Objective

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as anti-diabetic drugs and are approved for obesity treatment. However, GLP-1RAs also affect heart rate (HR) and arterial blood pressure (ABP) in rodents and humans. Although the activation of GLP-1 receptors (GLP-1R) is known to increase HR, the circuits recruited are unclear, and in particular, it is unknown whether GLP-1RAs activate preproglucagon (PPG) neurons, the brain source of GLP-1, to elicit these effects.

Methods

We investigated the effect of GLP-1RAs on heart rate in anaesthetized adult mice. In a separate study, we manipulated the activity of nucleus tractus solitarius (NTS) PPG neurons (PPG^NTS) in awake, freely behaving transgenic Glu-Cre mice implanted with biotelemetry probes and injected with AAV-DIO-hM3Dq:mCherry or AAV-mCherry-FLEX-DTA.

Results

Systemic administration of the GLP-1RA Ex-4 increased resting HR in anaesthetized or conscious mice, but had no effect on ABP in conscious mice. This effect was abolished by β-adrenoceptor blockade with atenolol, but unaffected by the muscarinic antagonist atropine. Furthermore, Ex-4-induced tachycardia persisted when PPG^NTS neurons were ablated, and Ex-4 did not induce expression of the neuronal activity marker cFos in PPG^NTS neurons. PPG^NTS ablation or acute chemogenetic inhibition of these neurons via hM4Di receptors had no effect on resting HR. In contrast, chemogenetic activation of PPG^NTS neurons increased resting HR. Furthermore, the application of GLP-1 within the subarachnoid space of the middle thoracic spinal cord, a major projection target of PPG neurons, increased HR.

Conclusions

These results demonstrate that both systemic application of Ex-4 or GLP-1 and chemogenetic activation of PPG^NTS neurons increases HR. Ex-4 increases the activity of cardiac sympathetic preganglionic neurons of the spinal cord without recruitment of PPG^NTS neurons, and thus likely recapitulates the physiological effects of PPG neuron activation. These neurons therefore do not play a significant role in controlling resting HR and ABP but are capable of inducing tachycardia and so are likely involved in cardiovascular responses to acute stress.

中文翻译：

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孤束核中的 PPG 神经元调节心率，但不介导 GLP-1 受体激动剂诱导的小鼠心动过速。

客观的

胰高血糖素样肽-1 受体激动剂 (GLP-1RA) 被用作抗糖尿病药物，并被批准用于肥胖症治疗。然而，GLP-1RAs 也会影响啮齿动物和人类的心率 (HR) 和动脉血压 (ABP)。虽然已知 GLP-1 受体 (GLP-1R) 的激活会增加 HR，但募集的电路尚不清楚，特别是 GLP-1RA 是否激活前胰高血糖素 (PPG) 神经元（GLP-1 的脑源）尚不清楚, 以引发这些影响。

方法

我们研究了 GLP-1RAs 对麻醉成年小鼠心率的影响。在另一项研究中，我们在清醒时操纵孤束核 (NTS) PPG 神经元 (PPG ^NTS ) 的活动，自由行为的转基因 Glu-Cre 小鼠植入生物遥测探针并注射 AAV-DIO-hM3Dq:mCherry 或 AAV-mCherry -FLEX-DTA。

结果

GLP-1RA Ex-4 的全身给药增加了麻醉或清醒小鼠的静息心率，但对清醒小鼠的 ABP 没有影响。用阿替洛尔阻断 β-肾上腺素能受体可消除这种作用，但不受毒蕈碱拮抗剂阿托品的影响。^{此外，当 PPG NTS}神经元被消融时，Ex-4 诱导的心动过速持续存在，并且 Ex-4 不诱导 PPG ^NTS神经元中神经元活动标记 cFos 的表达。通过 hM4Di 受体对这些神经元的PPG ^{NTS消融或急性化学遗传学抑制对静息 HR 没有影响。}相反，PPG ^{NTS的化学遗传学激活}神经元增加静息心率。此外，GLP-1 在中胸脊髓蛛网膜下腔（PPG 神经元的主要投射目标）内的应用增加了 HR。

结论

这些结果表明，Ex-4 或 GLP-1 的全身应用和 PPG ^NTS神经元的化学遗传学激活都会增加 HR。^{Ex-4 在不募集 PPG NTS}神经元的情况下增加了脊髓心脏交感神经节前神经元的活动，因此可能概括了 PPG 神经元激活的生理效应。因此，这些神经元在控制静息 HR 和 ABP 方面没有发挥重要作用，但能够诱导心动过速，因此可能参与心血管对急性压力的反应。