Oxytocin Signaling in the Control of Cardiometabolic Function in Diet-Induced Obesity

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 OT neuronal inhibition in the adverse effects associated with
DIO and 2) the extent to which increased PVN OT neuronal signaling can reverse these effects. Endpoints will
include HR, BP, food intake, body composition, body weight, and histological (cardiomyocyte cross sectional
area, myocardial lipid content) and genetic (inflammatory) markers of heart health. In Specific Aim 2 we will test
the translational hypothesis that OT 1) reverses the elevations of HR and BP associated with DIO and 2) can be
used as an adjunct to reduce elevations in HR and BP associated with β-3R agonist treatment in male and
female DIO rats. To test these hypotheses, we will determine the effects of chronic systemic OT alone and in
combination with CL 316243 on HR and BP in male and female DIO rats. Endpoints will include HR, BP, food
intake, body composition, body weight, and histological (cardiomyocyte cross sectional area, myocardial lipid
content) and genetic (inflammatory) markers of heart health. Our findings will create a preclinical infrastructure
upon which future studies are undertaken to address whether intranasal OT therapy may reverse these adverse
cardiometabolic effects associated with obesity in humans.

Grant Number: 5I01BX004102-08
NIH Institute/Center: VA
Principal Investigator: James Blevins