Resistance to acute NO-mimetic and EDHF-mimetic effects of leptin in the metabolic syndrome

Aims: We examined mechanisms leading to the impairment of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)-dependent vasorelaxation in response to acutely administered leptin in rats with the metabolic syndrome. Main methods: Effects of leptin on blood pressure and NO and cGMP in the aortic wall were studied in four groups of rats: (1) lean control, (2) obese, fed cafeteria diet for 3 months (hyperleptinemia and hyperinsulinemia), (3) hyperleptinemia induced by administration of exogenous leptin for 8 days, and (4) fructose-fed, receiving 20% fructose in the drinking water for 8 weeks (hyperinsulinemia with slightly elevated leptin). Keyfindings: Stimulatory effect of leptin on NO and cGMP production in the aortic wall was impaired in obese and hyperleptinemic groups but not in the fructose group. In contrast, EDHF-mimetic effect of leptin was impaired in obese and fructose-fed but not in the hyperleptinemic group. Leptin increased tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the aortic wall, and this effect was impaired in obese and fructose-fed animals. The EDHF-mimetic effect of leptin was abolished by phosphoinositide 3-kinase inhibitor. wortmannin, whereas its effect on NO was not. In addition, IRS-1 phosphorylation at Ser(307) and Set(612) was enhanced in obese and fructose-fed but not in hyperleptinemic rats. Significance: These results indicate that: (1) long-term hyperleptinemia induces resistance to acute vascular NO-mimetic effect of leptin in obesity/metabolic syndrome, (2) leptin stimulates EDHF in IRS-1 and PI3K-dependent manner, and this effect is impaired in obesity due to excessive serine phosphorylation of IRS-1. (C) 2009 Elsevier Inc. All rights reserved.