Investigation of the vagal neural pathways and neurotransmitters of the hypothalamus-medulla-liver axis involved in the glycemic control by central action of insulin

• Grant number: 23/08762-9
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2023 - October 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Vagner Roberto Antunes
• Grantee: Vagner Roberto Antunes
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated grant(s): 24/02152-7 - Electrophysiological properties and neurochemical identification of neurons involved in the hypothalamus-medulla-liver/pancreas axis that participates in glycemic control, AP.R
• Associated scholarship(s): 24/03842-7 - Neurochemical characterization of neurons in the paraventricular nucleus of the hypothalamus with projections to the dorsal motor nucleus of the vagus activated by the central action of insulin, BP.MS

Abstract

Glucose is an essential energy source for cells, and therefore, its plasma concentration must be finely controlled to avoid variations, otherwise, it can lead to serious health complications. The liver plays a crucial role in glucose regulation by producing, storing, and releasing it according to the body's needs. Besides to the liver, hormones such as glucagon and insulin act antagonistically to regulate blood glucose levels, depending on the individual's feeding state. Insulin plays a significant role in reducing glucose levels in the body by stimulating its uptake by skeletal muscle, suppressing hepatic glucose production, and regulating its own secretion. Previously we have shown that insulin injected into the brain of Wistar rats decreased glucose concentration in the hepatic vein, and this effect was dependent on the activation of the parasympathetic pathway of the autonomic nervous system (ANS). These findings suggest that the hypothalamus, specifically the paraventricular nucleus (PVN), is a key nucleus for central action of insulin to control hepatic glucose levels, as it maintains monosynaptic neural connections with the dorsal motor nucleus of the vagus (DMV), where the pre-autonomic neurons that innervate the liver are located. Therefore, one of the aims of this project is to identify the neural connections and neurotransmitters involved in the brain-liver axis that modulate hepatic glucose levels. Regarding neurotransmitters, there is evidence of a relationship between the neuropeptide oxytocin (OT) and glucose control. Insulin infusion into the brain increases plasma OT concentration, suggesting an interaction between oxytocinergic neurons in the PVN and the central action of insulin. Supporting these findings, recently published studies from our laboratory have shown that exogenous application of OT increased the excitability of liver-projecting DMV neurons. In addition, we observed a significant staining of oxytocinergic terminals surrounding liver-projecting DMV neurons. The hypothesis raised in this project is that OT may be the neurotransmitter involved in the central action of insulin, responsible to activate the parasympathetic pathway PVN>DMV>liver and playing an important role in controlling hepatic glucose levels. In addition to these findings, other previous studies from our laboratory have shown that insulin injected into the brain did not cause any changes in hepatic glucose levels or activity of the subdiaphragmatic hepatic vagus nerve in an animal model with autonomic dysfunction, known as SHR. Supporting these findings, another recent study we have shown that the DMV-liver neurons of sedentary SHR was not affected by exogenous application of OT. Conversely, the same approach performed in a group of SHR previously subjected to aerobic exercise for 4 weeks, we found that the application of OT increased the firing rate of DMV-liver neurons. With these findings we postulate another hypothesis that autonomic dysfunction, especially the reduction of the vagal component observed in SHR, may be one of the causes of both the failure of central action of insulin to affect the glucose control and the action of neurotransmitters, including OT, on DMV neurons that modulate hepatic functions. The present project proposes two approaches to improve autonomic dysfunction in SHR animals and test the central action of insulin to control hepatic glucose levels: i) a pharmacogenomic approach with gene interference in DMV neurons and a non-pharmacological with aerobic physical exercise, which is known to restore sympathovagal balance. In conclusion, the overall objective of this project is to identify the neural connections and phenotypes, as well as the neurotransmitters between hypothalamic and brainstem nuclei of the parasympathetic pathway of the ANS that integrate the brain-liver axis involved in the neural control of glucose levels under physiological conditions and in an animal model of autonomic dysfunction. (AU)