Sepsis-induced muscle growth hormone resistance occurs independently of STAT5 phosphorylation

2003 ◽  
Vol 285 (1) ◽  
pp. E63-E72 ◽  
Author(s):  
Ly Q. Hong-Brown ◽  
C. Randell Brown ◽  
Robert N. Cooney ◽  
Robert A. Frost ◽  
Charles H. Lang
Keyword(s):  
Growth Hormone ◽  
Muscle Growth ◽  
Cecal Ligation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Experimental Conditions ◽  
Igf I ◽  
Mrna Content ◽  
Socs Proteins ◽  
Gh Resistance

Growth hormone (GH) stimulates insulin-like growth factor I (IGF-I) synthesis in both liver and muscle. During sepsis, proinflammatory cytokines inhibit GH action in liver, but it is unknown whether sepsis also produces GH resistance in muscle. Sepsis was induced by cecal ligation and puncture, and 18 h later the effect of GH on signal transducer and activator of transcription (STAT) phosphorylation and IGF-I mRNA content was assessed in rat gastrocnemius and liver. The relative abundance of phosphorylated (p)STAT5a, pSTAT5b, pSTAT3, and pSTAT1 was increased in liver from control rats after GH. Sepsis alone also increased hepatic pSTAT5a, pSTAT3, and pSTAT1. Sepsis dramatically impaired the ability of GH to stimulate the phosphorylation of STAT5a and -5b, as well as to increase IGF-I mRNA in liver. In muscle from control rats, GH increased pSTAT5a and -5b, whereas content of pSTAT3 and pSTAT1 was not affected. Sepsis increased basal content of pSTAT3 but not pSTAT5a, pSTAT5b, or pSTAT1 in muscle. The GH-induced increase of pSTAT5a and -5b in muscle from septic rats was not inhibited, suggesting that muscle was not GH resistant. In contrast to these changes in pSTAT5, the ability of GH to increase IGF-I mRNA was completely absent in muscle from septic rats. Because the suppressor of cytokine signaling (SOCS) proteins may function as negative regulators of GH signaling, we examined the content of these proteins. Sepsis produced small (30–50%), albeit statistically significant, increases in SOCS-1, -2, and -3 protein in muscle. In contrast to muscle, the SOCS proteins in the liver did not change under the various experimental conditions, suggesting that these proteins are not responsible for the impaired phosphorylation of STAT5 by GH. In conclusion, sepsis produces GH resistance in both muscle and liver, with the locus of this impairment in muscle differing from that in liver and being independent of a defect in STAT5 phosphorylation.

scholarly journals Distinct mechanisms of induction of hepatic growth hormone resistance by endogenous IL-6, TNF-α, and IL-1β

2014 ◽  
Vol 307 (2) ◽  
pp. E186-E198 ◽  
Author(s):  
Yueshui Zhao ◽  
Xiaoqiu Xiao ◽  
Stuart J. Frank ◽  
Herbert Y. Lin ◽  
Yin Xia
Keyword(s):  
Growth Hormone ◽  
Target Gene ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Gh Receptor ◽  
Tnf Α ◽  
Igf I ◽  
Socs3 Expression ◽  
Gh Resistance

During inflammation, the liver becomes resistant to growth hormone (GH) actions, leading to downregulation of the GH target gene IGF-I and activation of catabolism. Proinflammatory cytokines IL-6, TNF-α, and IL-1β are critically involved in the pathogenesis of hepatic GH resistance. However, the mechanisms used by endogenous IL-6, TNF-α, and IL-1β to inhibit the hepatic GH-IGF-I pathway during inflammation are not fully understood. Here, we show that TNF-α and IL-1β inhibited GH receptor (GHR) expression but had minor effects on the downstream suppressor of cytokine signaling (SOCS)3, while IL-6 induced SOCS3 expression but had no effect on GHR expression in Huh-7 cells. Consistent with the in vitro observations, neutralization of TNF-α and IL-1β in mouse models of inflammation did not significantly alter SOCS3 expression stimulated by inflammation but restored GHR and IGF-I expression suppressed by inflammation. Neutralization of IL-6 did not alter inflammation-suppressed GHR expression but drastically reduced the inflammation-stimulated SOCS3 expression and restored IGF-I expression. Interestingly, when the GH-IGF-I pathway was turned off by maximal inhibition of GHR expression, IL-6 and SOCS3 were no longer able to regulate IGF-I expression. Taken together, our results suggest that TNF-α/IL-1β and IL-6 use distinct mechanisms to induce hepatic GH resistance, with TNF-α and IL-1β acting primarily on GHR and IL-6 acting primarily on SOCS3. IL-6 action may be superseded by factors such as TNF-α and IL-1β that inhibit GHR expression.

Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

2016 ◽  
Vol 26 (1) ◽  
Author(s):  
Amira Alkharusi ◽  
Mercedes Mirecki-Garrido ◽  
Zuheng Ma ◽  
Fahad Zadjali ◽  
Amilcar Flores-Morales ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Type I ◽  
Suppressor Of Cytokine Signaling ◽  
Β Cell ◽  
Diabetes In Mice ◽  
Socs Proteins ◽  
Stat Pathway

AbstractDiabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity.The elevated sensitivity of SOCS2We show that 6-month-old SOCS2Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.

IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1

2004 ◽  
Vol 287 (4) ◽  
pp. E591-E601 ◽  
Author(s):  
Jennifer M. Sacheck ◽  
Akira Ohtsuka ◽  
S. Christine McLary ◽  
Alfred L. Goldberg
Keyword(s):  
Protein Degradation ◽  
Muscle Atrophy ◽  
Muscle Growth ◽  
Ring Finger ◽  
Ubiquitin Ligases ◽  
Growth Stimulation ◽  
Akt Pathway ◽  
Myofibrillar Proteins ◽  
Igf I ◽  
Mrna Content

Muscle atrophy results primarily from accelerated protein degradation and is associated with increased expression of two muscle-specific ubiquitin ligases (E3s): atrogin-1 and muscle ring finger 1 (MuRF1). Glucocorticoids are essential for many types of muscle atrophy, and their effects are opposite to those of insulin-like growth factor I (IGF-I) and insulin, which promote growth. In myotubes, dexamethasone (Dex) inhibited growth and enhanced breakdown of long-lived cell proteins, especially myofibrillar proteins (as measured by 3-methylhistidine release), while also increasing atrogin-1 and MuRF1 mRNA. Conversely, IGF-I suppressed protein degradation and prevented the Dex-induced increase in proteolysis. IGF-I rapidly reduced atrogin-1 expression within 1 h by blocking mRNA synthesis without affecting mRNA degradation, whereas IGF-I decreased MuRF1 mRNA slowly. IGF-I and insulin also blocked Dex induction of these E3s and several other atrophy-related genes (“atrogenes”). Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA. IGF-I activates the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, and inhibition of this pathway [but not the calcineurin-nuclear factor of activated T cell (NFAT) or the MEK-ERK pathway] increased proteolysis and atrogin-1 mRNA expression. Thus an important component of growth stimulation by IGF-I, through the PI3K-Akt pathway, is its ability to rapidly suppress transcription of the atrophy-related E3 atrogin-1 and other atrogenes and degradation of myofibrillar proteins.

scholarly journals CXCR4-mediated Suppressor of Cytokine Signaling Up-regulation Inactivates Growth Hormone Function

2004 ◽  
Vol 279 (43) ◽  
pp. 44460-44466 ◽  
Author(s):  
Ruth Garzón ◽  
Silvia F. Soriano ◽  
José Miguel Rodríguez-Frade ◽  
Lucio Gómez ◽  
Ana Martín de Ana ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling

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 Liver X receptor agonist downregulates growth hormone signaling in the liver

2011 ◽  
Vol 8 (2) ◽  
Author(s):  
Fahad Zadjali ◽  
Ruyman Santana-Farre ◽  
Mercedes Mirecki-Garrido ◽  
Ewa Ellis ◽  
Gunnar Norstedt ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hepatic Steatosis ◽  
Hepatic Metabolism ◽  
Liver X Receptor ◽  
Cytokine Signaling ◽  
Hormone Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Lxr Agonists ◽  
Liver X Receptor Agonist ◽  
Gh Receptors

AbstractLiver X receptor (LXR) agonists have been shown to influence the development of hyperlipidemia and atherosclerosis in mouse models. It has also been demonstrated that some LXR agonists can cause hepatic steatosis in experimental animals. Growth hormone (GH) is known to regulate hepatic metabolism and the absence of hepatic GH receptors (GHR) leads to hepatic steatosis. In this study, we analyzed whether the actions of LXR agonists could involve interference with GH signaling. We showed that LXR agonists impair GH signaling in hepatocytes. LXR agonist treatment attenuated GH induction of suppressor of cytokine signaling 2 (

Induction of mRNA for IGF-I and -II during growth hormone-stimulated muscle hypertrophy

1988 ◽  
Vol 255 (4) ◽  
pp. E513-E517 ◽  
Author(s):  
J. D. Turner ◽  
P. Rotwein ◽  
J. Novakofski ◽  
P. J. Bechtel
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Growth Factors ◽  
Cardiac Muscle ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Gh3 Cells ◽  
Autocrine Factors ◽  
Igf I ◽  
Steady State Levels

The expression of insulin-like growth factor (IGF) genes during skeletal and cardiac muscle hypertrophy was examined using skeletal and cardiac muscle hypertrophy was examined using adult 5-mo-old female Wistar-Furth rats implanted with growth hormone-secreting GH3 cells. Control and treated animals were killed at 40, 60, and 80 days after initiation of the experiment. From the time of injection to day 80, body, heart, skeletal muscle, and liver weights increased 112, 93, 55, and 314%, respectively. RNA was extracted and steady-state levels of IGF-I and IGF-II mRNAs were quantitated using a solution-hybridization nuclease-protection assay. Low levels of mRNA for both growth factors were detected in control tissues. By day 80 IGF-I mRNA had increased eightfold and IGF-II mRNA sixfold in skeletal muscle from treated rats. In cardiac muscle the levels of mRNA for both growth factors rose three- to fourfold. Although growth hormone induced an increase in hepatic IGF-I mRNA, IGF-II mRNA remained nearly undetectable. This study shows that during growth hormone-stimulated muscle growth mRNAs for both IGF-I and IGF-II accumulate, supporting other observations implicating the IGFs as paracrine or autocrine factors involved in skeletal muscle growth.

scholarly journals Growth Enhancement in Suppressor of Cytokine Signaling 2 (SOCS-2)-Deficient Mice Is Dependent on Signal Transducer and Activator of Transcription 5b (STAT5b)

2002 ◽  
Vol 16 (6) ◽  
pp. 1394-1406 ◽  
Author(s):  
Christopher J. Greenhalgh ◽  
Patrick Bertolino ◽  
Sylvia L. Asa ◽  
Donald Metcalf ◽  
Jason E. Corbin ◽  
...  
Keyword(s):  
Postnatal Growth ◽  
Cytokine Signaling ◽  
Growth Enhancement ◽  
Signal Transducer ◽  
Primary Hepatocytes ◽  
Suppressor Of Cytokine Signaling ◽  
Embryonic Fibroblasts ◽  
Adult Mice ◽  
Igf I ◽  
Deficient Mice

Abstract Mice lacking suppressor of cytokine signaling-2 (SOCS-2) exhibit accelerated postnatal growth resulting in adult mice that are 1.3 to 1.5 times the size of normal mice. In this study we examined the somatotrophic pathway to determine whether the production or actions of GH or IGF-I are altered in these mice. We demonstrated that SOCS-2−/− mice do not have elevated GH levels and suffer no major pituitary dysmorphogenesis, and that SOCS-2-deficient embryonic fibroblasts do not have altered IGF-I signaling. Primary hepatocytes from SOCS-2−/− mice, however, did have moderately prolonged signal transducer and activator of transcription 5 signaling in response to GH stimulation. Furthermore, the deletion of SOCS-2 from mice also lacking signal transducer and activator of transcription 5b had little effect on growth, suggesting that the action of SOCS-2 may be the regulation of the GH signaling pathway.

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