scholarly journals Ghrelin Induces Leptin Resistance by Activation of Suppressor of Cytokine Signaling 3 Expression in Male Rats: Implications in Satiety Regulation

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3956-3969 ◽  
Author(s):  
Andrea Heldsinger ◽  
Gintautas Grabauskas ◽  
Xiaoyin Wu ◽  
ShiYi Zhou ◽  
Yuanxu Lu ◽  
...  
Keyword(s):  
Feeding Behavior ◽  
Neuronal Firing ◽  
Male Rats ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Inhibitory Effects ◽  
Suppressor Of Cytokine Signaling ◽  
Afferent Pathways ◽  
Stat3 Phosphorylation ◽  
Socs3 Expression

Abstract The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior.

scholarly journals Early Postnatal Hyperalimentation Impairs Renal Function via SOCS-3 Mediated Renal Postreceptor Leptin Resistance

Endocrinology ◽  
2012 ◽  
Vol 153 (3) ◽  
pp. 1397-1410 ◽  
Author(s):  
Miguel Angel Alejandre Alcazar ◽  
Eva Boehler ◽  
Eva Rother ◽  
Kerstin Amann ◽  
Christina Vohlen ◽  
...  
Keyword(s):  
Renal Function ◽  
Underlying Mechanism ◽  
Male Rats ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Control Male ◽  
Extracellular Matrix Molecules ◽  
And Function

Early postnatal hyperalimentation has long-term implications for obesity and developing renal disease. Suppressor of cytokine signaling (SOCS) 3 inhibits phosphorylation of signal transducer and activator of transcription (STAT) 3 and ERK1/2 and thereby plays a pivotal role in mediating leptin resistance. In addition, SOCS-3 is induced by both leptin and inflammatory cytokines. However, little is known about the intrinsic-renal leptin synthesis and function. Therefore, this study aimed to elucidate the implications of early postnatal hyperalimentation on renal function and on the intrinsic-renal leptin signaling. Early postnatal hyperalimentation in Wistar rats during lactation was induced by litter size reduction at birth (LSR) either to LSR10 or LSR6, compared with home cage control male rats. Assessment of renal function at postnatal day 70 revealed decreased glomerular filtration rate and proteinuria after LSR6. In line with this impairment of renal function, renal inflammation and expression as well as deposition of extracellular matrix molecules, such as collagen I, were increased. Furthermore, renal expression of leptin and IL-6 was up-regulated subsequent to LSR6. Interestingly, the phosphorylation of Stat3 and ERK1/2 in the kidney, however, was decreased after LSR6, indicating postreceptor leptin resistance. In accordance, neuropeptide Y (NPY) gene expression was down-regulated; moreover, SOCS-3 protein expression, a mediator of postreceptor leptin resistance, was strongly elevated and colocalized with NPY. Thus, our findings not only demonstrate impaired renal function and profibrotic processes but also provide compelling evidence of a SOCS-3-mediated intrinsic renal leptin resistance and concomitant up-regulated NPY expression as an underlying mechanism.

scholarly journals Genetic Correction of IL-10RB Deficiency Reconstitutes Anti-Inflammatory Regulation in iPSC-Derived Macrophages

2021 ◽  
Vol 11 (3) ◽  
pp. 221
Author(s):  
Dirk Hoffmann ◽  
Johanna Sens ◽  
Sebastian Brennig ◽  
Daniel Brand ◽  
Friederike Philipp ◽  
...  
Keyword(s):  
Disease Modeling ◽  
Integration Site ◽  
Cytokine Secretion ◽  
Cytokine Signaling ◽  
Stat3 Phosphorylation ◽  
Tnf Α ◽  
Socs3 Expression ◽  
Healthy Control ◽  
Anti Inflammatory ◽  
Inflammatory Regulation

Patient material from rare diseases such as very early-onset inflammatory bowel disease (VEO-IBD) is often limited. The use of patient-derived induced pluripotent stem cells (iPSCs) for disease modeling is a promising approach to investigate disease pathomechanisms and therapeutic strategies. We successfully developed VEO-IBD patient-derived iPSC lines harboring a mutation in the IL-10 receptor β-chain (IL-10RB) associated with defective IL-10 signaling. To characterize the disease phenotype, healthy control and VEO-IBD iPSCs were differentiated into macrophages. IL-10 stimulation induced characteristic signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) downstream signaling and anti-inflammatory regulation of lipopolysaccharide (LPS)-mediated cytokine secretion in healthy control iPSC-derived macrophages. In contrast, IL-10 stimulation of macrophages derived from patient iPSCs did not result in STAT3 phosphorylation and subsequent SOCS3 expression, recapitulating the phenotype of cells from patients with IL-10RB deficiency. In line with this, LPS-induced cytokine secretion (e.g., IL-6 and tumor necrosis factor-α (TNF-α)) could not be downregulated by exogenous IL-10 stimulation in VEO-IBD iPSC-derived macrophages. Correction of the IL-10RB defect via lentiviral gene therapy or genome editing in the adeno-associated virus integration site 1 (AAVS1) safe harbor locus led to reconstitution of the anti-inflammatory response. Corrected cells showed IL-10RB expression, IL-10-inducible phosphorylation of STAT3, and subsequent SOCS3 expression. Furthermore, LPS-mediated TNF-α secretion could be modulated by IL-10 stimulation in gene-edited VEO-IBD iPSC-derived macrophages. Our established disease models provide the opportunity to identify and validate new curative molecular therapies and to investigate phenotypes and consequences of additional individual IL-10 signaling pathway-dependent VEO-IBD mutations.

scholarly journals Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network

2020 ◽  
Author(s):  
Miriam Pagin ◽  
Simone Giubbolini ◽  
Cristiana Barone ◽  
Gaia Sambruni ◽  
Yanfen Zhu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cytokine Signaling ◽  
Normal Brain ◽  
Suppressor Of Cytokine Signaling ◽  
Self Renewal ◽  
Upstream Regulator ◽  
Socs3 Expression ◽  
Pharmacological Manipulations

AbstractThe Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSC). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, individually or in combination, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2). Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Further, Fos requirement for efficient long-term proliferation was demonstrated by the strong reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Suppressor of cytokine signaling 3 (Socs3) gene is strongly downregulated following Sox2 deletion, and its reexpression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 reexpression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, as well as results from the literature, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; in turn, Fos, Jun and Egr2 may activate Socs3. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.Significance statementProliferation and maintenance of NSC are essential during normal brain development, and, postnatally, for the maintenance of hippocampal function and memory until advanced age. Little is known about the molecular mechanisms that maintain the critical aspects of NSC biology (quiescence and proliferation) in postnatal age. Our work provides a methodology, transduction of genes deregulated following Sox2 deletion, that allows to test many candidate genes for their ability to sustain NSC proliferation. In principle, this may have interesting implications for identifying targets for pharmacological manipulations.

scholarly journals Platelet regulation of myeloid suppressor of cytokine signaling 3 accelerates atherosclerosis

2019 ◽  
Vol 11 (517) ◽  
pp. eaax0481 ◽  
Author(s):  
Tessa J. Barrett ◽  
Martin Schlegel ◽  
Felix Zhou ◽  
Mike Gorenchtein ◽  
Jennifer Bolstorff ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Cytokine Signaling ◽  
Platelet Activity ◽  
Suppressor Of Cytokine Signaling ◽  
Phagocytic Capacity ◽  
Monocyte Migration ◽  
Socs3 Expression ◽  
Platelet Aggregate ◽  
Inflammatory Phenotype

Platelets are best known as mediators of hemostasis and thrombosis; however, their inflammatory effector properties are increasingly recognized. Atherosclerosis, a chronic vascular inflammatory disease, represents the interplay between lipid deposition in the artery wall and unresolved inflammation. Here, we reveal that platelets induce monocyte migration and recruitment into atherosclerotic plaques, resulting in plaque platelet-macrophage aggregates. In Ldlr−/− mice fed a Western diet, platelet depletion decreased plaque size and necrotic area and attenuated macrophage accumulation. Platelets drive atherogenesis by skewing plaque macrophages to an inflammatory phenotype, increasing myeloid suppressor of cytokine signaling 3 (SOCS3) expression and reducing the Socs1:Socs3 ratio. Platelet-induced Socs3 expression regulates plaque macrophage reprogramming by promoting inflammatory cytokine production (Il6, Il1b, and Tnfa) and impairing phagocytic capacity, dysfunctions that contribute to unresolved inflammation and sustained plaque growth. Translating our data to humans with cardiovascular disease, we found that women with, versus without, myocardial infarction have up-regulation of SOCS3, lower SOCS1:SOCS3, and increased monocyte-platelet aggregate. A second cohort of patients with lower extremity atherosclerosis demonstrated that SOCS3 and the SOCS1:SOCS3 ratio correlated with platelet activity and inflammation. Collectively, these data provide a causative link between platelet-mediated myeloid inflammation and dysfunction, SOCS3, and cardiovascular disease. Our findings define an atherogenic role of platelets and highlight how, in the absence of thrombosis, platelets contribute to inflammation.

scholarly journals Functional Role of Suppressor of Cytokine Signaling 3 Upregulation in Hypothalamic Leptin Resistance and Long-Term Energy Homeostasis

Diabetes ◽  
2010 ◽  
Vol 59 (4) ◽  
pp. 894-906 ◽  
Author(s):  
A. S. Reed ◽  
E. K. Unger ◽  
L. E. Olofsson ◽  
M. L. Piper ◽  
M. G. Myers ◽  
...  
Keyword(s):  
Functional Role ◽  
Energy Homeostasis ◽  
Leptin Resistance ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Term Energy

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.

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