Plut Charles, Ribière Catherine, Giudicelli Yves, Dausse Jean-Pierre
Department of Biochemistry and Molecular Biology, Faculté de Médecine de Paris-Ile de France-Ouest, Université Versailles-St Quentin en Yvelines, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
J Pharmacol Exp Ther. 2003 Nov;307(2):544-9. doi: 10.1124/jpet.103.054726. Epub 2003 Sep 9.
Although obesity is associated with a state of leptin resistance, it has been suggested that leptin may contribute to the pathogenesis of obesity-related hypertension. In previous studies, we reported that cafeteria diet feeding induces hyperleptinaemia and hyperinsulinemia in both male and female rats, with hypertension occurring only in male rats. However, when female rats were neonatally treated with testosterone (T), these animals develop hypertension when fed the cafeteria diet. These observations led us to investigate leptin signaling and some neuropeptides that are leptin targets in the hypothalamus of male, intact female, and T-treated female cafeteria diet-fed rats. A decrease in the hypothalamic leptin receptors (Ob-Ra and Ob-Rb) and pro-opiomelanocortin (POMC) mRNA was observed only in male hypertensive cafeteria diet-fed rats. Although no alterations in Ob-R occurred in both groups of female cafeteria diet-fed rats, the hyperleptinaemic state of these animals had no influence on POMC mRNA levels. In intact female rats, expression of the suppressors of cytokines signaling SOCS-1, SOCS-2, SOCS-3, and cytokine inhibitor signaling were unaltered, whereas in T-treated females SOCS-3 was overexpressed. Finally SOCS-1 mRNA level was increased only in male rats. Because hyperinsulinemia was reported to counteract the leptin-induced stimulation of the sympathetic tone and because SOCS-1 and -3 are potential inhibitors of insulin signaling, our results suggest that the hypothalamic overexpression of SOCS-1 or SOCS-3 found in male or T-treated female rats after cafeteria diet feeding could block the negative influence of the hyperinsulinemia on the central pressor action of leptin, thereby contributing to their hypertensive state.
尽管肥胖与瘦素抵抗状态相关，但有研究表明瘦素可能参与肥胖相关高血压的发病机制。在之前的研究中，我们报道自由选择饮食喂养可导致雄性和雌性大鼠出现高瘦素血症和高胰岛素血症，然而只有雄性大鼠会发生高血压。但是，当雌性大鼠在新生期接受睾酮（T）处理后，这些动物在自由选择饮食喂养时会出现高血压。这些观察结果促使我们研究雄性、未处理雌性以及经T处理的雌性自由选择饮食喂养大鼠下丘脑的瘦素信号传导以及一些作为瘦素靶点的神经肽。仅在雄性高血压自由选择饮食喂养大鼠中观察到下丘脑瘦素受体（Ob-Ra和Ob-Rb）和阿黑皮素原（POMC）mRNA水平降低。尽管两组雌性自由选择饮食喂养大鼠的Ob-R均无改变，但这些动物的高瘦素血症状态对POMC mRNA水平没有影响。在未处理的雌性大鼠中，细胞因子信号抑制因子SOCS-1、SOCS-2、SOCS-3以及细胞因子抑制信号的表达未改变，而在经T处理的雌性大鼠中SOCS-3过度表达。最后，仅在雄性大鼠中SOCS-1 mRNA水平升高。由于据报道高胰岛素血症可抵消瘦素诱导的交感神经张力刺激，并且因为SOCS-1和-3是胰岛素信号的潜在抑制剂，我们的结果表明，在自由选择饮食喂养后的雄性或经T处理的雌性大鼠中发现的下丘脑SOCS-1或SOCS-3过度表达可能会阻断高胰岛素血症对瘦素中枢升压作用的负面影响，从而导致它们的高血压状态。
