Bełtowski Jerzy, Wójcicka Grazyna, Jamroz-Wiśniewska Anna, Marciniak Andrzej
Department of Pathophysiology, Medical University, Lublin, Poland.
Life Sci. 2009 Oct 7;85(15-16):557-67. doi: 10.1016/j.lfs.2009.08.002. Epub 2009 Aug 15.
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.
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 3months (hyperleptinemia and hyperinsulinemia), (3) hyperleptinemia induced by administration of exogenous leptin for 8days, and (4) fructose-fed, receiving 20% fructose in the drinking water for 8weeks (hyperinsulinemia with slightly elevated leptin).
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 Ser(612) was enhanced in obese and fructose-fed but not in hyperleptinemic rats.
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.
我们研究了在患有代谢综合征的大鼠中，急性给予瘦素后导致一氧化氮（NO）和内皮衍生超极化因子（EDHF）依赖性血管舒张受损的机制。
在四组大鼠中研究了瘦素对血压以及主动脉壁中NO和cGMP的影响：（1）瘦素对照组，（2）肥胖组，喂食“自助式饮食”3个月（高瘦素血症和高胰岛素血症），（3）通过给予外源性瘦素8天诱导的高瘦素血症组，（4）果糖喂养组，饮用含20%果糖的水8周（高胰岛素血症伴瘦素轻度升高）。
肥胖组和高瘦素血症组中，瘦素对主动脉壁中NO和cGMP生成的刺激作用受损，但果糖组未受损。相反，肥胖组和果糖喂养组中瘦素的EDHF模拟作用受损，但高瘦素血症组未受损。瘦素增加了主动脉壁中胰岛素受体底物-1（IRS-1）的酪氨酸磷酸化，肥胖组和果糖喂养组动物的这种作用受损。瘦素的EDHF模拟作用被磷酸肌醇3激酶抑制剂渥曼青霉素消除，而其对NO的作用未被消除。此外，肥胖组和果糖喂养组大鼠中Ser(307)和Ser(61)处的IRS-1磷酸化增强，但高瘦素血症组未增强。
这些结果表明：（1）长期高瘦素血症在肥胖/代谢综合征中诱导对瘦素急性血管NO模拟作用的抵抗，（2）瘦素以IRS-1和PI3K依赖性方式刺激EDHF，并且由于IRS-1的丝氨酸过度磷酸化，这种作用在肥胖中受损。
