Suppressor of Cytokine Signaling-3 Provides a Novel Interface in the Cross-Talk between Angiotensin II and Insulin Signaling Systems

Calegari, Vivian C.; Alves, Mônica; Picardi, Paty Karoll; Inoue, Rosana Yuri; Franchini, Kleber G.; Saad, Mário José Abdalla; Velloso, Lı́cio A.

doi:10.1210/en.2004-0466

Cited by 45 publications

(44 citation statements)

References 47 publications

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“…Cross-talk between the RAS and the insulin signaling system has drawn great attention because hypertension and insulin resistance often coexist (Calegari et al 2005, Velloso et al 2006. It has been shown that Ang II infusion induces insulin resistance as well as a substantial reduction in glucose disposal in normal skeletal muscle (Rao 1994, Richey et al 1999.…”

Section: Discussionmentioning

confidence: 99%

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

Muñoz

Giani²,

Mayer³

et al. 2009

Journal of Endocrinology

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The IkB kinase-b (IKK-b)/nuclear factor-kB signaling pathway has been suggested to link inflammation with obesity and insulin resistance. In addition, angiotensin (Ang) II is able to induce insulin resistance and an inflammatory state through Ang II receptor type 1 (AT1R). Accordingly, we examined whether inhibition of AT1R with irbesartan (IRB) can protect against the development of insulin resistance in obese Zucker rats (OZRs). IRB-treatment improved the insulin-stimulated insulin receptor (IR) phosphorylation at tyrosine (Tyr) residues 1158, 1162, 1163 (involved in activation of the IR kinase) and at Tyr972 (involved in substrate recognition). AT1R blockade also originated a dramatic increase in the phosphorylation of Akt and glycogen synthase kinase-3b. This was accompanied by a decrease in phosphorylation of IR on serine (Ser) 994, a residue that seems to be implicated in the regulation of IR kinase in OZR. In this study, we demonstrated that Ser994 of IR is a direct substrate for TANK-binding kinase 1 (TBK1), a new member of the IKK-related kinase family. TBK1 was found to co-immunoprecipitate with the IR, in the liver of OZR supporting an in vivo association between the IR and TBK1. Interestingly, a marked increase in the association between TBK1 and the IR was found in the liver of OZR as well as in other models of insulin resistance/diabetes. Taken together, these findings suggest that TBK1 could be involved in the insulin resistance mechanism related with IR Ser994 phosphorylation in a genetic model of diabetes.

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Section: Discussionmentioning

confidence: 99%

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

Muñoz

Giani²,

Mayer³

et al. 2009

Journal of Endocrinology

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“…The outstanding improvement in the molecular activation of this pathway, achieved with infliximab, may be the result of an alleviation of the functional activities of serine kinases, such as JNK and IkBK, which are targets of TNF-a and can affect insulin signaling by promoting the inhibitory serine phosphorylation of IR, IRS1, and IRS-2 (Paz et al 1997, Hirosumi et al 2002, Araujo et al 2005. The JAK2/STAT3 is a non-classical target of insulin signaling (Saad et al 1996) that participates in the crosstalk of the insulin signaling with several other pathways (Calegari et al 2005, including inflammatory pathways activated by cytokines. In addition, the JAK2/STAT3 pathway is a primary target for leptin signaling, a hormone known to exert anti-steatotic effects (Lee et al 2001) and to be modulated by a crosstalk with insulin (Carvalheira et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Barbuio

Milanski

Bértolo

et al. 2007

Journal of Endocrinology

137

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Non-alcoholic fatty liver disease, induced by nutritional factors, is one of the leading causes of hepatic dysfunction in the modern world. The activation of proinflammatory signaling in the liver, which is induced by systemic and locally produced cytokines, and the development of hepatic insulin resistance are two important factors associated with the progression from steatosis to steatohepatitis, a pre-cirrhotic condition. The objective of the present study was to evaluate the effect of inhibition of tumour necrosis factor (TNF)-a, using the monoclonal antibody infliximab, on the expression of cytokines, induction of steatosis and fibrosis, and insulin signal transduction in the liver of Wistar rats fed a high-fat diet. Ten days of treatment with infliximab significantly reduced the expression of the proinflammatory markers, TNF-a, IL-6, IL-1b, and SOCS-3, in the liver of rats fed a high-fat diet. This was accompanied by reduced fat deposition and fibrosis and by improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways. In conclusion, short-term inhibition of TNF-a with infliximab reduces inflammation and steatosis/fibrosis, while improving insulin signal transduction in an animal model treated with a high-fat diet.

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“…Depending on the tissue or cell line studied, insulin is able to induce the expression of SOCS-2 [69] and/or SOCS-3 [68,73] through the activation of STAT-5b. Once induced, SOCS-3 can bind to the Tyr 960 of the IR and hamper its capacity to induce the tyrosine phosphorylation of STAT5b, IRS-1 and IRS-2 [68,70,74].…”

Section: The Late Events Affected By the Insulin-ang II Cross-talkmentioning

confidence: 99%

“…When SOCS-3 is induced by Ang II in the heart and isolated cardiomyocytes, it interacts not only with the proteins of the Ang II signaling pathway but also with proteins that belong to the classical insulin signaling pathway [73] (Figure 2(c)). The time frames of these associations are closely related to the time frame required for Ang II to induce the expression of SOCS-3.…”

Section: The Late Events Affected By the Insulin-ang II Cross-talkmentioning

confidence: 99%

“…The time frames of these associations are closely related to the time frame required for Ang II to induce the expression of SOCS-3. Thus, it takes 10 min to begin the association between Ang IIinduced SOCS-3 with IR, IRS-1 and IRS-2 [73]. These associations last 180 min for IR and 120 min for IRS-1 and IRS-2.…”

Section: The Late Events Affected By the Insulin-ang II Cross-talkmentioning

confidence: 99%

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The multi‐faceted cross‐talk between the insulin and angiotensin II signaling systems

Velloso

Folli

Perego

et al. 2006

Diabetes Metabolism Res

102

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SummaryInsulin and angiotensin II are hormones that play pivotal roles in the control of two vital and closely related systems, the metabolic and the circulatory systems, respectively. A failure in the proper action of each of these hormones results, to a variable degree, in the development of two highly prevalent and commonly overlapping diseases -diabetes mellitus and hypertension. In recent years, a series of studies has revealed a tight connection between the signal transduction pathways that mediate insulin and angiotensin II actions in target tissues. This molecular cross-talk occurs at multiple levels and plays an important role in phenomena that range from the action of anti-hypertensive drugs to cardiac hypertrophy and energy acquisition by the heart. At the extracellular level, the angiotensin-converting enzyme controls angiotensin II synthesis but also interferes with insulin signaling through the proper regulation of angiotensin II and through the accumulation of bradykinin. At an early intracellular level, angiotensin II, acting through JAK-2/IRS-1/PI3-kinase, JNK and ERK, may induce the serine phosphorylation and inhibition of key elements of the insulin-signaling pathway. Finally, by inducing the expression of the regulatory protein SOCS-3, angiotensin II may impose a late control on the insulin signal. This review will focus on the main advances obtained in this field and will discuss the implications of this molecular cross-talk in the common clinical association between diabetes mellitus and hypertension.

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Suppressor of Cytokine Signaling-3 Provides a Novel Interface in the Cross-Talk between Angiotensin II and Insulin Signaling Systems

Cited by 45 publications

References 47 publications

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

The multi‐faceted cross‐talk between the insulin and angiotensin II signaling systems

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