Central leptin resistance results in decreased downstream signaling to brain circuits that regulate food intake and energy expenditure (EE), thereby promoting hyperphagia and obesity. 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 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 nervous system (SNS) 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 DIO rats. We will also determine if sympathetic outflow to both IBAT and white adipose tissue (WAT) mediates the effects of OT on EE by testing the extent to which pharmacological blockade of beta-3 adrenergic receptors (?-3-AR) impairs the ability of 4V OT administration to increase EE in DIO rats. In addition, we will determine if OT can be combined with low doses of the ?-3-AR agonist, CL316243, to increase EE and promote weight loss in DIO rats. Endpoints will include EE, IBAT temperature, norepinephrine turnover (NETO; marker of sympathetic activity), food intake, body composition (total and relative fat mass, lean mass), and BW. We anticipate these studies to establish a key role for SNS outflow to IBAT in the mechanism by which OT increases EE and elicits BW loss in DIO rats.
In Specific Aim 2 we will test the hypothesis that in DIO rhesus monkeys, intranasal OT reduces BW and improves glucose tolerance and other metabolic parameters, in part, by stimulating SNS outflow to BAT. To accomplish this, we will determine if intranasal OT increases the temperature of axillary BAT (ABAT, the predominant BAT depot found in rhesus monkeys) at a dose that elicits weight loss in DIO NHPs. We will also determine the extent to which intranasal OT elicits weight loss by reducing body adiposity while sparing lean mass and identify if these effects are associated with improvements in glucose tolerance. We will further identify if intranasal OT may also increase SNS outflow to WAT by measuring changes in subcutaneous WAT temperature and uncoupling protein-1 protein expression in subcutaneous WAT relative to ABAT (pre- and post-intervention). If we find that intranasal OT increases EE and BAT thermogenesis in the NHP model, these studies will provide evidence for a role for BAT activation in how OT elicits weight loss in a translational model of diet-induced obesity. Moreover, these studies will identify intranasal OT as a potential treatment option to evoke weight loss and improve glucose tolerance in humans and direct future studies to address the extent to which intranasal OT may reverse obesity in humans by stimulating BAT thermogenesis.
The obesity epidemic and its associated complications have become major health concerns in a high proportion of Veteran patients. The practical use of the fat-derived hormone leptin as a weight loss therapy has diminished because leptin does not reduce body weight in obese humans. Eliciting weight loss by activating brown adipose tissue (BAT) to increase energy expenditure (EE) has become an exciting new focus of research with the recent discovery of BAT in humans. Our data suggest that oxytocin (OT) may elicit weight loss in diet-induced obese (DIO) rodents by activating BAT to increase EE. We propose to test if activation of BAT is required for OT to elicit weight loss in DIO rodents and to investigate the translational question of whether chronic intranasal OT elicits weight loss, activates BAT and improves glucose tolerance in a DIO nonhuman primate (rhesus monkey) model of metabolic syndrome. These findings will direct future studies to address the extent to which intranasal OT may reverse obesity in humans by stimulating BAT thermogenesis.
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