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

Bjørbæk, Christian; El-Haschimi, Karim; Frantz, J. Daniel; Flier, Jeffrey S.

doi:10.1074/jbc.274.42.30059

Cited by 545 publications

(203 citation statements)

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“…Rabbit ␣LRb and ␣SHP-2 have previously been described (21, 37), as has ␣ SOCS3 (33). Polyclonal ␣HA and ␣STAT3 were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

“…The SOCS family was originally cloned based upon its ability to bind to tyrosine-phosphorylated Jak kinases, and a number of studies suggest some direct binding of SOCS proteins to Jak kinase (33,36,45). Although SOCS3 requires Tyr 985 of LRb in order to sensitively mediate repression of LRb signaling, some inhibition of ELR L985 -mediated signaling can be detected at high levels of SOCS3.…”

Section: Discussionmentioning

confidence: 99%

“…Leptin treatment induces SOCS3 via STAT3-mediated transcription, SOCS3 inhibits LRb signaling, and cellular SOCS3 levels are elevated in cell models of leptin resistance and in the hypothalami of some obese animals (21, 26,33). Thus, SOCS3 is a likely mediator of feedback inhibition on the leptin receptor and a potential mediator of physiologic leptin resistance.…”

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SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985

Bjørbæk

Lavery

Bates

et al. 2000

Journal of Biological Chemistry

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474

269

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Leptin, a hormone secreted by fat cells (1-3), mediates central hormonal and metabolic responses to nutritional status by binding and activating the long form of the leptin receptor (LRb) 1 in the hypothalamus (4). Alternate splicing of the LR primary transcript results in the production of multiple isoforms (LRa to -e) that contain a common extracellular domain (5-7). While most LR isoforms possess a short 32-40-amino acid intracellular tail, LRb contains a unique approximately 300-amino acid intracellular tail that is required for the normal regulation of energy balance and endocrine function (5-14).LRb is a member of the interleukin-6 receptor family of class I cytokine receptors (9,(15)(16)(17). Ligand binding to LRb results in the activation and tyrosine phosphorylation of Jak2 and the subsequent tyrosine phosphorylation of Tyr 985 and Tyr 1138 of LRb (18 -21). Tyrosine phosphorylation of cytokine and growth factor receptors activates intracellular signals by recruiting specific signaling proteins with specialized phosphotyrosinebinding domains, such as Src homology 2 (SH2) domains (22). The SH2 domain isoforms of different signaling proteins bind phosphotyrosine in the context of unique amino acid motifs; thus, each tyrosine phosphorylation site recruits specific downstream signaling proteins based on its surrounding amino acids. Phosphorylated Tyr 1138 of LRb recruits the SH2 domaincontaining transcription factor STAT3, resulting in the tyrosine phosphorylation of STAT3 and its translocation to the nucleus (17, 21,(23)(24)(25). Once in the nucleus, STAT3 mediates gene transcription, including transcription of the suppressor of cytokine signaling, SOCS3 (21, 26). Phosphorylated Tyr 985 of LRb recruits the SH2 domain-containing protein-tyrosine phosphatase SHP-2 (21, 27, 28). We have previously shown that Tyr 985 regulates ERK activation and c-fos transcription in cultured cells but does not alter phosphorylation of Jak2 or STAT3 during brief ligand stimulation (21). Others have suggested that Tyr 985 , by recruiting the tyrosine phosphatase SHP-2, may mediate dephosphorylation of LRb and Jak2, thereby attenuating LRb signaling (27,28).Mutations that disrupt leptin in rodents and humans result in morbid obesity and endocrine dysfunction (4, 29). Leptin levels are very high in obese humans, suggesting the presence of leptin resistance (4, 30). Human obesity/leptin resistance rarely results from genetic disruption of LRb (31), suggesting that other factors must mediate leptin resistance. A number of potential mechanisms for physiologic leptin resistance have been proposed, including saturation of a transport mechanism across the blood-brain barrier and the presence of biochemical inhibitors of LRb signaling, including SHP-2 and SOCS3 (4, 26 -28, 32-35).SOCS3 (also known as CIS3) is an SH2 domain-containing protein that inhibits signaling by certain cytokine receptor-Jak kinase complexes, either by directly inhibiting Jak2 activity or by targeting the complex to the proteosome (36). Leptin treatment induces...

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Section: Methodsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985

Bjørbæk

Lavery

Bates

et al. 2000

Journal of Biological Chemistry

Self Cite

474

269

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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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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

154

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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“…Leptin signalling is dependent on the presence of the long isoform of the leptin receptor (LerRb). Leptin stimulation activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway, leading to the formation of a LepRb/JAK2 complex that, after trans-phosphorylation, results in STAT3 activation and the induction of SOCS3 expression; SOCS3 in turn negatively regulates leptin signalling by phosphorylating JAK2 (Frederich et al 1995a, Bjørbaek et al 1999.…”

Section: Introductionmentioning

confidence: 99%

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

Martínez-Micaelo

González-Abuín

Ardévol

et al. 2015

Journal of Molecular Endocrinology

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Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar-Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.

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

Cited by 545 publications

References 52 publications

SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985

SOCS3 Mediates Feedback Inhibition of the Leptin Receptor via Tyr985

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

Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

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