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APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice.

Wang Y, Cheng KK, Lam KS, Wu D, Wang Y, Huang Y, Vanhoutte PM, Sweeney G, Li Y, Xu A - Diabetes (2011)

Bottom Line: However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear.In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

ABSTRACT

Objective: Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells.

Research design and methods: Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.

Results: Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.

Conclusions: APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.

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Transgenic expression of APPL1 counteracts dietary obesity–induced vascular insulin resistance. A–C: Concentration-dependent relaxations to insulin in mesenteric arteries isolated from APPL1-Tg mice and their WT littermates fed either STD or HFD at age of 8, 12, and 16 weeks. D: Data are shown as area under the curve (AUC). *P < 0.05; **P < 0.01 (n = 6–8).
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Figure 2: Transgenic expression of APPL1 counteracts dietary obesity–induced vascular insulin resistance. A–C: Concentration-dependent relaxations to insulin in mesenteric arteries isolated from APPL1-Tg mice and their WT littermates fed either STD or HFD at age of 8, 12, and 16 weeks. D: Data are shown as area under the curve (AUC). *P < 0.05; **P < 0.01 (n = 6–8).

Mentions: To further investigate the role of APPL1 in modulating vascular tone under pathological conditions, both APPL1-Tg mice and their WT littermates were fed HFD to induce obesity. Mice were killed after 8, 12, or 16 weeks of feeding with the diet. HFD induced a similar degree of body weight gain in APPL1-Tg mice and WT mice (data not shown). In WT mice, HFD resulted in a progressive impairment in insulin-evoked relaxation (Fig. 2). In 8- and 12-week-old WT mice, relaxations to insulin (100 nmol/L) were 71.6 ± 3.43% and 65.69 ± 2.77%, respectively, when fed STD but declined to 37.1 ± 13.8% and 23.7 ± 2.9% when fed HFD (Fig. 2A and B). In 16-week-old WT mice, insulin (100 nmol/L) induced relaxation under STD (52.2 ± 2.47%) but evoked contractions under HFD (−8.95 ± 3.07%) (Fig. 2C). The transgenic expression of APPL1 prevented the HFD-induced impairment in insulin-induced relaxation. In age-matched APPL1-Tg mice fed an HFD, the vasoconstrictor effect of insulin observed in 16-week-old WT mice was reversed to a relaxation (Fig. 2D).


APPL1 counteracts obesity-induced vascular insulin resistance and endothelial dysfunction by modulating the endothelial production of nitric oxide and endothelin-1 in mice.

Wang Y, Cheng KK, Lam KS, Wu D, Wang Y, Huang Y, Vanhoutte PM, Sweeney G, Li Y, Xu A - Diabetes (2011)

Transgenic expression of APPL1 counteracts dietary obesity–induced vascular insulin resistance. A–C: Concentration-dependent relaxations to insulin in mesenteric arteries isolated from APPL1-Tg mice and their WT littermates fed either STD or HFD at age of 8, 12, and 16 weeks. D: Data are shown as area under the curve (AUC). *P < 0.05; **P < 0.01 (n = 6–8).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198090&req=5

Figure 2: Transgenic expression of APPL1 counteracts dietary obesity–induced vascular insulin resistance. A–C: Concentration-dependent relaxations to insulin in mesenteric arteries isolated from APPL1-Tg mice and their WT littermates fed either STD or HFD at age of 8, 12, and 16 weeks. D: Data are shown as area under the curve (AUC). *P < 0.05; **P < 0.01 (n = 6–8).
Mentions: To further investigate the role of APPL1 in modulating vascular tone under pathological conditions, both APPL1-Tg mice and their WT littermates were fed HFD to induce obesity. Mice were killed after 8, 12, or 16 weeks of feeding with the diet. HFD induced a similar degree of body weight gain in APPL1-Tg mice and WT mice (data not shown). In WT mice, HFD resulted in a progressive impairment in insulin-evoked relaxation (Fig. 2). In 8- and 12-week-old WT mice, relaxations to insulin (100 nmol/L) were 71.6 ± 3.43% and 65.69 ± 2.77%, respectively, when fed STD but declined to 37.1 ± 13.8% and 23.7 ± 2.9% when fed HFD (Fig. 2A and B). In 16-week-old WT mice, insulin (100 nmol/L) induced relaxation under STD (52.2 ± 2.47%) but evoked contractions under HFD (−8.95 ± 3.07%) (Fig. 2C). The transgenic expression of APPL1 prevented the HFD-induced impairment in insulin-induced relaxation. In age-matched APPL1-Tg mice fed an HFD, the vasoconstrictor effect of insulin observed in 16-week-old WT mice was reversed to a relaxation (Fig. 2D).

Bottom Line: However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear.In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

ABSTRACT

Objective: Insulin stimulates both nitric oxide (NO)-dependent vasodilation and endothelin-1 (ET-1)-dependent vasoconstriction. However, the cellular mechanisms that control the dual vascular effects of insulin remain unclear. This study aimed to investigate the roles of the multidomain adaptor protein APPL1 in modulating vascular actions of insulin in mice and in endothelial cells.

Research design and methods: Both APPL1 knockout mice and APPL1 transgenic mice were generated to evaluate APPL1's physiological roles in regulating vascular reactivity and insulin signaling in endothelial cells.

Results: Insulin potently induced NO-dependent relaxations in mesenteric arteries of 8-week-old mice, whereas this effect of insulin was progressively impaired with ageing or upon development of obesity induced by high-fat diet. Transgenic expression of APPL1 prevented age- and obesity-induced impairment in insulin-induced vasodilation and reversed obesity-induced augmentation in insulin-evoked ET-1-dependent vasoconstriction. By contrast, genetic disruption of APPL1 shifted the effects of insulin from vasodilation to vasoconstriction. At the molecular level, insulin-elicited activation of protein kinase B (Akt) and endothelial NO synthase and production of NO were enhanced in APPL1 transgenic mice but were abrogated in APPL1 knockout mice. Conversely, insulin-induced extracellular signal-related kinase (ERK)1/2 phosphorylation and ET-1 expression was augmented in APPL1 knockout mice but was diminished in APPL1 transgenic mice. In endothelial cells, APPL1 potentiated insulin-stimulated Akt activation by competing with the Akt inhibitor Tribbles 3 (TRB3) and suppressed ERK1/2 signaling by altering the phosphorylation status of its upstream kinase Raf-1.

Conclusions: APPL1 plays a key role in coordinating the vasodilator and vasoconstrictor effects of insulin by modulating Akt-dependent NO production and ERK1/2-mediated ET-1 secretion in the endothelium.

Show MeSH
Related in: MedlinePlus