Sympathetic innervation of interscapular brown adipose tissue is not required for hindbrain administration of oxytocin to stimulate brown adipose tissue (BAT) thermogenesis and reduce weight gain and adiposity in DIO rats

Abstract

Previous studies indicate that CNS administration of oxytocin (OT) reduces body weight in high fat diet-induced obese (DIO) rodents by reducing food intake and increasing energy expenditure (EE). We recently demonstrated that hindbrain [fourth ventricular (4V)] administration of OT elicits weight loss and elevates interscapular brown adipose tissue temperature (TIBAT; surrogate marker of increased EE) in DIO rats. What remains unclear is whether OT-elicited weight loss requires increased sympathetic nervous system (SNS) outflow to IBAT. We hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to activate BAT and elicit weight loss in DIO rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT treatment to elicit weight loss and increase TIBAT in DIO rats. We initially determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO rats. NE content was selectively reduced in IBAT at weeks 1, 6 and 7 by 95, 97 and 86% (P<0.05), respectively and was unchanged in inguinal white adipose tissue or liver. We subsequently measured the effects of chronic 4V OT (16 nmol/day) or vehicle infusions on body weight, adiposity and food intake in DIO rats following bilateral surgical (or sham) denervation of SNS innervation of IBAT. We found that chronic 4V OT reduced weight gain and fat mass in both sham and denervated rats (P<0.05) with no difference in response between groups (P=NS). These effects were attributed, in part, to reduced energy intake (P<0.05). To assess if OT-elicited changes in BAT thermogenesis require intact SNS outflow to IBAT, we examined the effects of acute 4V OT (1, 5 μg) on TIBAT in DIO rats following sham or bilateral surgical SNS denervation to IBAT. We found that the low dose (1 μg) elevated TIBAT relative to baseline in denervated rats at 0.75 (0.05<P<0.1) and 1-h post-injection (P<0.05) in denervated rats; the higher dose (5 μg) elevated TIBAT relative to baseline in both groups at 0.75, 1, 1.25, 1.5, and 1.75-h post-injection (P<0.05) with no difference in response between groups (P=NS). Together, these findings support the hypothesis that hindbrain OT treatment evokes sustained weight loss and increases BAT thermogenesis through a mechanism that does not require SNS innervation to IBAT in DIO rats.