Previous studies indicate that oxytocin (OT) administration reduces body weight in high fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake and body composition. OT reduced body weight by approximately 4.5±1.4% in DIO mice relative to OT pre-treatment body weight (P<0.05). These effects were associated with reduced adiposity and adipocyte size (inguinal white adipose tissue (IWAT)] (P<0.05) and attributed, in part, to reduced energy intake (P<0.05) at a dose that did not increase kaolin intake (P=NS). OT tended to increase uncoupling protein-1 expression in IWAT (0.05<P<0.1) suggesting that OT stimulates browning of WAT. To assess OT-elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of 4V OT on interscapular BAT temperature (TIBAT). 4V OT (1 μg) elevated TIBAT at 0.75 (P=0.08), 1, and 1.25 h (P<0.05) post-injection; a higher dose (5 μg) elevated TIBAT at 0.75, 1, 1.25, 1.5, 1.75 (P<0.05), and 2-h (0.05<P<0.1) post-injection. Together, these findings support the hypothesis that chronic hindbrain OT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis at a dose that is not associated with evidence of visceral illness.

Previous studies have indicated that oxytocin (OT) reduces body weight in diet-induced obese (DIO) rodents through reductions in energy intake and increases in energy expenditure. We recently demonstrated that hindbrain [fourth ventricular (4V)] administration of OT evokes weight loss and elevates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. What remains unclear is whether OT can be used as an adjunct with other drugs that directly target beta-3 receptors in IBAT to promote BAT thermogenesis and reduce body weight in DIO rats. We hypothesized that the combined treatment of OT and the beta-3 agonist, CL 316243, would produce an additive effect to decrease body weight and adiposity in DIO rats by reducing energy intake and increasing BAT thermogenesis. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle (VEH) in combination with daily intraperitoneal injections of CL 316243 (0.5 mg/kg) or VEH on food intake, TIBAT, body weight and body composition. OT and CL 316243 alone reduced body weight by 7.8 ± 1.3% (P &lt; 0.05) and 9.1 ± 2.1% (P &lt; 0.05), respectively, but the combined treatment produced more pronounced weight loss (15.5 ± 1.2%; P &lt; 0.05) than either treatment alone. These effects were associated with decreased adiposity, adipocyte size, energy intake and increased uncoupling protein 1 (UCP-1) content in epididymal white adipose tissue (EWAT) (P &lt; 0.05). In addition, CL 316243 alone (P &lt; 0.05) and in combination with OT (P &lt; 0.05) elevated TIBAT and IBAT UCP-1 content and IBAT thermogenic gene expression. These findings are consistent with the hypothesis that the combined treatment of OT and the beta-3 agonist, CL 316243, produces an additive effect to decrease body weight. The findings from the current study suggest that the effects of the combined treatment on energy intake, fat mass, adipocyte size and browning of EWAT were not additive and appear to be driven, in part, by transient changes in energy intake in response to OT or CL 316243 alone as well as CL 316243-elicited reduction of fat mass and adipocyte size and induction of browning of EWAT.

Existing studies show that CNS oxytocin (OT) signaling is important in the control of energy balance, but it is unclear which neurons may contribute to these effects. Our goals were to examine (1) the dose-response effects of acute OT administration into the third (3V; forebrain) and fourth (4V; hindbrain) ventricles to assess sensitivity to OT in forebrain and hindbrain sites, (2) the extent to which chronic 4V administration of OT reduces weight gain associated with the progression of diet-induced obesity, and (3) whether nucleus tractus solitarius (NTS) catecholamine neurons are downstream targets of 4V OT. Initially, we examined the dose-response effects of 3V and 4V OT (0.04, 0.2, 1, or 5 μg). 3V and 4V OT (5 μg) suppressed 0.5-h food intake by 71.7 ± 6.0% and 60 ± 12.9%, respectively. 4V OT (0.04, 0.2, 1 μg) reduced food intake by 30.9 ± 12.9, 42.1 ± 9.4, and 56.4 ± 9.0%, respectively, whereas 3V administration of OT (1 μg) was only effective at reducing 0.5-h food intake by 38.3 ± 10.9%. We subsequently found that chronic 4V OT infusion, as with chronic 3V infusion, reduced body weight gain (specific to fat mass) and tended to reduce plasma leptin in high-fat diet (HFD)-fed rats, in part, through a reduction in energy intake. Lastly, we determined that 4V OT increased the number of hindbrain caudal NTS Fos (+) neurons (156 ± 25) relative to vehicle (12 ± 3). The 4V OT also induced Fos in tyrosine hydroxylase (TH; marker of catecholamine neurons) (+) neurons (25 ± 7%) relative to vehicle (0.8 ± 0.3%). Collectively, these findings support the hypothesis that OT within the hindbrain is effective at reducing food intake, weight gain, and adiposity and that NTS catecholamine neurons in addition to non-catecholaminergic neurons are downstream targets of CNS OT.

Previous studies indicate that oxytocin (OXT) reduces body weight (BW) in high fat diet (HFD)‐induced obese (DIO) rodents through mechanisms that may involve an enhanced ability of OXT to reduce food intake as well as increase energy expenditure. We have previously demonstrated that chronic fourth ventricular (4V) infusions of OXT (as a strategy to target hindbrain OXT receptors) evokes weight loss in DIO rats. Based on these findings, we hypothesized that increased hindbrain OXT signaling would elicit BW loss in DIO mice maintained on a HFD (60% kcal from fat). To test this hypothesis, age‐matched mice were fed HFD or chow for 4 months prior to implantation of 4V cannulas and 28‐day minipumps that infused OXT (16 nmol/day) or vehicle (VEH; saline). Food intake and BW were tracked for 28 days. Body composition was assessed immediately prior to VEH or OXT treatment and near treatment completion using Quantitative Magnetic Resonance (QMR; EchoMRI 4‐in‐1). OXT preferentially reduced BW by approximately 4.5±1.4% in DIO mice relative to chow‐fed mice (P<0.05; N=9–11/group). OXT‐elicited BW loss was associated with reductions in body adiposity, adipocyte size [inguinal white adipose tissue (IWAT)] and serum leptin (P<0.05). These effects were attributed, in part, to an enhanced effect of OXT to reduce energy intake in DIO mice (P<0.05) at a dose that was not associated with increased kaolin intake (pica behavior; P=NS). While reductions in energy intake contribute to OXT’s effects on BW, chronic 4V OXT appeared to increase uncoupling protein‐1 (UCP‐1) expression in IWAT (0.05

Previous studies have indicated that oxytocin (OXT) reduces body weight in high fat diet (HFD)‐induced obese (DIO) rodents, nonhuman primates and obese humans through reductions in energy intake and increases in energy expenditure. Recent findings support a role for brown adipose tissue (BAT) thermogenesis in OXT‐elicited weight loss as chronic administration 1) increases interscapular brown adipose tissue (IBAT) temperature (TIBAT) in DIO rats during a period that coincides with the OXT’s initial weight‐lowering effect and 2) upregulates beta‐3 receptor mRNA expression in IBAT. Based on these findings, we hypothesized that OXT would enhance the effectiveness of the beta‐3 receptor agonist, CL 316243, to evoke weight loss in DIO rats. To test this hypothesis, rats were fed a HFD for approximately 7 months prior to being implanted with a fourth ventricular (4V) cannula (as a strategy to target hindbrain OXT receptors), 28‐day minipump that infused OXT (16 nmol/day) or vehicle (VEH; saline) and temperature transponder underneath an IBAT depot. DIO rats were subsequently matched for body weight and adiposity, as well as OXT‐elicited reductions in body weight during the first week of the infusion period, prior to receiving 1x daily injections of VEH (sterile water, IP) or CL 316243 at a dose (0.5 mg/kg, IP) found to stimulate TIBAT in a separate group of DIO rats (P<0.05; N=4–5/group). Daily energy intake, TIBAT and body weight were tracked for 28 days. Body composition was assessed immediately prior to VEH or OXT treatment and near treatment completion using Quantitative Magnetic Resonance (QMR; EchoMRI 4‐in‐1). Preliminary data indicate that OXT (16 nmol/day) alone and CL 316243 alone tended to reduce body weight by approximately 6.5±2.2% (0.05

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

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