Hypothalamic oxytocin neuron activation rescues cardiac metabolism through cardiac cholinergic signaling in type 2 diabetes

Cardiac autonomic neuropathy (CAN) is a serious complication of type 2 diabetes (T2D) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests as a decline in parasympathetic tone and overactivation of sympathetic activity that contributes to resting tachycardia and fixed heart rate, and myocardial infarction. Although it is a common complication, very little is known regarding how CAN directly increases the risk for myocardial injury and disease, and thus there are no current unified treatment algorithms other than lifestyle changes, glycemic control and management of cardiovascular risk factors. We have recently identified a novel mechanism for restoring cardioprotective parasympathetic tone to the heart to reduce myocardial damage in diseases with similar autonomic dysfunction, such as heart failure, myocardial infarct, and sleep apnea. Brainstem parasympathetic cardiac vagal neurons (CVNs) receive powerful excitation from a population of oxytocin (OXT) neurons that originate in the paraventricular nucleus of the hypothalamus (PVN). These unique neurons co-release OXT and enhance excitatory glutamatergic neuro-transmission to CVNs. Based upon our novel results in diseases with similar autonomic imbalances, our overall hypothesis is that PVN OXT neuron activation is cardioprotective in type 2 diabetes. This overarching hypothesis will be tested in two Specific Aims. Aim 1 will determine if PVN OXT neuron activation improves cardiac metabolic flexibility by increasing glucose oxidation. Animals will be injected intravenously with heavy-carbon-labelled glucose or palmitate to measure substrate utilization by the heart. Carbon tracing of metabolites in left ventricular samples will reveal changes to energy utilization caused by treatment. Mass-spectrometry will be used to identify the metabolites to test the hypothesis that OXT neuron activation improves cardiac energy metabolism as a mechanism of protection. Aim 2 will determine if PVN OXT neuron activation improves cardiomyocyte calcium cycling and contractility. We will test our hypothesis that PVN OXT neuron activation confers cardioprotection by improving calcium homeostasis and contractility in cardiomyocytes. Using collagenase digestion of hearts from Control, T2D, and Treatment animals we will use assess contractility and calcium flux of individual cardiomyocytes with IonOptix. We will probe for changes to calcium handling protein expression using western blot. Project Number: 1F31HL174131-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Anna Nilsson | Institution: UNIVERSITY OF HAWAII AT MANOA, HONOLULU, HI | Award Amount: $43,903 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F10A-R (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31HL17413101A1