Abstract
Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT.Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2+/+ and IRS2−/− mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2+/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2+/+ and IRS2−/− littermates to evaluate vasodilator properties of PVAT.Results: IRS2−/− RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2+/+ RA. IRS2+/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2−/− RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2+/+ PVAT (17 ± 4.8, p = 0.014), yet induced a 10 ± 7.6% decrease in diameter in the presence of IRS2−/− PVAT. Adipocytes in IRS2−/− PVAT (1314 ± 161 μm2) were larger (p = 0.0013) than of IRS2+/+ PVAT (915 ± 63 μm2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2+/+ and IRS2−/− PVAT, as were expression of pro-inflammatory genes (TNF-α, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2−/− and IRS2+/+ PVAT.Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion.
Highlights
Insulin signaling in adipose tissue has been shown to regulate insulin’s effects in muscle
To gain insight into the role of IRS2 in insulin-dependent vasoreactivity in muscle, we first examined the reactivity of IRS2+/+ and IRS2−/− gracilis muscle resistance arteries (RA) obtained from IRS2+/+ and IRS2−/− mice in response to insulin and other vasoactive molecules.IRS2+/+ and IRS2−/−RA showed normal endothelial and smooth muscle function, as reflected by responses to acetylcholine (Figure 1A), sodium nitroprusside (Figure 1B), and exogenous ET-1 (Figure 1C)
Insulin induced vasoconstriction in isolated IRS2+/+RA, which was inhibited by the non-selective ET-1 receptor antagonist PD142893 (Figures 2A,B)
Summary
Insulin signaling in adipose tissue has been shown to regulate insulin’s effects in muscle. Perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin’s actions on the vessel wall as well as the vasoactive properties of PVAT. Resistance to insulin’s vasodilator effects is characteristic of insulin resistant and type 2 diabetic subjects (Jiang et al, 1999; Okon et al, 2005), and has been shown to contribute to increased vascular resistance (Woerdeman et al, 2016), defects in organ perfusion and atherosclerosis (RaskMadsen et al, 2010). As such, understanding and reversing defects in vascular insulin signaling contributes to prevention of cardiovascular complications of obesity and DM2. The roles of IRS1 and−2 in insulin’s vasoconstrictor actions have not been studied
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