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

Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for leptin to regulate a number of physiological functions. Available evidence from human studies indicates that leptin has a mainly permissive role, with leptin administration being effective in states of leptin deficiency, less effective in states of leptin adequacy, and largely ineffective in states of leptin excess. Results from interventional studies in humans demonstrate that leptin administration in subjects with congenital complete leptin deficiency or subjects with partial leptin deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, leptin's effects are largely absent in the obese hyperleptinemic state, probably due to leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of leptin and the potential clinical applications of leptin or its analogs in human therapeutics.

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Abstract 021: Role of Central Nervous System Suppressor of Cytokine Signaling 3 (socs3) in Regulating Metabolic and Cardiovascular Function in Obesity

Hypertension ◽

10.1161/hyp.70.suppl_1.021 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Jussara M do Carmo ◽

John N Freeman ◽

Alexandre A da Silva ◽

Sydney P Moak ◽

John E Hall

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Glucose Tolerance ◽

Cardiovascular Effects ◽

Negative Regulator ◽

Leptin Resistance ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Female Mice

Suppressor of cytokine signaling 3 (SOCS3), a negative regulator of leptin signaling, is upregulated in obesity and may contribute to development of leptin resistance. We determined whether deletion of SOCS3 in the entire central nervous system (CNS) would protect mice from adverse metabolic and cardiovascular effects of a high fat diet (HFD). SOCS3 flox/flox /Nestin-cre mice were generated by breeding SOCS3 flox/flox with Nestin-Cre mice. Male and female mice with CNS deletion of SOCS3 (SOCS3 flox/flox /Nestin-Cre, n=5-10) or control (SOCS3 flox/flox , n=6-10) were fed a HFD plus sucrose from 6 until 22 weeks of age. Mean arterial pressure (MAP) and heart rate (HR) were recorded by telemetry and oxygen consumption (VO 2 ) was monitored by indirect calorimetry in 22-week-old mice. Compared to control mice, SOCS3 flox/flox /Nestin-Cre mice were lighter (male: 34±3 vs. 45±3 and female: 27±1 vs. 37±2 g) and had elevated VO 2 (94±12 vs. 69±6 ml/kg/min) but there were no significant differences in food intake (male: 3.3±0.7 vs. 3.8±0.5 and female: 3.0±0.6 vs. 3.0±0.5 g/day) or plasma glucose (male: 148±8 vs. 198±31 and female 149±12 vs. 164±12 mg/dl). Male SOCS3 flox/flox /Nestin-Cre mice had similar MAP (115±2 vs. 116±1 mmHg) but higher HR (657±3 vs. 592±3 bpm) compared to control mice. However, female SOCS3 flox/flox /Nestin-cre mice had higher MAP (121±1 vs. 108±1 mmHg) and HR (655±2 vs. 606±5 bpm) compared to control mice. No significant differences were observed in glucose tolerance in SOCS3 flox/flox /Nestin-Cre vs. control mice (AUC: 391±36 vs. 429±54 mg/dL x 120 min in males and 459±70 vs. 372±51 mg/dL x 120 min in females). These results indicate that CNS SOCS3 deletion reduced body weight and increased energy expenditure and HR but did not improve glucose tolerance in male or female mice fed a HFD. However, HFD significantly increased BP in female SOCS3 flox/flox /Nestin-Cre mice compared to control mice fed a HFD, suggesting a sex difference in the role of CNS SOCS3 signaling in BP regulation in obesity. (NHLBI PO1HL51971and NIGMS P20GM104357)

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

Endocrinology ◽

10.1210/en.2011-1670 ◽

2012 ◽

Vol 153 (3) ◽

pp. 1397-1410 ◽

Cited By ~ 17

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.

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The role of CXC-chemokine receptor CXCR2 and suppressor of cytokine signaling-3 (SOCS-3) in renal cell carcinoma

BMC Cancer ◽

10.1186/1471-2407-14-149 ◽

2014 ◽

Vol 14 (1) ◽

Cited By ~ 15

Author(s):

Anastasios Stofas ◽

Georgia Levidou ◽

Christina Piperi ◽

Christos Adamopoulos ◽

Georgia Dalagiorgou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Chemokine Receptor ◽

Renal Cell ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Cxc Chemokine ◽

Chemokine Receptor Cxcr2

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Role of Suppressor of Cytokine Signaling 2 during the development and resolution of an experimental arthritis

Cellular Immunology ◽

10.1016/j.cellimm.2021.104476 ◽

2022 ◽

pp. 104476

Author(s):

Allysson Cramer ◽

Izabela Galvão ◽

Nathália Venturini de Sá ◽

Paulo Gaio ◽

Natália Fernanda de Melo Oliveira ◽

...

Keyword(s):

Experimental Arthritis ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling

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Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽

10.1161/circ.118.suppl_18.s_467-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Christina Grothusen ◽

Harald Schuett ◽

Stefan Lumpe ◽

Andre Bleich ◽

Silke Glage ◽

...

Keyword(s):

Foam Cell ◽

Low Density Lipoprotein ◽

Cell Formation ◽

Density Lipoprotein ◽

Foam Cell Formation ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

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

10.1101/2020.03.17.995621 ◽

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.

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Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

International Journal of Molecular Sciences ◽

10.3390/ijms21124238 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4238

Author(s):

Dorota Anna Zieba ◽

Weronika Biernat ◽

Malgorzata Szczesna ◽

Katarzyna Kirsz ◽

Justyna Barć ◽

...

Keyword(s):

Body Weight ◽

Leptin Receptor ◽

Fat Body ◽

Density Lipoprotein ◽

Reproductive Hormones ◽

Leptin Resistance ◽

Nonesterified Fatty Acid ◽

Cytokine Signaling ◽

Leptin Signaling

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

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Effects of Ecklonia cava ethanolic extracts on airway hyperresponsiveness and inflammation in a murine asthma model: Role of suppressor of cytokine signaling

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2007.07.009 ◽

2008 ◽

Vol 62 (5) ◽

pp. 289-296 ◽

Cited By ~ 59

Author(s):

Se-Kwon Kim ◽

Da-Young Lee ◽

Won-Kyo Jung ◽

Ji-Hye Kim ◽

Inhak Choi ◽

...

Keyword(s):

Airway Hyperresponsiveness ◽

Ecklonia Cava ◽

Cytokine Signaling ◽

Suppressor Of Cytokine Signaling ◽

Asthma Model ◽

Ethanolic Extracts ◽

Murine Asthma Model

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miR-221 and miR-155 regulate human dendritic cell development, apoptosis, and IL-12 production through targeting of p27kip1, KPC1, and SOCS-1

Blood ◽

10.1182/blood-2010-12-322503 ◽

2011 ◽

Vol 117 (16) ◽

pp. 4293-4303 ◽

Cited By ~ 182

Author(s):

Changming Lu ◽

Xin Huang ◽

Xiaoxiao Zhang ◽

Kristin Roensch ◽

Qing Cao ◽

...

Keyword(s):

Cytokine Signaling ◽

Wild Type ◽

Suppressor Of Cytokine Signaling ◽

Hematopoietic Progenitor ◽

Monocyte Differentiation ◽

P27kip1 Protein ◽

And Function ◽

Antigen Presenting ◽

Dc Maturation

Abstract Dendritic cells (DCs) are potent antigen-presenting cells derived from hematopoietic progenitor cells and circulating monocytes. To investigate the role of microRNAs (miRNAs) during DC differentiation, maturation, and function, we profiled miRNA expression in human monocytes, immature DCs (imDCs), and mature DCs (mDCs). Stage-specific, differential expression of 27 miRNAs was found during monocyte differentiation into imDCs and mDCs. Among them, decreased miR-221 and increased miR-155 expression correlated with p27kip1 accumulation in DCs. Silencing of miR-221 or overexpressing of miR-155 in DCs resulted in p27kip1 protein increase and DC apoptosis. Moreover, mDCs from miR-155−/− mice were less apoptotic than those from wild-type mice. Silencing of miR-155 expression had little effect on DC maturation but reduced IL-12p70 production, whereas miR-155 overexpression in mDCs enhanced IL-12p70 production. Kip1 ubiquitination-promoting complex 1, suppressor of cytokine signaling 1, and CD115 (M-CSFR) were functional targets of miR-155. Furthermore, we provide evidence that miR-155 indirectly regulated p27kip1 protein level by targeting Kip1 ubiquitination-promoting complex 1. Thus, our study uncovered miRNA signatures during monocyte differentiation into DCs and the new regulatory role of miR-221 and miR-155 in DC apoptosis and IL-12p70 production.

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