Prediabetic cardiomyopathy is attenuated by hypothalamic PVN oxytocin neuron activation

Diagnoses of prediabetes and metabolic syndromes, such as metabolic-associated steatotic liver disease (MASLD), are increasing at an alarming rate worldwide, often simultaneously. A significant consequence of these is high risk of cardiovascular disease, highlighting the need for cardiac-specific therapeutics for intervention during the prediabetic stage. Recent studies have demonstrated that chemogenetic activation of the cardiac parasympathetic system through hypothalamic oxytocin (OXT) neurons provides cardioprotective effects in heart disease models by targeting excitatory neurotransmission to brainstem cardiac vagal neurons. In a prediabetic rat model, we hypothesized that stimulating this neural network would offer cardioprotection. To test this, we induced prediabetes through prolonged high-fat, high-fructose feeding. We stereotactically injected viral vectors into the paraventricular nucleus (PVN) of the hypothalamus in neonatal rats to express designer receptors exclusively activated by designer drugs (i.e. Designer Receptors Exclusively Activated by Designer Drugs; DREADDs) in a subset of PVN OXT neurons, chronically activated using the designer drug clozapine N-oxide (CNO). Treated animals exhibited improved cardiac diastolic function and reduced left ventricular fibrosis compared to non-treated diseased animals after 4 weeks of CNO, with no change to systemic insulin resistance, hyperinsulinaemia, and elevated triglycerides. Transcriptional analysis of left ventricular tissue indicates the preservation of pathways involved in metabolism (Pdk4, Pdp1 and Hk2) and ion handling (Sln, Atp1a2 and Atp1a4) in treated compared to diseased animals. These findings underscore the benefits of stimulating the OXT network to counteract prediabetic cardiomyopathy, independent of systemic prediabetes. OXT neurons and their downstream networks appear to be a promising therapeutic target for activating protective parasympathetic-mediated cellular pathways within the heart during prediabetic cardiomyopathy. KEY POINTS: Male rats fed a long-term high-fat, high-fructose diet develop prediabetes, marked by systemic insulin resistance and hyperinsulinaemia, along with characteristics of metabolic-associated steatotic liver disease. Animals exhibit prediabetic cardiomyopathy marked by diastolic dysfunction, interstitial fibrosis, a thickened left ventricular wall and tachycardia with reduced heart rate variability. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)-mediated chemogenetic activation of oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus improves cardiac diastolic dysfunction, reduces fibrosis and restores autonomic balance without impacting systemic insulin resistance or hyperinsulinaemia. Transcriptomic analysis of the left ventricle suggests that activation of hypothalamic oxytocin neurons influences cardiac metabolism and ion handling, potentially serving as mechanisms of protection. Our data demonstrate for the first time that paraventricular oxytocin neuron activation is a cardiac-specific approach to improve prediabetic cardiomyopathy.