Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
University of Virginia, Department of Pharmacology, Charlottesville, VA 22908, USA.
Neurosci Lett. 2022 Aug 10;785:136773. doi: 10.1016/j.neulet.2022.136773. Epub 2022 Jul 6.
The action of leptin in brain to increase sympathetic nerve activity (SNA) and blood pressure depends upon functional Angiotensin II (AngII) type 1a receptors (AT1aR); however, the sites and mechanism of interaction are unknown. Here we identify one site, the hypothalamic arcuate nucleus (ArcN), since prior local blockade of AT1aR in the ArcN with losartan or candesartan in anesthetized male rats essentially eliminated the sympathoexcitatory and pressor responses to ArcN leptin nanoinjections. Unlike mice, in male and female rats, AT1aR and LepR rarely co-localized, suggesting that this interdependence occurs indirectly, via a local interneuron or network of neurons. ArcN leptin increases SNA by activating pro-opiomelanocortin (POMC) inputs to the PVN, but this activation requires simultaneous suppression of tonic PVN Neuropeptide Y (NPY) sympathoinhibition. Because AngII-AT1aR inhibits ArcN NPY neurons, we propose that loss of AT1aR suppression of NPY blocks leptin-induced increases in SNA; in other words, ArcN-AngII-AT1aR is a gatekeeper for leptin-induced sympathoexcitation. With obesity, both leptin and AngII increase; therefore, the increased AT1aR activation could open the gate, allowing leptin (and insulin) to drive sympathoexcitation unabated, leading to hypertension.
瘦素在大脑中通过增加交感神经活动（SNA）和血压来发挥作用，这取决于功能性血管紧张素 II（AngII）类型 1a 受体（AT1aR）；然而，其作用部位和相互作用机制尚不清楚。在这里，我们确定了一个部位，即下丘脑弓状核（ArcN），因为先前在麻醉雄性大鼠的 ArcN 中局部阻断 AT1aR 受体（使用氯沙坦或坎地沙坦），基本上消除了 ArcN 瘦素纳米注射引起的交感神经兴奋和升压反应。与小鼠不同，在雄性和雌性大鼠中，AT1aR 和 LepR 很少共定位，这表明这种相互依赖是间接的，通过局部中间神经元或神经元网络发生。ArcN 瘦素通过激活 POMC 对 PVN 的输入来增加 SNA，但这种激活需要同时抑制 PVN 神经肽 Y（NPY）的紧张性抑制作用。由于 AngII-AT1aR 抑制 ArcN NPY 神经元，我们提出，AT1aR 抑制 NPY 的丧失阻止了瘦素诱导的 SNA 增加；换句话说，ArcN-AngII-AT1aR 是瘦素诱导的交感兴奋的守门员。随着肥胖的发生，瘦素和 AngII 都会增加；因此，增加的 AT1aR 激活可能会打开这扇门，允许瘦素（和胰岛素）不受抑制地驱动交感神经兴奋，导致高血压。
