STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Moh, Akira; Zhang, Wenjun; Yu, Sidney; Wang, Jun; Xu, Xuming; Li, Jiliang; Fu, Xin

doi:10.2337/db06-1582

Cited by 46 publications

(35 citation statements)

References 38 publications

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“…2B). This is consistent with a reported positive role of STAT3 in glycogen synthesis via suppressing glycogen synthase kinase-3␤ expression (38). More important, however, in STAT3 knockdown cells 2ϫAA no longer inhibited insulin-stimulated glycogen synthesis, indicating that depletion of STAT3 protected insulin sensitivity from inhibition by excess amino acids.…”

Section: Stat3 Mediates the Effect Of Amino Acids On Suppressingsupporting

confidence: 80%

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Kim¹,

Yoon²,

Chen

2009

Journal of Biological Chemistry

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Nutrient overload is associated with the development of obesity, insulin resistance, and type II diabetes. High plasma concentrations of amino acids have been found to correlate with insulin resistance. At the cellular level, excess amino acids impair insulin signaling, the mechanisms of which are not fully understood. Here, we report that STAT3 plays a key role in amino acid dampening of insulin signaling in hepatic cells. Excess amino acids inhibited insulin-stimulated Akt phosphorylation and glycogen synthesis in mouse primary hepatocytes as well as in human hepatocarcinoma HepG2 cells. STAT3 knockdown protected insulin sensitivity from inhibition by amino acids. Amino acids stimulated the phosphorylation of STAT3 at Ser 727 , but not Tyr 705 . Replacement of the endogenous STAT3 with wild-type, but not S727A, recombinant STAT3 restored the ability of amino acids to inhibit insulin signaling, suggesting that Ser 727 phosphorylation was critical for STAT3-mediated amino acid effect. Furthermore, overexpression of STAT3-S727D was sufficient to inhibit insulin signaling in the absence of excess amino acids. Our results also indicated that mammalian target of rapamycin was likely responsible for the phosphorylation of STAT3 at Ser 727 in response to excess amino acids. Finally, we found that STAT3 activity and the expression of its target gene socs3, known to be involved in insulin resistance, were both stimulated by excess amino acids and inhibited by rapamycin. In conclusion, our study reveals STAT3 as a novel mediator of nutrient signals and identifies a Ser 727 phosphorylation-dependent and Tyr 705 phosphorylation-independent STAT3 activation mechanism in the modulation of insulin signaling.Insulin resistance is a major risk factor and a principal defect in type II diabetes. Nutrient overload in affluent societies has been associated with increased occurrence of metabolic syndrome (1, 2). High protein diets are associated with altered glucose metabolism and increased occurrence of type II diabetes (3, 4). Elevated plasma concentrations of amino acids have long been found in obesity and insulin-resistant states (5-8). Furthermore, amino acid infusion induces insulin resistance in healthy individuals (9). Most recently, it has been reported that branched-chain amino acids in diet contribute to insulin resistance in high fat diet-fed rats and that a similar consequence of such a dietary pattern may exist in human (10). Currently, a role of dietary proteins in the pathogenesis of insulin resistance has been well recognized (11) (14); among them the mammalian target of rapamycin (mTOR) has been shown to phosphorylate STAT3 in neuronal cells (15, 16) and IL-6-stimulated hepatocytes (17).As a negative feedback control, STATs induce the expression of SOCS proteins, which are characterized by their ability to down-regulate cytokine signaling (18). SOCSs also play an important role in the pathogenesis of insulin resistance by integrating cytokine signaling with insulin signaling (19). Overexpression of SOCS3 inhibited ...

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Section: Stat3 Mediates the Effect Of Amino Acids On Suppressingsupporting

confidence: 80%

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Kim¹,

Yoon²,

Chen

2009

Journal of Biological Chemistry

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“…(n ϭ 9 -21 per group.) * , P Ͻ 0.05. effect on gluconeogenesis, recent studies have pointed to the role of STAT3 in sensitizing insulin signaling by down-regulating the Akt2 inhibitor glycogen synthase kinase-3 beta (GSK-3␤) (30). This observation could also contribute to the increased hepatic insulin sensitivity seen during the hyperinsulinemic-euglycemic clamp.…”

Section: Discussionmentioning

confidence: 94%

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats

Erion

Yonemitsu

Nie

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

169

120

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Hepatic gluconeogenesis is a major contributing factor to hyperglycemia in the fasting and postprandial states in type 2 diabetes mellitus (T2DM). Because Sirtuin 1 (SirT1) induces hepatic gluconeogenesis during fasting through the induction of phosphoenolpyruvate carboxylase kinase (PEPCK), fructose-1,6-bisphosphatase (FBPase), and glucose-6-phosphatase (G6Pase) gene transcription, we hypothesized that reducing SirT1, by using an antisense oligonucleotide (ASO), would decrease fasting hyperglycemia in a rat model of T2DM. SirT1 ASO lowered both fasting glucose concentration and hepatic glucose production in the T2DM rat model. Whole body insulin sensitivity was also increased in the SirT1 ASO treated rats as reflected by a 25% increase in the glucose infusion rate required to maintain euglycemia during the hyperinsulinemiceuglycemic clamp and could entirely be attributed to increased suppression of hepatic glucose production by insulin. The reduction in basal and clamped rates of glucose production could in turn be attributed to decreased expression of PEPCK, FBPase, and G6Pase due to increased acetylation of signal transducer and activator of transcription 3 (STAT3), forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), known substrates of SirT1. In addition to the effects on glucose metabolism, SirT1 ASO decreased plasma total cholesterol, which was attributed to increased cholesterol uptake and export from the liver. These results indicate that inhibition of hepatic SirT1 may be an attractive approach for treatment of T2DM. gluconeogenesis ͉ glucose 6 phosphatase ͉ phosphoenolpyruvate carboxykinase ͉ type 2 diabetes mellitus ͉ hepatic insulin resistance T ype 2 diabetes mellitus (T2DM) is associated with an increased rate of hepatic glucose production that contributes to fasting hyperglycemia (1-3). Specifically, increased endogenous glucose production can be accounted for by increased rates of hepatic gluconeogenesis (4). Inhibition of hepatic gluconeogenesis has been shown to improve fasting plasma glucose levels and decrease endogenous glucose production in T2DM patients (5). Furthermore, inhibition of transcriptional gluconeogenic activators, such as forkhead box O1 (FOXO1), and peroxisome proliferator-activated receptor-␥ coactivator 1␣ (PGC-1␣), in turn improved hepatic insulin resistance in rodent models of diabetes (6, 7). Therefore inhibitors of gluconeogenesis are potentially excellent targets for treatment of poorly controlled T2DM.Sirtuin1 (SirT1) is a NAD ϩ -dependent deacetylase activated in response to fasting and caloric restriction (8). In the ␤-cells of the pancreas, SirT1 has been shown to increase insulin secretion through repression of uncoupling protein 2 (UCP2) (9). In adipose tissue, SirT1 has been shown to inhibit adipogenesis and decrease lipolysis through inhibition of peroxisome proliferator-activated receptor-␥ (PPAR␥) (10). In liver tissue, SirT1 activates gluconeogenesis transcription through deacetylation of PGC-1␣, FOXO1, and signa...

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“…SOCS3 can directly suppress the insulin signaling pathway through binding to phosphorylated tyrosine of the insulin receptor and insulin receptor substrate 1 (43)(44)(45). STAT3 was found to sensitize insulin signaling through suppression of glycogen synthase kinase 3␤, a negative regulator of the insulin signaling pathway (46). It should also be noted that there is a well established link between HIF1␣ and mitochondrial function, wherein the inhibition of HIF1 in adipocytes increases mitochondrial activity (47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible Factor 1α Regulates a SOCS3-STAT3-Adiponectin Signal Transduction Pathway in Adipocytes

Jiang

Kim

et al. 2013

Journal of Biological Chemistry

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Background: HIF1␣ in adipose tissue was induced during the pathogenesis of type 2 diabetes. Results: The HIF1␣ inhibitor acriflavine increased the expression of adiponectin through decreased expression of the novel HIF1␣ target gene Socs3 and transcriptional activation of Stat3 in vivo and in vitro. Conclusion: HIF1␣ regulates an adipocyte SOCS3-STAT3-adiponectin signal transduction pathway. Significance: Inhibitors of HIF1␣ provide a potential therapeutic target for the treatment of type 2 diabetes.

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STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Cited by 46 publications

References 38 publications

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

Signal Transducer and Activator of Transcription 3 (STAT3) Mediates Amino Acid Inhibition of Insulin Signaling through Serine 727 Phosphorylation

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats

Hypoxia-inducible Factor 1α Regulates a SOCS3-STAT3-Adiponectin Signal Transduction Pathway in Adipocytes

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