal transduction and STAT5b DNA binding

2007 ◽  
Vol 292 (6) ◽  
pp. E1856-E1862 ◽  
Author(s):  
Yu Chen ◽  
Difei Sun ◽  
Vidya M. R. Krishnamurthy ◽  
Ralph Rabkin
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Janus Kinase ◽  
Cytokine Gene Expression ◽  
Cytokine Signaling ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Gram-negative sepsis with release of endotoxin is a frequent cause of cachexia that develops partly because of resistance to growth hormone (GH) with reduced insulin-like growth factor-I (IGF-I) expression. We set out to more fully characterize the mechanisms for the resistance and to determine whether in addition to a defect in the janus kinase 2 (JAK2)-signal transducer and activator of transcription (STAT) 5b pathway, required for GH-induced IGF-I expression, there might also be a more distal defect. Conscious rats were given endotoxin and studied 4 h later. In liver of these animals, GH-induced JAK2 and STAT5 phosphorylation was impaired and appeared to be caused, at least in part, by a marked increase in hepatic tumor necrosis factor-α and interleukin-6 mRNA expression accompanied by elevated levels of inhibitors of GH signaling, namely cytokine-inducible suppressors of cytokine signaling-1 and -3 and cytokine-inducible SH2 protein (CIS). Nuclear phosphorylated STAT5b levels were significantly depressed to 61% of the control values and represent a potential cause of the reduced GH-induced IGF-I expression. In addition, binding of phosphorylated STAT5b to DNA was reduced to an even greater extent and averaged 17% of the normal control value. This provides a further explanation for the impaired IGF-I gene transcription. Interestingly, when endotoxin-treated rats were treated with GH, there was a marked increase in proinflammatory cytokine gene expression in the liver. If such a response were to occur in humans, this might provide a partial explanation for the adverse effect of GH treatment reported in critically ill patients.

scholarly journals Effects of Short-Term Insulin-Like Growth Factor-I (IGF-I) or Growth Hormone (GH) Treatment on Bone Metabolism and on Production of 1,25-Dihydroxycholecalciferol in GH-Deficient Adults1

1998 ◽  
Vol 83 (1) ◽  
pp. 81-87 ◽  
Author(s):  
Tarcisio Bianda ◽  
Yvonne Glatz ◽  
Roger Bouillon ◽  
Ernst Rudolf Froesch ◽  
Christoph Schmid
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Bone Formation ◽  
Bone Turnover ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Administration of insulin-like growth factor-I (IGF-I) or growth hormone (GH) is known to stimulate bone turnover and kidney function. To investigate the effects of IGF-I and GH on markers of bone turnover, eight adult GH-deficient patients (48 ± 14 yr of age) were treated with IGF-I (5 μg/kg/h in a continuous sc infusion) and GH (0.03 IU/kg/daily sc injection at 2000 h) in a randomized cross-over study. We monitored baseline values for three consecutive days before initiating the five-day treatment period, as well as the wash-out period of ten weeks. Serum osteocalcin, carboxyterminal and aminoterminal propeptide of type I procollagen (PICP and PINP, respectively) increased significantly within 2–3 days of both treatments (P < 0.02) and returned to baseline levels within one week after the treatment end. The changes in resorption markers were less marked as compared with formation markers. Total 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) rose significantly, whereas PTH and calcium levels remained unchanged during either treatment. Conclusions: Because the rapid increase in markers of bone formation was not preceded by an increase in resorption markers, IGF-I is likely to stimulate bone formation by a direct effect on osteoblasts. Moreover, because PTH, calcium, and phosphate remained unchanged, IGF-I appears to stimulate renal 1α-hydroxylase activity in vivo.

scholarly journals Aspects of Growth Hormone and Insulin-Like Growth Factor-I Related to Neuroprotection, Regeneration, and Functional Plasticity in the Adult Brain

2006 ◽  
Vol 6 ◽  
pp. 53-80 ◽  
Author(s):  
N. David Åberg ◽  
Katarina Gustafson Brywe ◽  
Jörgen Isgaard
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Signaling Pathway ◽  
Cell Types ◽  
Adult Brain ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-I–stimulated proliferationin vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging.Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-Iin vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.

Alterations of growth plate and abnormal insulin-like growth factor I metabolism in growth-retarded hypokalemic rats: effect of growth hormone treatment

2009 ◽  
Vol 297 (3) ◽  
pp. F639-F645 ◽  
Author(s):  
Helena Gil-Peña ◽  
Enrique Garcia-Lopez ◽  
Oscar Alvarez-Garcia ◽  
Vanessa Loredo ◽  
Eduardo Carbajo-Perez ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Mrna Expression ◽  
Growth Plate ◽  
Female Rats ◽  
Insulin Like Growth Factor ◽  
Gh Treatment ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Hypokalemic tubular disorders may lead to growth retardation which is resistant to growth hormone (GH) treatment. The mechanism of these alterations is unknown. Weaning female rats were grouped ( n = 10) in control, potassium-depleted (KD), KD treated with intraperitoneal GH at 3.3 mg·kg−1·day−1 during the last week (KDGH), and control pair-fed with KD (CPF). After 2 wk, KD rats were growth retarded compared with CPF rats, the osseous front advance (±SD) being 67.07 ± 10.44 and 81.56 ± 12.70 μm/day, respectively. GH treatment did not accelerate growth rate. The tibial growth plate of KD rats had marked morphological alterations: lower heights of growth cartilage (228.26 ± 23.58 μm), hypertrophic zone (123.68 ± 13.49 μm), and terminal chondrocytes (20.8 ± 2.39 μm) than normokalemic CPF (264.21 ± 21.77, 153.18 ± 15.80, and 24.21 ± 5.86 μm). GH administration normalized these changes except for the distal chondrocyte height. Quantitative PCR of insulin-like growth factor I (IGF-I), IGF-I receptor, and GH receptor genes in KD growth plates showed downregulation of IGF-I and upregulation of IGF-I receptor mRNAs, without changes in their distribution as analyzed by immunohistochemistry and in situ hybridization. GH did not further modify IGF-I mRNA expression. KD rats had normal hepatic IGF-I mRNA levels and low serum IGF-I values. GH increased liver IGF-I mRNA, but circulating IGF-I levels remained reduced. This study discloses the structural and molecular alterations induced by potassium depletion on the growth plate and shows that the lack of response to GH administration is associated with persistence of the disturbed process of chondrocyte hypertrophy and depressed mRNA expression of local IGF-I in the growth plate.

Effect of insulin-like growth factor I and/or growth hormone on diaphragm of malnourished adolescent rats

1997 ◽  
Vol 82 (4) ◽  
pp. 1064-1070 ◽  
Author(s):  
Michael I. Lewis ◽  
Thomas J. Lorusso ◽  
Mario Fournier
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Fiber Type ◽  
Fatigue Properties ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Fiber Size ◽  
Igf I ◽  
Adolescent Rats ◽  
Growth Factor I

Lewis, Michael I., Thomas J. LoRusso, and Mario Fournier.Effect of insulin-like growth factor I and/or growth hormone on diaphragm of malnourished adolescent rats. J. Appl. Physiol. 82(4): 1064–1070, 1997.—Young growing animals appear to have significantly reduced “nutritional reserve” to short periods of unstressed starvation compared with adults, with resultant growth arrest and/or atrophy of diaphragm (Dia) muscle fibers. The aim of this study was to assess in an adolescent rat model of acute nutritional deprivation (ND; 72 h) the impact of insulin-like growth factor I (IGF-I), with or without added growth hormone (GH), on the cross-sectional areas (CSA) of individual Dia muscle fibers. Five groups were studied: 1) control (Ctr); 2) ND; 3) ND given IGF-I (ND/IGF-I); 4) ND given GH (ND/GH); and 5) ND given a combination of IGF-I and GH (ND/IGF-I/GH). IGF-I was given by a subcutaneously implanted osmotic minipump (200 μg/day), whereas GH was administered twice daily by a subcutaneous injection (250 μg every 12 h). Isometric contractile and fatigue properties of the Dia were determined in vitro. Forces were normalized for muscle CSA (i.e., specific force). Dia fiber type proportions were determined histochemically, and fiber CSA was quantified by using a computer-based image-processing system. Total serum IGF-I concentrations were significantly reduced in ND and ND/GH animals, compared with Ctr, and elevated in the groups receiving IGF-I. The provision of growth factors did not alter the contractile or fatigue properties of ND animals. Dia fiber type proportions were similar among the groups. In ND animals, there was a significant reduction in the CSA of types I, IIa, IIx, and IIc Dia fibers compared with Ctr. The administration of IGF-I alone or in combination with GH to ND animals significantly diminished the reduction in Dia fiber size. GH alone had no effect on Dia fiber size in ND animals. We conclude that with acute ND the peripheral resistance to the action of GH appears to be bypassed by the administration of IGF-I alone or in combination with GH.

Sign in / Sign up

Export Citation Format

Share Document