We and others have shown that the nonapeptide, oxytocin (OT), circumvents leptin resistance and elicits body weight (BW) loss in diet-induced obese (DIO) rodents, nonhuman primates and obese humans, by reducing both food intake and increasing energy expenditure (EE). The discovery of recruitable brown adipose tissue (BAT) in humans has renewed interest in targeting BAT to elicit weight loss by increasing EE. OT neurons that project directly from the parvocellular paraventricular nucleus (pPVN) to the hindbrain nucleus of the solitary tract (NTS) are positioned to regulate energy homeostasis by reducing food intake and increasing BAT thermogenesis.
In Specific Aim 1 we will test the hypothesis that OT-induced stimulation of sympathetic outflow to interscapular (IBAT) contributes to its ability to elicit weight loss in DIO rodents. To test this, we will determine whether disrupting sympathetic activation of IBAT blocks the ability of fourth ventricular (4V) OT administration to increase EE and elicit weight loss in male and female DIO rats. We will also determine if sympathetic outflow to both IBAT and white adipose tissue mediate the effects of OT on EE by testing the extent to which pharmacological blockade of beta-3 adrenergic receptors impairs the ability of 4V OT administration to increase EE in male and female DIO rats. Endpoints will include EE, IBAT temperature (TIBAT), norepinephrine turnover (NETO), food intake, and BW. We anticipate these studies to establish a key role for sympathetic outflow to IBAT in the mechanism by which OT increases EE and elicits BW loss.
In Specific Aim 2 we will test the hypothesis that increased OT receptor (OTR) signaling within the NTS elicits prolonged weight loss through distinct mechanisms that simultaneously reduce food intake and activate IBAT to increase EE. To accomplish this we will reduce NTS OTR signaling by using both viral and pharmacological approaches. This strategy will enable us to identify the extent to which these OTRs are required for effects of both exogenous 4V OT administration and activation of endogenous OT signaling via chemogenetic excitation of pPVN OT neurons, the sole source of endogenous OT relevant to sympathetic outflow. If we find that disrupting NTS OTR signaling attenuates the ability of both exogenous and endogenous OT to reduce food intake as well as increase EE, these studies will establish a key role for an OT-containing neurocircuit projecting from pPVN to NTS in the control of energy balance. We also hypothesize that deficient NTS OTR signaling mimics the metabolic and behavioral impairments associated with DIO and leptin resistance, and abrogates the anti-obesity effect of chronic systemic OT treatment. To test this, we will administer a Cre- expressing AAV into the NTS of Oxtrflox mice to ablate OTRs from NTS neurons and measure responsiveness to systemic leptin or chronic systemic OT. Together, our findings will delineate whether NTS OTRs mediate the anti-obesity effects of OT through a mechanism that requires increased SNS outflow to IBAT and direct future studies to address whether intranasal OT may reverse human obesity by stimulating BAT thermogenesis.
The obesity epidemic and its associated complications have become major health concerns. Our data suggest that oxytocin (OT) may elicit weight loss by activating brown fat to increase energy expenditure. We will test if activation of brown fat is required for OT to evoke weight loss and if reducing OT signaling in a CNS site that controls brown fat contributes to leptin resistance, obesity and the anti-obesity effects of chronic systemic OT.
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