Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa, Japan
Department of Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Diabetes. 2015 Nov;64(11):3725-36. doi: 10.2337/db15-0282. Epub 2015 Aug 26.
Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals.
内脂素-1 作用于下丘脑并调节自主神经系统。然而，内脂素-1 对自主神经系统的下丘脑机制尚不清楚。在这项研究中，我们发现脑室（ICV）内给予内脂素-1 增加了大鼠细胞外信号调节激酶（ERK）的活性。此外，ICV 注射内脂素-1 刺激了肾脏、肝脏和白色脂肪组织（WAT）以及血压的交感神经活性，这些作用由于 ERK 的药理学抑制而被消除。内脂素-1 注入室旁核（PVN）也观察到肾交感神经兴奋和高血压作用。此外，内脂素-1 增加了 PVN 中磷酸化（p）-ERK1/2 阳性神经元的数量，并增加了促肾上腺皮质激素释放激素（CRH）表达神经元中的蛋白共表达。CRH 信号转导的药理学阻断抑制了内脂素-1 对肾交感神经和高血压的反应。最后，肥胖动物（如高脂肪饮食喂养的大鼠和瘦素受体缺陷型 Zucker 肥胖大鼠）中，WAT 的交感刺激和对内脂素-1 的 p-ERK1/2 水平增加对内脂素-1 的反应得以保留。这些发现表明，内脂素-1 通过 PVN-CRH 神经元中的 ERK 信号调节自主神经系统，以维持心血管功能，而内脂素-1 的抗肥胖作用是通过肥胖动物下丘脑 ERK 依赖性交感神经兴奋介导的。
