Department of Applied Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
College of Life and Health Sciences, Chubu University, Kasugai, Japan.
FASEB J. 2023 Sep;37(9):e23141. doi: 10.1096/fj.202300879RR.
Insulin not only regulates glucose and/or lipid metabolism but also modulates brain neural activity. The nucleus tractus solitarius (NTS) is a key central integration site for sensory input from working skeletal muscle and arterial baroreceptors during exercise. Stimulation of the skeletal muscle exercise pressor reflex (EPR), the responses of which are buffered by the arterial baroreflex, leads to compensatory increases in arterial pressure to supply blood to working muscle. Evidence suggests that insulin signaling decreases neuronal excitability in the brain, thus antagonizing insulin receptors (IRs) may increase neuronal excitability. However, the impact of brain insulin signaling on the EPR remains fully undetermined. We hypothesized that antagonism of NTS IRs increases EPR function in normal healthy rodents. In decerebrate rats, stimulation of the EPR via electrically induced muscle contractions increased peak mean arterial pressure (MAP) responses 30 min following NTS microinjections of an IR antagonist (GSK1838705, 100 μM; Pre: Δ16 ± 10 mmHg vs. 30 min: Δ23 ± 13 mmHg, n = 11, p = .004), a finding absent in sino-aortic baroreceptor denervated rats. Intrathecal injections of GSK1838705 did not influence peak MAP responses to mechano- or chemoreflex stimulation of the hindlimb muscle. Immunofluorescence triple overlap analysis following repetitive EPR stimulation increased c-Fos overlap with EPR-sensitive nuclei and IR-positive cells relative to sham operation (p < .001). The results suggest that IR blockade in the NTS potentiates the MAP response to EPR stimulation. In addition, insulin signaling in the NTS may buffer EPR stimulated increases in blood pressure via baroreflex-mediated mechanisms during exercise.
胰岛素不仅调节葡萄糖和/或脂质代谢，还调节大脑神经活动。孤束核（NTS）是运动过程中来自工作骨骼肌和动脉压力感受器的感觉输入的关键中枢整合部位。刺激骨骼肌运动加压反射（EPR），其反应被动脉压力反射缓冲，导致动脉压代偿性增加以向工作肌肉供血。有证据表明，胰岛素信号降低大脑中的神经元兴奋性，因此拮抗胰岛素受体（IR）可能会增加神经元兴奋性。然而，大脑胰岛素信号对 EPR 的影响尚未完全确定。我们假设，NTS IR 的拮抗作用会增加正常健康啮齿动物的 EPR 功能。在去大脑大鼠中，通过电诱导肌肉收缩刺激 EPR 会增加 NTS 微注射 IR 拮抗剂（GSK1838705，100 μM；Pre：Δ16±10mmHg 与 30min：Δ23±13mmHg，n=11，p=0.004）后 30 分钟的峰值平均动脉压（MAP）反应，在去窦弓压力感受器大鼠中则没有这种现象。鞘内注射 GSK1838705不会影响机械或化学反射刺激后肢肌肉对峰值 MAP 反应。重复 EPR 刺激后的免疫荧光三重重叠分析增加了 c-Fos 与 EPR 敏感核和 IR 阳性细胞的重叠，与假手术相比（p<0.001）。结果表明，NTS 中的 IR 阻断增强了 EPR 刺激对 MAP 反应的作用。此外，在运动过程中，NTS 中的胰岛素信号可能通过压力反射介导的机制缓冲 EPR 刺激引起的血压升高。
