Effects of Combined Oxytocin and Beta-3 Receptor Agonist (CL 316243) Treatment on Body Weight and Adiposity in Male Diet-Induced Obese Rats

Abstract

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 < 0.05) and 9.1 ± 2.1% (P < 0.05), respectively, but the combined treatment produced more pronounced weight loss (15.5 ± 1.2%; P < 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 < 0.05). In addition, CL 316243 alone (P < 0.05) and in combination with OT (P < 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.

Hindbrain Administration of Oxytocin Reduces Food Intake, Weight Gain and Activates Catecholamine Neurons in the Hindbrain Nucleus of the Solitary Tract in Rats

“…Consistent with our previously published findings in DIO Long-Evans rats [30], chronic 4V OT failed to significantly impact IWAT adipocyte size in HFD-fed CD ® IGS rats (P = NS) (Figures 5A,B and 6A). OT tended to reduce EWAT adipocyte size in HFD-fed CD ® IGS rats, although this did not reach significance (P = 0.148; Figures 5C,D and 6B).…”

“…Plasma leptin and insulin were measured using electrochemiluminescence detection Meso Scale Discovery (MSD ® , Rockville, MD, USA) using established procedures [6,12,29,30,46]. Intra-assay coefficient of variation (CV) for leptin was 2.7% and 3.2% for insulin.…”

“…We recently found that chronic 4V OT administration is sufficient to ameliorate dietinduced obesity in CD ® IGS and Long-Evans rats [6,30] and C57Bl/6J mice [12], but one other important question is whether hindbrain (4V) administration may also prevent the progression of diet-induced obesity. While we recently identified that chronic 3V infusion of OT can reduce weight gain associated with diet-induced obesity in CD ® IGS rats, the extent to which these effects may have been mediated, in part, by activation of hindbrain OTRs is not clear.…”

Oxytocin as an Anti-obesity Treatment

“…(2) Is the parvocellular PVN OT projection to the NTS less dense in the mouse model compared to the rat model? Existing findings at least provide indirect evidence in support of a descending PVN to NTS OT projection in a mouse model ( Blouet et al, 2009 ; Matarazzo et al, 2012 ; Ryan et al, 2017 ; Wu et al, 2017 ) and implicate an important role for OTRs within the caudal hindbrain in the control of body weight through reductions of food intake (homeostatic and hedonic) and increases in BAT thermogenesis or core temperature (as surrogate marker of energy expenditure) in both mice ( Blouet et al, 2009 ; Matarazzo et al, 2012 ; Ryan et al, 2017 ; Edwards et al, 2021b ) and rats ( Baskin and Bastian, 2010 ; Blevins and Ho, 2013 ; Ho et al, 2014 ; Ong et al, 2015 , 2017 ; Roberts et al, 2017 ; Edwards et al, 2021a ).…”

“…It is well documented that OT reduces food intake (including chow, purified low and high fat diet or sucrose solution) following systemic ( Arletti et al, 1989 , 1990 ; Deblon et al, 2011 ; Maejima et al, 2011 , 2015 , 2017 ; Morton et al, 2012 ; Altirriba et al, 2014 ; Ho et al, 2014 ; Blevins et al, 2015 ; Iwasaki et al, 2015 , 2019 ; Balazova et al, 2016 ; Klockars A. et al, 2017 ; Iwasa et al, 2019b , 2020 ; Erdenebayar et al, 2020 ), intranasal ( Maejima et al, 2015 ) or CNS administration ( Arletti et al, 1989 , 1990 ; Olson et al, 1991a ; Lokrantz et al, 1997 ; Rinaman and Rothe, 2002 ; Kublaoui et al, 2008 ; Deblon et al, 2011 ; Morton et al, 2012 ; Mullis et al, 2013 ; Ho et al, 2014 ; Noble et al, 2014 ; Ong et al, 2015 ; Herisson et al, 2016 ; Klockars O. A. et al, 2017 ; Klockars et al, 2018 ; Liu et al, 2020a ; Edwards et al, 2021a , b ). While many such investigations have targeted the lateral ventricles, 3V and 4V, which lack the anatomical resolution to differentiate receptor populations, recent findings indicate that OT reduces food intake following direct injections into the ARC ( Maejima et al, 2014 ), CeA ( Klockars et al, 2018 ), basolateral amygdala ( Klockars et al, 2018 ), VMH ( Noble et al, 2014 ; Klockars O.…”