1. Introduction
The neuropeptide, oxytocin (OT), has been largely associated with eliciting prosocial (i.e. pair bonds and increased trust) [
1,
2] and reproductive behavior (i.e. uterine contraction, milk ejection reflex) [
3,
4], but the role of OT in the regulation of body weight, particularly in female rodents [
5,
6,
7,
8], is not entirely clear. Recent studies have shown that acute intracerebroventricular (ICV) OT administration reduces food intake in female single-minded 1 (SIM1) haploinsufficient mice [
9] and female rats [
10]. However, few long-term treatment studies exploring the mechanism (s) by which chronic central nervous system (CNS) administration of OT reduces body weight and adiposity in female rodents have been reported.
Although suppression of food intake is thought to contribute, at least in part, to the effects of hindbrain (fourth ventricle (4V)) OT-elicited weight loss in male rodents, the findings from pair-feeding studies from male rodents suggest that OT-elicited reductions of food intake cannot fully explain OT elicited weight loss [
11,
12,
13]. In addition to OT’s well established effects on food intake, previous studies in rodents and nonhuman primates have shown that OT may also evoke weight loss, in part, by stimulating energy expenditure (EE) [
14,
15,
16,
17] and lipolysis [
12,
14,
18]. While it is clear that brown adipose tissue thermogenesis (BAT) plays an important role in the regulation of EE (see [
19,
20] for review), less is known about whether OT’s effects on EE result from 1) non-shivering BAT thermogenesis, 2) spontaneous physical activity-induced thermogenesis [
21], 3) non-shivering and shivering thermogenesis in skeletal muscle [
22,
23] or through the anabolic effects of OT on muscle [
24,
25], 5) white adipose tissue thermogenesis or 6) hormonal mediators (e.g. fibroblast growth factor-21 [
26], irisin [
27], leptin [
28], thyroid hormone [
29] or secretin [
30,
31] (see [
32,
33] for review). We and others have found that acute injections of OT into either the forebrain (third (3V)) or hindbrain (4V) elevate interscapular BAT temperature (T
IBAT) (surrogate measure of BAT thermogenesis) [
34,
35] and/or core temperature [
36] in male rats or mice. Furthermore, the onset of OT-elicited weight loss coincides with OT-elicited elevations of T
IBAT in male diet-induced obese (DIO) rats [
34]. In addition, an earlier study found that chemogenetic excitation of hypothalamic paraventricular nucleus (PVN) OT neurons increases both subcutaneous BAT temperature and EE in
Oxytocin-Ires Cre mice [
37]. In addition, a recent study reported that chronic subcutaneous infusion of OT increases core temperature, IBAT thermogenic gene expression and differentiation of BAT
in vitro in male DIO mice [
38]. On the other hand, genetic knockdown or pharmacological blockade of OT signaling reduces cold-induced BAT thermogenesis [
39,
40,
41,
42], decreases EE [
16,
17,
39,
43] and promotes obesity [
17,
43,
44,
45] in mice. We recently determined the impact of bilateral surgical sympathetic nervous system (SNS) denervation to IBAT on the ability of chronic hindbrain (4V) OT infusion to reduce body weight and adiposity in male DIO mice. We found that chronic 4V OT produced similar reductions of body weight and adiposity between groups suggesting that SNS innervation of IBAT is not required for OT to reduce body weight and adiposity in male DIO mice [
35]. This finding raised the question as to whether OT stimulates IBAT thermogenesis and evokes weight loss through a mechanism that requires increased SNS outflow to IBAT in female high fat diet (HFD)-fed rats and whether the effect of OT on BAT thermogenesis may involve hindbrain oxytocin receptors (OTR). Here, we aimed to determine the role of SNS outflow to IBAT in contributing to the effect of chronic hindbrain (4V) OT to stimulate BAT thermogenesis and evoke weight loss in a female HFD-fed rat model.
Based on our previous findings that linked 4V OT to increases in BAT thermogenesis in male DIO rats, we hypothesized that OT-induced stimulation of SNS outflow to IBAT contributes to its ability to stimulate non-shivering BAT thermogenesis and evoke weight loss in female HFD-fed rats. To assess if SNS innervation of BAT is required for OT to stimulate non-shivering thermogenesis in IBAT (as surrogate measure of energy expenditure), we determined the effects of acute 4V injections of OT (0.5, 1, and 5 μg) on TIBAT in female HFD-fed rats following bilateral surgical SNS denervation to IBAT. To determine whether SNS innervation of IBAT is required for OT to elicit weight loss, we measured the ability of chronic 4V OT (16 nmol/day over 29 days) to decrease body weight and adiposity in female HFD-fed rats following bilateral surgical or sham denervation of IBAT. We subsequently determined if these effects were associated with a reduction of adipocyte size and energy intake. To test whether the effects of chronic 4V OT to reduce body weight and adiposity could translate to other female rodent models of diet-induced obesity (DIO), we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two different strains of female HFD-fed mice (C57BL/6J and DBA/2J). Our findings suggest that 1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and 2) the effects of OT to elicit weight loss translate to other mouse models of diet-induced obesity (DIO).
4. Discussion
The objectives of the current set of studies were to 1) establish whether sympathetic innervation of IBAT is required for 4V (hindbrain) administration of OT to stimulate BAT thermogenesis and decrease body weight and adiposity in female HFD-fed rats and 2) establish whether the ability of hindbrain (4V) infusion of OT to elicit weight loss translates to other rodent species. To accomplish these goals, we examined the effect of disrupting SNS activation of IBAT on OT-induced stimulation of TIBAT and reduction of body weight in HFD-fed rats. We initially determined the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg) to stimulate TIBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg) stimulated TIBAT similarly between sham rats and denervated rats. We subsequently determined if OT-elicited reductions of body weight and adiposity require intact SNS outflow to IBAT. To accomplish this, we determined the effect of bilateral surgical or sham denervation of IBAT on the ability of chronic 4V OT (16 nmol/day) or vehicle administration to reduce body weight, adiposity and food intake in female HFD-fed rats. Chronic 4V OT reduced body weight gain (sham: -18.0±4.9 g; denervation: -15.9±3.7 g) and adiposity (sham: -13.9±3.7 g; denervation: -13.6±2.4 g) relative to vehicle treatment and these effects were similar between groups. These effects were attributed, in part, to reduced energy intake evident during weeks 2 and 3. To test whether the effects of 4V OT to elicit weight loss translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight in two separate strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and/or energy intake in female HFD-fed C57BL/6J and DBA/2J mice. Together, these findings support the hypothesis that sympathetic innervation of IBAT is not necessary for OT to increase BAT thermogenesis and reduce body weight and adiposity in female HFD-fed rats.
We have now determined that chronic 4V OT-elicited reduction of body weight loss does not require SNS innervation of IBAT in multiple animal models (female HFD-fed rats and male DIO mice) [
35]. These data suggest that 4V administration of OT increases BAT thermogenesis and evokes weight loss through a mechanism that does not require SNS innervation of IBAT in male and female rodent models. As mentioned in [
35], we have not addressed what mechanism might be required for hindbrain (4V) OT to stimulate BAT thermogenesis if not through SNS innervation of IBAT. We have largely ruled out the possibility that, in mice, 4V OT might be leaking into the periphery to act at peripheral OTRs by showing that systemic administration of OT, at a centrally effective dose was unable to replicate the effects of hindbrain (4V) OT to reduce body weight and stimulate BAT thermogenesis in DIO mice [
35]. One mechanism that we did not address in this body of work is whether 4V OT-elicited activation of hindbrain and/or spinal cord OTRs might elicit the release of epinephrine from the adrenal medulla and activate BAT thermogenesis through direct activation of β-adrenergic receptors. However, we recently determined that systemic administration of the β3-AR antagonist, SR 59230A, failed to block the effects of acute 4V OT to increase T
IBAT (unpublished findings) in male DIO Long-Evans rats, suggesting that signaling through the β3-AR is not required for OT-elicited BAT thermogenesis. Other potential mediators of 4V-OT elicited BAT thermogenesis include other beta-receptor subtypes, namely the β1-AR and β2-AR, both of which are expressed in IBAT in both mice [
71] and rats [
72,
73]. While we did not find a significant increase in β1-AR mRNA expression in response to 4V OT in IBAT in this study, we did see an increase in β1-AR mRNA expression in IWAT (see discussion below). It is well appreciated that the β1-AR is important in the control of thermogenesis in rodents [
74,
75] but the β2-AR may be more important in the control of thermogeneis in humans than rodents [
76,
77,
78]. Furthermore, β1-AR and β2-AR have nearly equal affinity for L-epinephrine in Chinese hamster ovary cells [
79] and epinephrine administration to brown adipocytes stimulates fatty acids and respiration [
80]. However, only 1% of parvocellular pt magnocellular PVN OT neurons have poly-synaptic projections to the adrenal gland [
81], despite the hindbrain and spinal cord being relay sites in outgoing poly-synaptic projections to the adrenal gland [
81,
82]. Future studies should address whether adrenal demedulation impairs the ability of hindbrain (4V) OT to stimulate BAT thermogenesis and elicit weight loss in DIO rodents.
Our finding that 4V OT treatment elicited an increase in both β1-AR and Cidea mRNA expression in IWAT raises the possibility that WAT browning or beiging may also contribute, in part, to the metabolic effects of 4V OT in female rodents. Beige depots within WAT may account for up to 5% of total UCP-1 [
83,
84]. It is possible that hindbrain OTRs could also be a component of descending projections that originate in the PVN and are important in the regulation of SNS outflow to IWAT [
85]. In fact, there are well established poly-synaptic circuits that link parvocellular PVN OT neurons to IWAT [
86,
87]. Thus, OT neurons within the parvocellular PVN are anatomically situated to control WAT thermogenesis. One outstanding question is whether these effects are mediated by parvocellular PVN OT neurons that project directly to the hindbrain (nucleus tractus solitarius [
88,
89]) and/or spinal cord [
89]. Further studies that determine the extent to which 4V OT treatment 1) elicits more functional changes in IWAT thermogenesis (increased temperature of IWAT) [
85,
90] and 2) reduces body weight and adiposity in animals following IWAT denervation will be helpful in assessing the role of WAT in contributing to the effects of 4V OT to reduce body weight and adiposity.
We acknowledge the possibility that the effects of 4V OT on BAT thermogenesis in female rats could be due, in part, to increased activity-induced thermogenesis [
21] as well as skeletal muscle thermogenesis [
22,
23]. While we did not assess the effects of 4V OT on non-shivering and shivering thermogenesis in skeletal muscle [
22,
23] in this study, we recently determined that acute 4V administration of OT (5 μg) stimulated T
IBAT, core temperature and gross motor activity in male DIO rats (unpublished observations). However, we found that 4V OT-associated elevations of T
IBAT and core temperature occurred before significant increases in gross motor activity suggesting that changes in gross motor activity are not likely tied to the changes in T
IBAT and core temperature that preceded changes in activity. Our findings are similar to what others have reported following ICV (0.5 μg) [
91] and ventromedial hypothalamic administration (1 nmol ≈ 1.0072 μg) [
15]. Taken together, acute CNS administration of OT can increase activity in rodents, but, based on our unpublished findings, these activity related increases do not appear to contribute to the effects of 4V OT on BAT thermogenesis in male DIO rats. It remains to be determined if this holds true in female HFD-fed rats.
One limitation to this study is that we did not account for the contribution of other BAT depots in contributing to the ability of 4V OT to stimulate BAT thermogenesis and reduce body weight in IBAT denervated rats. We chose to make IBAT the focus of our studies given that it contains up to 45% of total UCP-1 [
92] and represents ≥ 70% of total BAT mass [
93]. In addition, this particular depot is the best characterized of BAT depots [
94]. However, other BAT depots [axillary (subscapular), cervical, mediastinal and perirenal depots] show cold-induced elevations of UCP-1 [
83]. In particular, the axillary (subscapular), cervical, periaortic and perirenal BAT depots [
19,
84] may provide up to 50% of total UCP-1 mRNA. Fischer reported that the axillary (subscapular) depot, also showed a significant 2-fold increase of total UCP-1 (UCP-1/scBAT) in response to HFD (diet-induced thermogenesis) in IBAT denervated mice [
92]. There also appeared to be an increase of axillary UCP-1 in response to HFD in sham mice but it was not significant and there were no significant differences in UCP-1 between sham vs denervation groups in response to HFD [
92]. Moreover, Nugyen reported that is potential crosstalk between SNS circuits that innervate IBAT and WAT [
85]. Nguyen found that there is increased NE turnover and IWAT UCP-1 mRNA expression in hamsters following SNS denervation of IBAT [
85]. It will be helpful to selectively denervate other BAT and WAT depots in order to determine whether these depots may contribute, in part, to the effects of 4V OT to reduce body weight gain in female rodents.
While a recent study reported that systemic infusions of OT (100 nmol/day) result in an elevation of core temperature and increased IBAT gene expression in male HFD-fed mice (C57BL6/J) [
38], we found that systemic infusion (16 and 50 nmol/day) resulted in a reduction of T
IBAT temperature in female DBA/2J mice. Similarly, we found that acute peripheral administration of OT (5 and 10 μg/μL) elicited an initial reduction of T
IBAT prior to a subsequent elevation of T
IBAT [
35]. Furthermore, others have found that systemic injections of higher doses (1 mg/kg) have also resulted in hypothermic effects [
95], which is through to be mediated, in part, by activation of
arginine vasopressin receptor 1A (AVPR1A) [
96]
. It is possible that differences between our study and Yuan’s study are due, in part, to strain, sex, age, length of time that the mice were maintained on the HFD prior to study onset (8 weeks rather than 18 weeks in our study) and/or time of day that the core temperature vs T
IBAT measurements were taken. Being able to include measurements of core temperature and T
IBAT from the same animal will help enable more direct comparisons with other studies.
Based on recent findings [
10], it is possible that differences in estrus cycle might have impaired the effectiveness of OT to reduce food intake during the measurement period. The authors found that there was an impaired ability of ICV OT to reduce food intake during the pro-estrus stage of the estrus cycle, during which time there is an increase in estrogen [
10]. Despite this, we still found an effect of 4V OT to reduce weight gain suggesting that other mechanisms (i.e. lipolysis, energy expenditure) may also contribute to 4V OT-elicited changes in body weight in female rodents. Future studies, however, should take into account estrus cycle when measuring energy intake in response to OT treatment.
Our findings showing that chronic 4V administration of OT reduced energy intake in female DBA/2J DIO mice recapitulated the effects an earlier study that found following chronic systemic administration in female DIO C57BL/6J mice [
97]. However, we failed to find an effect of chronic 4V OT to reduce food intake in female DIO C57BL/6J mice. In addition, we found that systemic OT (16 or 50 nmol/day) produced transient reductions of body weight gain in female DIO DBA/2J mice at doses that the authors (≈ 27.6 and 55.1 nmol/day) found to reduce body weight in female DIO C57BL/6J mice [
97]. However, the authors in that study used a different strain of mice (C57BL/6J) that were younger (18 weeks vs 31 weeks at onset of minipump infusions in our study), heavier (34.20 grams vs 31.2±1.4 g in our study) and had been on the HFD diet for a shorter period of time (12 weeks vs 24 weeks at onset of minipump infusions in our study). Thus, there are several differences between studies that might account for the contradictory effects.
In conclusion, our findings indicate that there is no significant difference in the effectiveness of the β3-AR agonist, CL 316243, to stimulate IBAT in female IBAT denervated rats relative to female sham-operated rats with intact SNS innervation of IBAT. In addition, we found that acute 4V administration of OT at both the low (0.5 µg) and high dose (5 µg) resulted in similar increases in TIBAT at in female sham and IBAT denervated rats. Furthermore, we also found that there was no difference in the effectiveness of chronic 4V OT (16 nmol/day) to reduce body weight gain and adiposity in female sham and IBAT denervated rats. Consistent with what we found in the HFD-fed rat model, we found that chronic 4V OT (16 nmol/day) treatment reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice relative to chronic 4V vehicle treatment in control mice. Together, these findings suggest that 1) sympathetic innervation of IBAT is not required for OT to increase BAT thermogenesis and reduce body weight in female HFD-fed rats and 2) chronic hindbrain (4V) administration of OT reduces weight gain and adiposity in two different strains of female HFD-fed mice.
Figure 1.
A-D. Effect of systemic β3-AR agonist (CL 31643) administration (0.1 and 1 mg/kg) on IBAT temperature (TIBAT), energy intake and body weight post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Animals were subsequently adapted to a 4-h fast prior to receiving IP injections of CL 316243 (0.1 or 1 mg/kg, IP) or vehicle (sterile water) where each animal received each treatment at approximately 7-day intervals. A/B, Effect of CL 316243 on TIBAT in A) sham operated or B) IBAT denervated DIO rats; C, Effect of CL 316243 on change in energy intake in sham or IBAT denervated DIO rats; D, Effect of CL 316243 on change in body weight in sham or IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05 CL 316243 vs. vehicle.
Figure 1.
A-D. Effect of systemic β3-AR agonist (CL 31643) administration (0.1 and 1 mg/kg) on IBAT temperature (TIBAT), energy intake and body weight post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Animals were subsequently adapted to a 4-h fast prior to receiving IP injections of CL 316243 (0.1 or 1 mg/kg, IP) or vehicle (sterile water) where each animal received each treatment at approximately 7-day intervals. A/B, Effect of CL 316243 on TIBAT in A) sham operated or B) IBAT denervated DIO rats; C, Effect of CL 316243 on change in energy intake in sham or IBAT denervated DIO rats; D, Effect of CL 316243 on change in body weight in sham or IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05 CL 316243 vs. vehicle.
Figure 2.
A-B: Effect of acute 4V OT administration (1 and 5 μg) on TIBAT post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to receiving acute 4V injections of OT or vehicle. Animals were subsequently adapted to a 4-h fast prior to receiving acute 4V injections of OT or vehicle A/B, Effect of acute 4V OT on TIBAT in A) sham operated or B) IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 2.
A-B: Effect of acute 4V OT administration (1 and 5 μg) on TIBAT post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to receiving acute 4V injections of OT or vehicle. Animals were subsequently adapted to a 4-h fast prior to receiving acute 4V injections of OT or vehicle A/B, Effect of acute 4V OT on TIBAT in A) sham operated or B) IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 3.
A-D: Effect of acute 4V OT administration (0.5 μg) on TIBAT post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to receiving acute 4V injections of OT or vehicle. Animals were subsequently adapted to a 4-h fast prior to receiving acute 4V injections of OT or vehicle A/B, Effect of acute 4V OT on TIBAT in A) sham operated or B) IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 3.
A-D: Effect of acute 4V OT administration (0.5 μg) on TIBAT post-sham or IBAT denervation in female HFD-fed rats. Rats were maintained on HFD (60% kcal from fat; N=4-8/group) for approximately 4.5 months prior to undergoing a sham or bilateral surgical IBAT denervation and implantation of temperature transponders underneath IBAT. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to receiving acute 4V injections of OT or vehicle. Animals were subsequently adapted to a 4-h fast prior to receiving acute 4V injections of OT or vehicle A/B, Effect of acute 4V OT on TIBAT in A) sham operated or B) IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 4.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake post-sham or IBAT denervation in female HFD-fed rats. A, Rats were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.75-5.25 months prior to undergoing a sham or bilateral surgical IBAT denervation. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in sham operated or IBAT denervated DIO rats; B, Effect of chronic 4V OT or vehicle on body weight change in sham operated or IBAT denervated DIO rats; C, Effect of chronic 4V OT or vehicle on adiposity in sham operated or IBAT denervated DIO rats; D, Effect of chronic 4V OT or vehicle on adiposity in sham operated or IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 4.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake post-sham or IBAT denervation in female HFD-fed rats. A, Rats were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.75-5.25 months prior to undergoing a sham or bilateral surgical IBAT denervation. Rats were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in sham operated or IBAT denervated DIO rats; B, Effect of chronic 4V OT or vehicle on body weight change in sham operated or IBAT denervated DIO rats; C, Effect of chronic 4V OT or vehicle on adiposity in sham operated or IBAT denervated DIO rats; D, Effect of chronic 4V OT or vehicle on adiposity in sham operated or IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 5.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake in female HFD-fed C57BL/6J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-10/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female C57BL/6J mice rats; B, Effect of chronic 4V OT or vehicle on body weight change in female C57BL/6J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female C57BL/6J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female C57BL/6J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 5.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake in female HFD-fed C57BL/6J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-10/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female C57BL/6J mice rats; B, Effect of chronic 4V OT or vehicle on body weight change in female C57BL/6J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female C57BL/6J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female C57BL/6J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 6.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake in female HFD-fed DBA/2J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female DBA/2J mice; B, Effect of chronic 4V OT or vehicle on body weight change in female DBA/2J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 6.
A-D: Effect of chronic 4V OT infusions (16 nmol/day) on body weight, adiposity and energy intake in female HFD-fed DBA/2J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female DBA/2J mice; B, Effect of chronic 4V OT or vehicle on body weight change in female DBA/2J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 7.
A-D: Effect of chronic systemic OT infusions (16 and 50 nmol/day) on body weight, adiposity and energy intake in female HFD-fed DBA/2J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female DBA/2J mice; B, Effect of chronic 4V OT or vehicle on body weight change in female DBA/2J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Figure 7.
A-D: Effect of chronic systemic OT infusions (16 and 50 nmol/day) on body weight, adiposity and energy intake in female HFD-fed DBA/2J mice. A, Mice were maintained on HFD (60% kcal from fat; N=7-8/group) for approximately 4.5 months prior to implantation of temperature transponders underneath IBAT. Mice were subsequently implanted with 4V cannulas and allowed to recover for 2 weeks prior to being implanted with subcutaneous minipumps that were subsequently attached to the 4V cannula. A, Effect of chronic 4V OT or vehicle on body weight in female DBA/2J mice; B, Effect of chronic 4V OT or vehicle on body weight change in female DBA/2J mice; C, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice; D, Effect of chronic 4V OT or vehicle on adiposity in female DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05, †0.05<P<0.1 OT vs. vehicle.
Table 1.
Plasma measurements following acute injections of 4V OT (5 μg/μL) or vehicle in female sham and IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=2-3/group).
Table 1.
Plasma measurements following acute injections of 4V OT (5 μg/μL) or vehicle in female sham and IBAT denervated DIO rats. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=2-3/group).
Table 2.
Changes in TIBAT following 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. A, Changes in TIBAT following 4V infusions of OT or vehicle in ad libitum fed female sham or IBAT denervated DIO rats; B, Changes in TIBAT following 4V infusions of OT or vehicle in 4-h fasted female sham or IBAT denervated DIO rats. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 2.
Changes in TIBAT following 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. A, Changes in TIBAT following 4V infusions of OT or vehicle in ad libitum fed female sham or IBAT denervated DIO rats; B, Changes in TIBAT following 4V infusions of OT or vehicle in 4-h fasted female sham or IBAT denervated DIO rats. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 3.
A-B. Changes in IBAT and IWAT gene expression following 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. A, Changes in IBAT mRNA expression 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats; B, Changes in IWAT mRNA expression 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 3.
A-B. Changes in IBAT and IWAT gene expression following 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. A, Changes in IBAT mRNA expression 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats; B, Changes in IWAT mRNA expression 4V infusions of OT or vehicle in female sham or IBAT denervated DIO rats. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 4.
Plasma measurements following chronic 4V infusions of OT (16 nmol/day) or vehicle in female HFD-fed C57BL/6J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7-10/group).
Table 4.
Plasma measurements following chronic 4V infusions of OT (16 nmol/day) or vehicle in female HFD-fed C57BL/6J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7-10/group).
Table 5.
Plasma measurements following chronic 4V infusions of OT (16 nmol/day) or vehicle in female HFD-fed DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7-8/group).
Table 5.
Plasma measurements following chronic 4V infusions of OT (16 nmol/day) or vehicle in female HFD-fed DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7-8/group).
Table 6.
Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in female DBA/2J mice. A, Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in ad libitum fed female DBA/2J mice; B, Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in 4-h fasted female DBA/2J mice. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 6.
Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in female DBA/2J mice. A, Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in ad libitum fed female DBA/2J mice; B, Changes in TIBAT following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in 4-h fasted female DBA/2J mice. Shared letters are not significantly different from one another. Data are expressed as mean ± SEM. *P<0.05 OT, †0.05<P<0.1 OT vs. vehicle (N=7-8/group).
Table 7.
Plasma measurements following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in female HFD-fed DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7/group).
Table 7.
Plasma measurements following chronic systemic infusions of OT (16 and 50 nmol/day) or vehicle in female HFD-fed DBA/2J mice. Data are expressed as mean ± SEM. *P<0.05 OT vs. vehicle (N=7/group).