We and others have shown that the nonapeptide, oxytocin (OT), circumvents leptin resistance to elicit body weight loss in obese rodents, nonhuman primates and humans, by reducing food intake while increasing energy expenditure (EE). The identification of recruitable brown adipose tissue (BAT) in humans (95) has renewed interest in drugs that target BAT to elicit weight loss by increasing EE, in conjunction with strategies that reduce food intake. Oxytocin (OT) is a downstream target of the adiposity signal, leptin, and is an attractive therapeutic target to treat obesity in humans (46, 105) because it reduces body weight in DIO rodents even in the presence of “leptin resistance,” which impairs leptin-induced reduction in food intake (60). Aside from eliciting weight loss, OT also elicits beneficial cardiometabolic effects in genetically obese rodent models (77) and reduces blood pressure (BP) in normal (74) and spontaneously hypertensive rats (75). Furthermore, chemogenetic activation of paraventricular nucleus (PVN) OT neurons reduces heart rate (HR) and BP in lean rats and a rat model of heart failure (24, 34). OT neurons that project directly from the parvocellular PVN to the 1) hindbrain nucleus of the solitary tract and/or spinal cord and 2) dorsal motor nucleus of the vagus (79, 85) are positioned to reduce food intake and stimulate EE and decrease HR and BP, respectively. These circuits are therefore potential targets for pharmacological therapies to reverse the elevation in HR and BP associated with diet-induced obesity (DIO; (88, 99)). We recently found in DIO rats, central (25) or systemic OT (Preliminary Data) administered in combination with the beta-3 receptor (β-3R) agonist, CL 316243, is a more effective anti-obesity regimen than either OT or CL 31243 alone. However, we and others have also found CL 316243 and the FDA-approved β-3R agonist, mirabegron, may also increase HR and BP at doses that elevate EE and/or elicit weight loss (Preliminary Data). What remains unclear is whether systemic OT could be used as an adjunct to CL 316243 to promote body weight loss while averting deleterious effects on HR and BP. In Specific Aim 1 we will test the hypothesis that DIO-associated inhibition of PVN OT neurons contributes to the elevated HR and BP associated with DIO. To test this hypothesis, we will employ a chemogenetic strategy to determine if chronic inhibition of PVN OT neurons in low fat diet-fed mice mimics the adverse effects of DIO on HR and BP associated with DIO in male and female DIO Oxytocin-Ires-Cre mice (transgenic mice that express Cre recombinase in OT- expressing cells; available at JAX ®). We further hypothesize that activation of PVN OT neurons will reverse the adverse effects of DIO on HR and BP in DIO. To test this hypothesis, we will examine if chronic chemogenetic excitation of PVN OT neurons attenuates the elevated HR and BP associated with DIO. We anticipate these studies will identify 1) an important role for PVN ...