Biology subjects

Rambousek, J. R.

Publications and source records attributed to Rambousek, J. R..

3 recordsLinked to original sources

bioRxiv2024

Effects of systemic oxytocin and beta-3 receptor agonist (CL 316243) treatment on body weight and adiposity in male diet-induced obese rats

Previous studies have implicated hindbrain oxytocin (OT) receptors in the control of food intake and brown adipose tissue (BAT) thermogenesis. We recently demonstrated that hindbrain [fourth ventricle (4V)] administration of oxytocin (OT) could be used as an adjunct to drugs that directly target beta-3 adrenergic receptors ({beta}3-AR) to elicit weight loss in diet-induced obese (DIO) rodents. What remains unclear is whether systemic OT can be used as an adjunct with the {beta}3-AR agonist, CL 316243, to increase BAT thermogenesis and elicit weight loss in DIO rats. We hypothesized that systemic OT and {beta}3-AR agonist (CL 316243) treatment would produce an additive effect to reduce body weight and adiposity in DIO rats by decreasing food intake and stimulating BAT thermogenesis. To test this hypothesis, we determined the effects of systemic (subcutaneous) infusions of OT (50 nmol/day) or vehicle (VEH) when combined with daily systemic (intraperitoneal) injections of CL 316243 (0.5 mg/kg) or VEH on body weight, adiposity, food intake and brown adipose tissue temperature (TIBAT). OT and CL 316243 monotherapy decreased body weight by 8.0{+/-}0.9% (P<0.05) and 8.6{+/-}0.6% (P<0.05), respectively, but OT in combination with CL 316243 produced more substantial weight loss (14.9{+/-}1.0%; P<0.05) compared to either treatment alone. These effects were associated with decreased adiposity, energy intake and elevated TIBAT during the treatment period. The findings from the current study suggest that the effects of systemic OT and CL 316243 to elicit weight loss are additive and appear to be driven primarily by OT-elicited changes in food intake and CL 316243-elicited increases in BAT thermogenesis.

neuroscience↗

bioRxiv2024

Sympathetic innervation of interscapular brown adipose tissue is not a predominant mediator of OT-elicited reductions of body weight gain and adiposity in male diet-induced obese rats

Recent studies indicate that central administration of oxytocin (OT) reduces body weight (BW) in high fat diet-induced obese (DIO) rodents by reducing energy intake and increasing energy expenditure (EE). Previous studies in our lab have shown that administration of OT into the fourth ventricle (4V; hindbrain) elicits weight loss and stimulates interscapular brown adipose tissue temperature (TIBAT) in DIO rats. We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of IBAT contributes to its ability to activate BAT and reduce BW in DIO rats. To test this, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of TIBAT and reduction of BW in DIO rats. We first confirmed that bilateral surgical SNS denervation to IBAT was successful based on having achieved [≥] 60% reduction in IBAT norepinephrine (NE) content from DIO rats. NE content was selectively reduced in IBAT by 94.7 {+/-} 2.7, 96.8 {+/-} 1.8 and 85.9 {+/-} 6.1% (P<0.05) at 1, 6 and 7-weeks post-denervation, respectively, and was unchanged in liver or inguinal white adipose tissue. We then measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (1, 5 {micro}g) to stimulate TIBAT in DIO rats. We found that the high dose of 4V OT (5 {micro}g) stimulated TIBAT similarly between sham and denervated rats (P=NS) and that the effects of 4V OT to stimulate TIBAT did not require beta-3 adrenergic receptor signaling. We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day) or vehicle infusion to reduce BW, adiposity, and energy intake in DIO rats. Chronic 4V OT reduced BW gain by -7.2 {+/-} 9.6 g and -14.1 {+/-} 8.8 g in sham and denervated rats (P<0.05 vs vehicle treatment), respectively, and this effect was similar between groups (P=NS). These effects were associated with reductions in adiposity and energy intake (P<0.05). Collectively, these findings support the hypothesis that sympathetic innervation of IBAT is not required for central OT to increase BAT thermogenesis and reduce BW gain and adiposity in male DIO rats.

neuroscience↗

bioRxiv2024

The Novel Chimeric Multi-Agonist Peptide (GEP44) Reduces Energy Intake and Body Weight in Male and Female Diet-Induced Obese Mice in a Glucagon-Like Peptide-1 Receptor-Dependent Manner

We recently reported that a novel chimeric peptide (GEP44) targeting both the glucagon-like peptide-1 receptor (GLP-1R) and neuropeptide Y1- and Y2 receptor (Y1R and Y2R) reduced energy intake and body weight (BW) in diet-induced obese (DIO) rats. We hypothesized that GEP44 reduces energy intake and BW primarily through a GLP-1R dependent mechanism. To test this hypothesis, GLP-1R+/+ mice and GLP-1R null (GLP-1R-/-) mice were fed a high fat diet for 4 months to elicit diet-induced obesity prior to undergoing a sequential 3-day vehicle period, 3-day drug treatment (5, 10, 20 or 50 nmol/kg; GEP44 vs the selective GLP-1R agonist, exendin-4) and a 3-day washout. Energy intake, BW, core temperature and activity were measured daily. GEP44 (10, 20 and 50 nmol/kg) reduced BW after 3-day treatment in DIO male GLP-1R+/+ mice by - 1.5{+/-}0.6, -1.3{+/-}0.4 and -1.9{+/-}0.4 grams, respectively (P<0.05), with similar effects being observed in female GLP-1R+/+ mice. These effects were absent in male and female DIO GLP-1R-/- mice suggesting that GLP-1R signaling contributes to GEP44-elicited reduction of BW. Further, GEP44 decreased energy intake in both male and female DIO GLP-1R+/+ mice, but GEP44 appeared to produce more consistent effects across multiple doses in males. In GLP-1R-/- mice, the effects of GEP44 on energy intake were only observed in males and not females, suggesting that GEP44 may reduce energy intake, in part, through a GLP-1R independent mechanism in males. In addition, GEP44 reduced core temperature and activity in both male and female GLP-1R+/+ mice suggesting that it may also reduce energy expenditure. Lastly, we show that GEP44 reduced fasting blood glucose in DIO male and female mice through GLP-1R. Together, these findings support the hypothesis that the chimeric peptide, GEP44, reduces energy intake, BW, core temperature, and glucose levels in male and female DIO mice primarily through a GLP-1R dependent mechanism.

pharmacology and toxicology↗