Irbesartan restores the in-vivo insulin signaling pathway leading to Akt activation in obese Zucker rats

Muñoz, Marina Cecilia; Argentino, Danila P.; Dominici, Fernando Pablo; Turyn, Daniel; Toblli, Jorge Eduardo

doi:10.1097/01.hjh.0000239297.63377.3f

Cited by 41 publications

(73 citation statements)

References 55 publications

(94 reference statements)

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“…In accordance with our previous reports (Coba et al 2003, Muñoz et al 2006, IR Ser994 phosphorylation was almost undetectable in the liver of LZR (Fig. 3).…”

Section: Degree Of Phosphorylation Of the Ir At Ser994supporting

confidence: 81%

“…irbesartan, IRB), on insulin sensitivity (Henriksen et al 2001, Shiuchi et al 2004, Muñoz et al 2006. In a previous study, we demonstrated that blockade of the AT1R with IRB leads to an improvement of the response to insulin at the early stages of the insulin signaling pathway in the liver of OZRs which correlates with a reduction of the phosphorylation of the IR at Ser994 (Muñoz et al 2006).…”

Section: Introductionmentioning

confidence: 99%

“…9% NaCl) in a final volume of 0 . 1 ml was injected via this vein as described previously (Muñoz et al 2006). To obtain data under basal conditions, animals were injected with diluent.…”

Section: Animal Models and Surgerymentioning

confidence: 99%

“…IR Ser994 is one of the potential inhibitory sites of the IR kinase as determined by site-directed mutagenesis (Strack et al 1997(Strack et al , 2000. In previous works, we demonstrated that phosphorylation at this site was increased in IR isolated from the liver of obese Zucker rats (OZRs; Coba et al 2003, Muñoz et al 2006. Among the serine kinases implicated in Ser phosphorylation of the IR and the IRSs, protein kinase C (PKC) is one candidate with potential pathophysiological relevance.…”

Section: Introductionmentioning

confidence: 99%

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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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“…In accordance with our previous reports (Coba et al 2003, Muñoz et al 2006, IR Ser994 phosphorylation was almost undetectable in the liver of LZR (Fig. 3).…”

Section: Degree Of Phosphorylation Of the Ir At Ser994supporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

“…9% NaCl) in a final volume of 0 . 1 ml was injected via this vein as described previously (Muñoz et al 2006). To obtain data under basal conditions, animals were injected with diluent.…”

Section: Animal Models and Surgerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

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“…After insulin administration, Zucker fatty rats show a decreased phosphorylation of Akt in liver compared with the lean rats, which reflects local insulin resistance. 48 These suggest that periodontal inflammation in the obese rats leads to aortic insulin resistance.…”

Section: Periodontitis and Aortic Insulin Signaling D Ekuni Et Almentioning

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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Screening and identification of differentially expressed genes in goose hepatocytes exposed to free fatty acid

Pan¹,

Wang²,

Kang³

et al. 2010

J of Cellular Biochemistry

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The overaccumulation of triglycerides in hepatocytes induces hepatic steatosis; however, little is known about the mechanism of goose hepatic steatosis. The aim of this study was to define an experimental model of hepatocellular steatosis with TG overaccumulation and minimal cytotoxicity, using a mixture of various proportions of oleate and palmitate free fatty acids (FFAs) to induce fat-overloading, then using suppressive subtractive hybridization and a quantitative PCR approach to identify genes with higher or lower expression levels after the treatment of cells with FFA mixtures. Overall, 502 differentially expressed clones, representing 21 novel genes and 87 known genes, were detected by SSH. Based on functional clustering, up- and down-regulated genes were mostly related to carbohydrate and lipid metabolism, enzyme activity and signal transduction. The expression of 20 selected clones involved with carbohydrate and lipid metabolism pathways was further studied by quantitative PCR. The data indicated that six clones similar to the genes ChREBP, FoxO1, apoB, IHPK2, KIF1B, and FSP27, which participate in de novo synthesis of fatty acid and secretion of very low density lipoproteins, had significantly lower expression levels in the hepatocytes treated with FFA mixtures. Meanwhile, 13 clones similar to the genes DGAT-1, ACSL1, DHRS7, PPARα, L-FABP, DGAT-2, PCK, ACSL3, CPT-1, A-FABP, PPARβ, MAT, and ALDOB had significantly higher expression levels in the hepatocytes treated with FFA mixtures. These results suggest that several metabolic pathways are altered in goose hepatocytes, which may be useful for further research into the molecular mechanism of goose hepatic steatosis.

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Irbesartan restores the in-vivo insulin signaling pathway leading to Akt activation in obese Zucker rats

Cited by 41 publications

References 55 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

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

Screening and identification of differentially expressed genes in goose hepatocytes exposed to free fatty acid

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