doi: 10.1038/sj.bjp.0706807. Epub 2006 Jun 19.
Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats
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- PMID:16783408
- PMCID: PMC1751931
- DOI: 10.1038/sj.bjp.0706807
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Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats
Angels Fisas et al. Br J Pharmacol.2006 Aug.
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- Br J Pharmacol. 2007 Jun;151(4):564. Vrang, N [added]; Sørensen, R V [added]
Abstract
E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.
Figures
Effects of E-6837 and sibutramine on body weight in DIO female Wistar rats during treatment and withdrawal in comparison with vehicle. (a) Subsequent to a baseline period of 7 days (Days −6 to 0), rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks (Days 1–28) and monitored for another 6 weeks (Days 29–70) upon withdrawal. Treatment and withdrawal periods range between Days 2 and 29 and between Days 30 and 71, respectively, thereby representing body weight for a particular day as the effect of the compound dose administered the day before.P-values for mean comparisons between compounds along treatment and withdrawal periods: treatment period: vehicleversus E-6837:P<0.0001, vehicleversus sibutramine:P<0.0001, E-6837versus sibutramine:P=0.80; withdrawal period: vehicleversus E-6837:P<0.0001, vehicleversus sibutramine:P=0.01, E-6837versus sibutramine:P=0.01.*P<0.05 denotes significant differences from the control group in Dunnett's test within ANOVA single point calculations (one independent test for each time value). As a result of the known multiple testing problem they do not represent trueP-values; instead, they were included for illustrative purposes to visualize the time-intervals registering the most important differences. (b) Body weight changes per week during treatment period. Significant differences (Tukey's test:*, relative to vehicle;+, between E-6837 and sibutramine) at the end of each week are indicated: (*,+)P<0.05,***P<0.001. (c) Body weight change during treatment, during withdrawal and following both treatment and withdrawal (overall) periods. Significant differences (Tukey's test:*, relative to vehicle;+, between E-6837 and sibutramine) at the end of each period and at the end of the whole study are indicated: (*,+)P<0.05,**P<0.01,***P<0.001.
Effects of E-6837 and sibutramine on daily food intake in female DIO Wistar rats during treatment and withdrawal in comparison with vehicle. (a) Rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks and followed for 6 weeks upon withdrawal.P-values for mean comparisons between compounds along treatment and withdrawal periods. Treatment period: vehicleversus E-6837:P=0.001, vehicleversus sibutramine:P=0.02, E-6837versus sibutramine:P=0.39; withdrawal period: vehicleversus E-6837:P<0.0001, vehicleversus sibutramine:P=0.01, E-6837versus sibutramine:P=0.04. (b) Food intake changes per week during the treatment period. (c) Food intake changes per week during the withdrawal period. Significant differences relative to vehicle, at the end of each weak are indicated:*P<0.05,**P<0.01,***P<0.001.
Effects of E-6837 and sibutramine on daily fat chow, chocolate and nuts intake in female DIO Wistar rats during treatment in comparison with vehicle. Rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks.P-values for mean comparisons between compounds along treatment period. (a) Daily fat chow intake: vehicleversus E-6837:P=0.79, vehicleversus sibutramine:P=0.006, E-6837versus sibutramine:P=0.01; (b) Daily chocolate intake: vehicleversus E-6837:P=0.08, vehicleversus sibutramine:P=0.87, E-6837versus sibutramine:P=0.06; (c) Daily nuts intake: vehicleversus E-6837:P=0.02, vehicleversus sibutramine:P=0.10, E-6837versus sibutramine:P=0.51.
Effects of E-6837 and sibutramine on daily water intake in female DIO Wistar rats during treatment and withdrawal in comparison with vehicle. Rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks and followed for 6 weeks upon withdrawal.P-values for mean comparisons between compounds along treatment and withdrawal periods. Treatment period: vehicleversus E-6837:P=0.10, vehicleversus sibutramine:P=0.34, E-6837versus sibutramine:P=0.02; withdrawal period: vehicleversus E-6837:P=0.14, vehicleversus sibutramine:P=0.19, E-6837versus sibutramine:P=0.94.
Effect of chronic treatment of female DIO Wistar rats with E-6837 or sibutramine on body composition determined by chemical analyses. Rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks. Results (weight per rat (g)) are expressed as treatment group means (adjusted for differences in body weight of the groups at baseline (Day 1)) and s.e.m. (calculated from the residuals of the statistical means). Significant differences from vehicle controls by Tukey's test are denoted by**P<0.01 and***P<0.001.
Effects of E-6837 and sibutramine on plasma glucose and insulin levels in female DIO Wistar rats after a glucose challenge test. Rats were treated with E-6837 (30 mg kg−1, twice a day, p.o.) and sibutramine (5 mg kg−1 day−1, p.o.) for 4 weeks. Following overnight starvation at the end of the treatment period all groups of rats were challenged with 800 mg kg−1, s.c. glucose load. (a) Plasma glucose concentrations;P values for mean comparisons between compounds along treatment period: vehicleversus E-6837:P=0.002, vehicleversus sibutramine:P=0.70, E-6837versus sibutramine:P=0.007. (b) Plasma insulin concentrations;P values for mean comparisons between compounds along treatment period: vehicleversus E-6837:P=0.06, vehicleversus sibutramine:P=0.15, E-6837versus sibutramine:P=0.63. Significant differences from Tukey's test are denoted by** (between compound and vehicle) and by+ (between E-6837 and sibutramine),**P<0.01, (+)P<0.05.
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