scholarly journals Suppressor of Cytokine Signaling-3 (SOCS-3), a Potential Mediator of Interleukin-6-dependent Insulin Resistance in Hepatocytes

2003 ◽  
Vol 278 (16) ◽  
pp. 13740-13746 ◽  
Author(s):  
Joseph J. Senn ◽  
Peter J. Klover ◽  
Irena A. Nowak ◽  
Teresa A. Zimmers ◽  
Leonidas G. Koniaris ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Interleukin 6 ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Potential Mediator

scholarly journals HIV-protease inhibitors induce expression of suppressor of cytokine signaling-1 in insulin-sensitive tissues and promote insulin resistance and type 2 diabetes mellitus

2008 ◽  
Vol 294 (3) ◽  
pp. E558-E567 ◽  
Author(s):  
Michael J. Carper ◽  
W. Todd Cade ◽  
Margaret Cam ◽  
Sheng Zhang ◽  
Anath Shalev ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Protease Inhibitors ◽  
Hiv Protease ◽  
Signaling Cascade ◽  
Cytokine Signaling ◽  
Hiv Protease Inhibitors ◽  
Suppressor Of Cytokine Signaling ◽  
Zdf Rats

Insulin resistance, hyperglycemia, and type 2 diabetes are among the sequelae of metabolic syndromes that occur in 60–80% of human immunodeficiency virus (HIV)-positive patients treated with HIV-protease inhibitors (PIs). Studies to elucidate the molecular mechanism(s) contributing to these changes, however, have mainly focused on acute, in vitro actions of PIs. Here, we examined the chronic (7 wk) in vivo effects of the PI indinavir (IDV) in male Zucker diabetic fatty ( fa/fa) (ZDF) rats. IDV exposure accelerated the diabetic state and dramatically exacerbated hyperglycemia and oral glucose intolerance in the ZDF rats, compared with vehicle-treated ZDF rats. Oligonucleotide gene array analyses revealed upregulation of suppressor of cytokine signaling-1 (SOCS-1) expression in insulin-sensitive tissues of IDV rats. SOCS-1 is a known inducer of insulin resistance and diabetes, and immunoblotting analyses revealed increases in SOCS-1 protein expression in adipose, skeletal muscle, and liver tissues of IDV-administered ZDF rats. This was associated with increases in the upstream regulator TNF-α and downstream effector sterol regulatory element-binding protein-1 and a decrease in IRS-2. IDV and other PIs currently in clinical use induced the SOCS-1 signaling cascade also in L6 myotubes and 3T3-L1 adipocytes exposed acutely to PIs under normal culturing conditions and in tissues from Zucker wild-type lean control rats administered PIs for 3 wk, suggesting an effect of these drugs even in the absence of background hyperglycemia/hyperlipidemia. Our findings therefore indicate that induction of the SOCS-1 signaling cascade by PIs could be an important contributing factor in the development of metabolic dysregulation associated with long-term exposures to HIV-PIs.

scholarly journals Isoproterenol is a positive regulator of the suppressor of cytokine signaling-3 gene expression in 3T3-L1 adipocytes

2002 ◽  
Vol 175 (3) ◽  
pp. 727-733 ◽  
Author(s):  
M Fasshauer ◽  
J Klein ◽  
U Lossner ◽  
R Paschke
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Mrna Expression ◽  
Adenylyl Cyclase ◽  
Insulin Signaling ◽  
Tnf Alpha ◽  
Cytokine Signaling ◽  
Dependent Manner ◽  
Suppressor Of Cytokine Signaling ◽  
Beta Adrenergic

SOCS (suppressor of cytokine signaling)-3 has recently been shown to be an insulin- and tumor necrosis factor (TNF)-alpha-induced negative regulator of insulin signaling. To further clarify a potential involvement of SOCS-3 in the development of insulin resistance, we measured differentiation-dependent SOCS-3 mRNA expression in 3T3-L1 adipocytes and studied its regulation by various hormones known to impair insulin signaling using quantitative real-time RT-PCR. There was a differentiation-dependent downregulation of SOCS-3 mRNA by 50% over the 9 day adipocyte differentiation course. Interestingly, besides insulin and TNF-alpha, chronic treatment of differentiated 3T3-L1 cells with 10 microM isoproterenol for 16 h stimulated SOCS-3 gene expression by about 3.5-fold. Furthermore, isoproterenol stimulated SOCS-3 mRNA expression in a dose-dependent manner with significant activation detectable at concentrations as low as 10 nM isoproterenol. Moreover, a strong 27- and 47-fold activation of SOCS-3 mRNA expression could be seen after 1 h of isoproterenol and GH treatment respectively. The stimulatory effect of isoproterenol could be almost completely reversed by pretreatment of 3T3-L1 cells with the beta-adrenergic antagonist propranolol. Finally, isoproterenol's action could be mimicked by stimulation of G(S)-proteins with cholera toxin and of adenylyl cyclase with forskolin and dibutyryl cAMP. Taken together, our results demonstrate a differentiation-dependent downregulation of SOCS-3 in adipocytes and suggest that SOCS-3 gene expression is stimulated by beta-adrenergic agents via activation of a G(S)-protein-adenylyl cyclase-dependent pathway. As SOCS-3 is a novel inhibitor of insulin signaling, the data support a possible role of this protein as a selectively regulated mediator of catecholamine-induced insulin resistance.

scholarly journals Interleukin-6 deficiency modulates testicular function by increasing the expression of suppressor of cytokine signaling 3 (SOCS3) in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thaís Alves-Silva ◽  
Geanne Arantes Freitas ◽  
Talita Guerreiro Rodrigues Húngaro ◽  
Adriano Cleis Arruda ◽  
Lila Missae Oyama ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Reproductive Tract ◽  
Physiological Role ◽  
Cytokine Signaling ◽  
Sperm Production ◽  
Suppressor Of Cytokine Signaling ◽  
Male Reproductive Tract ◽  
The Impact ◽  
Daily Sperm Production

AbstractSeveral cytokines have been reported to participate in spermatogenesis, including interleukin-6 (IL6). However, not many studies have been conducted on the loss of Il6 on the male reproductive tract. Nonetheless, there is considerable knowledge regarding the pathological and physiological role of IL6 on spermatogenesis. In this way, this study evaluated the impact of Il6 deficiency on mice testicles in the absence of infection or inflammation. We showed that Il6 deficiency increases daily sperm production, the number of spermatids, and the testicular testosterone and dihydrotestosterone levels. Besides that, mice with a deleted Il6 (IL6KO) showed increased testicular SOCS3 levels, with no changes in pJAK/JAK and pSTAT3/STAT3 ratios. It is worth noting that the aforementioned pathway is not the only pathway to up-regulate SOCS3, nor is it the only SOCS3 target, thus proposing that the increase of SOCS3 in the testis occurs independently of the JAK-STAT signaling in IL6KO mice. Therefore, we suggest that the lack of Il6 drives androgenic production by increasing SOCS3 in the testis, thus leading to an increase in spermatogenesis.

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