Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance

Bjørbæk, Christian; Elmquist, Joel K.; Frantz, J. Daniel; Shoelson, Steven E.; Flier, Jeffrey S.

doi:10.1016/s1097-2765(00)80062-3

Cited by 873 publications

(304 citation statements)

References 46 publications

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“…32,41,42 Socs3 has been also proposed as a potential mediator of the insulin resistance induced by some hormones. 43,44 SOCS proteins disrupt insulin signaling by binding to the insulin receptor and/or by targeting Irs1 Periodontitis and aortic insulin signaling D Ekuni et al Figure 3 Cross-sections of descending aorta in the control and periodontitis groups.…”

Section: Discussionmentioning

confidence: 99%

Effects of periodontitis on aortic insulin resistance in an obese rat model

Ekuni

Tomofuji

Irie

et al. 2010

Laboratory Investigation

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The combination of obesity and its associated risk factors, such as insulin resistance and inflammation, results in the development of atherosclerosis. However, the effects of periodontitis on atherosclerosis in an obese body remain unclear. The aim of the study was to investigate the effects of ligature-induced periodontitis in Zucker fatty rats on initiation of atherosclerosis by evaluating aortic insulin resistance. Zucker fatty rats (n ¼ 24) were divided into two groups. In the periodontitis group, periodontitis was ligature-induced for 4 weeks, whereas the control group was left unligated. After the 4-week experimental period, descending aorta was used for measuring the levels of lipid deposits, immunohistochemical analysis, and evaluation of gene expression. Levels of serum C-reactive protein (CRP), tumor necrosis factora (TNF-a), and insulin were also measured. Rats in the periodontitis group had significantly enhanced lipid deposits in the aorta, but not in the control group. Expression of suppressor of cytokine signaling 3, vascular cell adhesion molecule 1, reactive oxygen species, nitrotyrosine, and endothelin-1 in the periodontitis group was more intense than that in the control group. Significantly decreased levels of phosphatidylinositol 3-kinase (Pi3k) catalytic b-polypeptide (Pi3kcb), Pi3kp85, and insulin receptor substrate 1 and 2 were observed in the periodontitis group. Levels of serum CRP and TNF-a were significantly increased in the periodontitis group. Under insulin-stimulated conditions, aorta in the periodontitis group altered the Akt phosphorylation. Periodontitis in obesity induced the initial stage of atherosclerosis and disturbed aortic insulin signaling.

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Section: Discussionmentioning

confidence: 99%

Effects of periodontitis on aortic insulin resistance in an obese rat model

Ekuni

Tomofuji

Irie

et al. 2010

Laboratory Investigation

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“…In addition, forced expression of SOCS-3 blocks leptin receptormediated signal transduction in mammalian cell lines. Furthermore, in the Agouti mouse, a model characterized by hyperleptinemia and resistance to both central and peripheral leptin administration, basal SOCS-3 mRNA levels are increased in those hypothalamic nuclei that express SOCS-3 in normal animals after leptin administration (29). We have thus identified a potential negative feedback circuit connecting peripheral leptin to expression of an inhibitor of leptin signaling in leptin-responsive hypothalamic neurons.…”

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confidence: 89%

“…We have earlier demonstrated that leptin specifically induces expression of SOCS-3 mRNA in regions of the hypothalamus that express the long form of the leptin receptor (29). In addition, forced expression of SOCS-3 blocks leptin receptormediated signal transduction in mammalian cell lines.…”

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confidence: 99%

“…The SH2 domain of SOCS is thought to bind to phosphorylated tyrosine residues on JAK proteins (22,25), while the SOCS-box may play a role in preventing degradation of SOCS proteins (25,26). Members of the cytokine superfamily including leptin, interleukin-6, interferon-␥, leukemia-inhibitory factor, erythropoietin (EPO), and growth hormone induce transcription of one or more of the cis or socs genes in vivo and in vitro, and when expressed in cell lines, CIS and SOCS proteins inhibit signaling and biological activities of cytokines (20,21,(27)(28)(29)(30)(31). These results suggest that CIS and SOCS proteins can function as inducible intracellular negative regulators of cytokine signal transduction.…”

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confidence: 99%

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The Role of SOCS-3 in Leptin Signaling and Leptin Resistance

Bjørbæk

El-Haschimi

Frantz

et al. 1999

Journal of Biological Chemistry

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538

184

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We earlier demonstrated that leptin induces expression of SOCS-3 mRNA in the hypothalamus. Furthermore, transfection data suggest that SOCS-3 is an inhibitor of leptin signaling. However, little is known about the regulation of SOCS-3 expression by leptin and the mechanism by which SOCS-3 inhibits leptin action. We here show that in CHO cells stably expressing the long form of the leptin receptor (CHO-OBRl), leptin induces transient expression of endogenous SOCS-3 mRNA but not of CIS, SOCS-1, or SOCS-2 mRNA. SOCS-3 protein levels were maximal after 2-3 h of leptin treatment and remained elevated at 20 h. Furthermore, in leptin-pretreated CHO-OBRl cells, proximal leptin signaling was blocked for more than 20 h after pretreatment, thus correlating with increased SOCS-3 expression. Leptin pretreatment did not affect cell surface expression of leptin receptors as measured by 125 I-leptin binding assays. In transfected COS cells, forced expression of SOCS-3 results in inhibition of leptin-induced tyrosine phosphorylation of JAK2. Finally, JAK2 co-immunoprecipitates with SOCS-3 in lysates from leptin-treated COS cells. These results suggest that SOCS-3 is a leptin-regulated inhibitor of proximal leptin signaling in vivo. Excessive SOCS-3 activity in leptin-responsive cells is therefore a potential mechanism for leptin resistance, a characteristic feature in human obesity.Leptin is a 16-kDa hormone derived from adipose tissue that acts on specific regions of the brain to regulate food intake, energy expenditure, and neuroendocrine function (1-5). Leptin is structurally related to cytokines (6) and acts on receptors that belong to the cytokine receptor superfamily (7). Several different leptin receptor isoforms exists including a long form (OBRl), which is highly expressed in regions of the hypothalamus (8 -10). In vitro and in vivo studies demonstrate that leptin activates cytokine-like signal transduction via the long form of the leptin receptor (9,11,12). Upon leptin stimulation, intracellular Janus tyrosine kinases (JAKs) are activated via transphosphorylation and phosphorylate tyrosine residues on the long form leptin receptor and on signal transducers and activators of transcription (STAT) 1 proteins (13,14). Phosphorylated STAT proteins dimerize and translocate to the nucleus to activate gene transcription (15,16). Lack of functional leptin in lep ob /lep ob mice or of the intracellular domain of the long form of the leptin receptor in db/db mice produces severe obesity (1,8,17). Although rare cases with mutations in the leptin and the leptin receptor genes causing extreme obesity in humans have been described (18,19), most humans with obesity have resistance to leptin that has yet to be explained. Potential mechanisms for leptin resistance include defects in transport of leptin across the blood brain barrier, defects in leptin signal transduction in leptin receptor-expressing neurons in the hypothalamus, and antagonism of leptin's physiologic actions at one or more steps beyond the initial leptin-responsive neur...

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“…In obese humans and in rodent models of high-fat (HF), high-energy, diet-induced obesity, plasma leptin levels are elevated as a result of an increased adiposity, and this is associated with a blunted response to exogenous leptin. Leptin resistance has been widely reported in neurons of the arcuate nucleus of obese animals and is associated with a lack of STAT3 phosphorylation (pSTAT3) in response to exogenous leptin (3,4,28). Both suppressor of cytokine signaling-3 (SOCS-3) and protein tyrosine phosphatase 1B (PTP1B) have been shown to play a role in the development of leptin resistance.…”

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confidence: 99%

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

Lartigue

Serre

Espero

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

151

142

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de Lartigue G, Barbier de la Serre C, Espero E, Lee J, Raybould HE. Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons. Am J Physiol Endocrinol Metab 301: E187-E195, 2011. First published April 26, 2011; doi:10.1152/ajpendo.00056.2011.-Ingestion of high-fat, high-calorie diets is associated with hyperphagia, increased body fat, and obesity. The mechanisms responsible are currently unclear; however, altered leptin signaling may be an important factor. Vagal afferent neurons (VAN) integrate signals from the gut in response to ingestion of nutrients and express leptin receptors. Therefore, we tested the hypothesis that leptin resistance occurs in VAN in response to a high-fat diet. Sprague-Dawley rats, which exhibit a bimodal distribution of body weight gain, were used after ingestion of a high-fat diet for 8 wk. Body weight, food intake, and plasma leptin levels were measured. Leptin signaling was determined by immunohistochemical localization of phosphorylated STAT3 (pSTAT3) in cultured VAN and by quantifaction of pSTAT3 protein levels by Western blot analysis in nodose ganglia and arcuate nucleus in vivo. To determine the mechanism of leptin resistance in nodose ganglia, cultured VAN were stimulated with leptin alone or with lipopolysaccharide (LPS) and SOCS-3 expression measured. SOCS-3 protein levels in VAN were measured by Western blot following leptin administration in vivo. Leptin resulted in appearance of pSTAT3 in VAN of low-fat-fed rats and rats resistant to diet-induced obesity but not diet-induced obese (DIO) rats. However, leptin signaling was normal in arcuate neurons. SOCS-3 expression was increased in VAN of DIO rats. In cultured VAN, LPS increased SOCS-3 expression and inhibited leptin-induced pSTAT3 in vivo. We conclude that VAN of diet-induced obese rats become leptin resistant; LPS and SOCS-3 may play a role in the development of leptin resistance.lipopolysaccharide; high-fat diet; suppressor of cytokine signaling-3 THE GUT PLAYS A CRUCIAL ROLE in sensing luminal contents that is important for the efficient digestion and absorption of ingested nutrients but also in integration of other physiological processes that regulate metabolism and energy expenditure, such as pancreatic ␤-cell function, hepatic function, and also food intake (34). In response to the presence or absence of food, enteroendocrine cells of the gut release anorexic or orexigenic hormones, respectively. The first site of integration of these signals occurs at the level of vagal afferent neurons (VAN), which project to and stimulate second-order neurons in the dorsal vagal complex of the hindbrain (27). VAN express receptors for many of the anorexigenic and orexigenic hormones released from the gut wall and mediate changes in gastrointestinal function and food intake in response to luminal nutrients (18).Leptin is a gut and adipose tissue-derived hormone that regulates a range of biological functions and processes, including energy intake and expenditure, body fat, neuroendocrine systems...

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Identification of SOCS-3 as a Potential Mediator of Central Leptin Resistance

Cited by 873 publications

References 46 publications

Effects of periodontitis on aortic insulin resistance in an obese rat model

Effects of periodontitis on aortic insulin resistance in an obese rat model

The Role of SOCS-3 in Leptin Signaling and Leptin Resistance

Diet-induced obesity leads to the development of leptin resistance in vagal afferent neurons

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