Holt, MK;
Cook, DR;
Brierley, DI;
Richards, JE;
Reimann, F;
Gourine, AV;
Marina, N;
(2020)
PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice.
Molecular Metabolism
, Article 101024. 10.1016/j.molmet.2020.101024.
(In press).
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Trapp_PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice_Pre-proof.pdf - Accepted Version Download (3MB) | Preview |
Abstract
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. While 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, 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 thus 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.
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