Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity
Chronic antidiabetic and cardiovascular actions of leptin: role of CNS and increased adrenergic activity
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DOI：
10.1152/ajpregu.00187.2006
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发表时间：
2006-11-01
影响因子：
2.8
通讯作者：
Hall, John E.
中科院分区：
文献类型：
--
作者：
da Silva, Alexandre A.;Tallam, Lakshmi S.;Hall, John E.
本研究探讨了直接中枢神经系统（CNS）的行动和增加肾上腺素能活性介导的慢性抗糖尿病和心血管作用的瘦素的重要性。胰岛素缺乏的大鼠（链脲佐菌素，50毫克/公斤）被用来检查独立于胰岛素的变化，瘦素对葡萄糖稳态的影响。雄性Sprague-Dawley大鼠装有动脉和静脉导管以及脑室内插管，用于24小时/天的血压（BP）和心率（HR）监测以及静脉内和脑室内输注。胰岛素缺乏型糖尿病伴有明显的高血糖、暴食、血压下降和心率明显下降。静脉或脑室内注射瘦素治疗后，血糖水平完全恢复到对照值（分别为384 +/- 58至102 +/- 28和307 +/- 38至65 +/- 7 mg/dl）、摄食量、BP和HR（分别为304 +/- 8至364 +/- 7和317 +/- 13至423 +/- 9 bpm）。联合阻断α（1）、β（1）和β（2）肾上腺素能受体可使HR升高减弱30%~ 50%，但对瘦素的抗糖尿病和饮食作用无影响。阻断β（3）-肾上腺素能受体并不能减弱瘦素对慢性心血管或代谢的影响。这些数据表明，瘦素通过其在中枢神经系统中的直接作用，在胰岛素缺乏大鼠中具有强大的抗糖尿病作用，而不依赖于外周α（1）、β（1）、β（2）和β（3）肾上腺素能活性的增加。瘦素还发挥重要的长期心血管作用，其部分通过α（1）-和β（1）/β（2）-肾上腺素能激活介导。这些发现为长期控制葡萄糖稳态和心血管调节的新途径提供了新的见解。
This study examined the importance of direct central nervous system (CNS) actions and increased adrenergic activity in mediating the chronic antidiabetic and cardiovascular actions of leptin. Insulin-deficient rats (streptozotocin, 50 mg/kg) were used to examine the effects of leptin on glucose homeostasis independent of changes in insulin. Male Sprague-Dawley rats were instrumented with arterial and venous catheters and intracerebroventricular cannula for 24-h/day blood pressure (BP) and heart rate (HR) monitoring and intravenous and intracerebroventricular infusions. Insulin-deficient diabetes was associated with marked hyperglycemia, hyperphagia, decreased BP, and pronounced fall in HR. Leptin treatment, intravenous or intracerebroventricular, completely restored to control values plasma glucose levels (384 +/- 58 to 102 +/- 28 and 307 +/- 38 to 65 +/- 7 mg/dl, respectively), food intake, BP, and HR (304 +/- 8 to 364 +/- 7 and 317 +/- 13 to 423 +/- 9 bpm, respectively). Combined blockade of alpha(1)-, beta(1)-, and beta(2)-adrenergic receptors attenuated the rise in HR by 30 to 50% but had no effect on the antidiabetic and dietary actions of leptin. Blockade of beta(3)-adrenergic receptors did not attenuate the chronic cardiovascular or metabolic effects of leptin. These data demonstrate that leptin, via its direct actions in the CNS, has powerful antidiabetic actions in insulin-deficient rats independent of increased peripheral alpha(1), beta(1), beta(2), and beta(3)-adrenergic activity. Leptin also exerts important long-term cardiovascular actions that are partially mediated via alpha(1)- and beta(1)/beta(2)-adrenergic activation. These findings provide new insights into novel pathways for long-term control of glucose homeostasis and cardiovascular regulation.