Sympathetic innervation of interscapular brown adipose tissue is not required for hindbrain administration of oxytocin to stimulate brown adipose tissue (BAT) thermogenesis and elicit weight loss in DIO mice

Abstract

Previous studies indicate that oxytocin (OT) administration 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 mice. 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 mice. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on the ability of 4V OT administration to elicit weight loss and increase TIBAT in DIO mice. We initially determined whether bilateral surgical SNS denervation to IBAT was successful as noted by ≥ 60% reduction in IBAT norepinephrine (NE) content in DIO mice. NE content was selectively reduced in IBAT at 1, 6 and 7 weeks post-denervation by 96, 77 and 94% (P<0.05), respectively and was unchanged in inguinal white adipose tissue, pancreas 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 mice following sham or bilateral surgical denervation of IBAT. Chronic 4V OT reduced body weight by 5.9% and 5.4% in sham and denervated mice (P<0.05), respectively and this effect was similar between groups (P=NS). OT produced corresponding reductions in fat mass (P<0.05) that were also similar between groups (P=NS) and these effects were attributed, in part, to reduced energy intake (P<0.05). To assess if OT-elicited changes on BAT thermogenesis require intact SNS outflow to IBAT, we examined the effects of acute 4V OT (1, 5 μg) on TIBAT in DIO mice following sham or bilateral surgical SNS denervation to IBAT. We found that the high dose (5 μg) elevated TIBAT in sham mice at 0.75, 1, and 1.25-h post-injection (P<0.05) and tended to elevate TIBAT at 1.5 and 1.75-h post-injection (0.05<P<0.1). The same dose also elevated TIBAT in denervated mice at 0.75, 1, 1.25, 1.5, 2 and 3-h post-injection (P<0.05) and tended to elevate TIBAT at 4-h post-injection (0.05<P<0.1) with no difference in response between groups at 0.75, 1, and 1.25-h post-injection (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 mice.