Center on Functional Genomics of Hypertension, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Am J Physiol Heart Circ Physiol. 2012 Jul 15;303(2):H197-206. doi: 10.1152/ajpheart.00974.2011. Epub 2012 May 18.
The sympathetic nervous system, leptin, and renin-angiotensin system (RAS) have been implicated in obesity-associated hypertension. There is increasing evidence for the presence of both leptin and angiotensin II receptors in several key brain cardiovascular and metabolic control regions. We tested the hypothesis that the brain RAS plays a facilitatory role in the sympathetic nerve responses to leptin. In rats, intracerebroventricular (ICV) administration of losartan (5 μg) selectively inhibited increases in renal and brown adipose tissue (BAT) sympathetic nerve activity (SNA) produced by leptin (10 μg ICV) but did not reduce the SNA responses to corticotrophin-releasing factor (CRF) or the melanocortin receptor agonist MTII. In mice with deletion of angiotensin II type-1a receptors (AT(1a)R(-/-)), increases in renal and BAT SNA induced by leptin (2 μg ICV) were impaired whereas SNA responses to MTII were preserved. Decreases in food intake and body weight with ICV leptin did not differ in AT(1a)R(-/-) vs. AT(1a)R(+/+) mice. ICV leptin in rats increased AT(1a)R and angiotensin-converting enzyme (ACE) mRNA in the subfornical organ and AT(1a)R mRNA in the arcuate nucleus, suggesting leptin-induced upregulation of the brain RAS in specific brain regions. To evaluate the role of de novo production of brain angiotensin II in SNA responses to leptin, we treated rats with captopril (12.5 μg ICV). Captopril attenuated leptin effects on renal and BAT SNA. In conclusion, these studies provide evidence that the brain RAS selectively facilitates renal and BAT sympathetic nerve responses to leptin while sparing effects on food intake.
交感神经系统、瘦素和肾素-血管紧张素系统（RAS）与肥胖相关的高血压有关。越来越多的证据表明，在几个关键的脑心血管和代谢控制区域中，都存在瘦素和血管紧张素 II 受体。我们检验了这样一个假设，即脑 RAS 在瘦素引起的交感神经反应中起促进作用。在大鼠中，脑室（ICV）给予氯沙坦（5μg）选择性抑制了瘦素（10μg ICV）引起的肾脏和棕色脂肪组织（BAT）交感神经活动（SNA）的增加，但并未减少对促肾上腺皮质释放因子（CRF）或黑素皮质素受体激动剂 MTII 的 SNA 反应。在血管紧张素 II 型 1a 受体（AT（1a）R（-/-））缺失的小鼠中，瘦素（2μg ICV）引起的肾脏和 BAT SNA 的增加受损，而 MTII 的 SNA 反应则得到保留。ICV 给予瘦素后，食欲和体重下降在 AT（1a）R（-/-）与 AT（1a）R（+/+）小鼠之间没有差异。ICV 给予大鼠瘦素可增加下丘脑中的 AT（1a）R 和血管紧张素转换酶（ACE）mRNA，以及弓状核中的 AT（1a）R mRNA，提示瘦素诱导特定脑区的脑 RAS 上调。为了评估脑内血管紧张素 II 从头合成在瘦素引起的 SNA 反应中的作用，我们用卡托普利（12.5μg ICV）处理大鼠。卡托普利减弱了瘦素对肾脏和 BAT SNA 的作用。总之，这些研究提供的证据表明，脑 RAS 选择性地促进了肾脏和 BAT 交感神经对瘦素的反应，同时对摄食的影响则得到了保留。
