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Keywords:

  • serotonin;
  • feeding;
  • anorexia

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: We examined the effectiveness of sibutramine to modulate food intake and body composition in rats with two levels of adiposity imposed by the duration of their maintenance on a moderate-fat diet.

Research Methods and Procedures: Male Sprague–Dawley rats were fed a 32% fat diet from weaning until 2 or 4 months of age, at which point, body fat was either 15% or 25%, respectively, as measured by DXA. Sibutramine (0.6 or 2 mg/kg, orally) was then given daily for 2 weeks.

Results: Food intake and body weight decreased acutely in a dose-related manner in both groups with sibutramine treatment. In all rats, food intake suppression was attenuated after multiple days of sibutramine. Both 15%- and 25%-fat rats had a persistent decrease in weight gain over the 2-week period in response to sibutramine. The older, 25%-fat rats were more sensitive to sibutramine than the younger, 15%-fat rats with regard to the magnitude of overall food intake inhibition, decrease in body weight gain, and caloric efficiency. Despite these differences, sibutramine produced the same relative reductions in fat mass and had no effect on lean mass in the two groups.

Discussion: Thus, sibutramine produced equivalent efficacy on carcass fat loss in both groups, despite less inhibition of feeding and body weight gain in leaner rats. Whether these changes are a result of the leaner rats being younger and on a steeper growth curve compared with older, fatter rats or whether this is a direct function of their level of adiposity remains to be determined.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Obesity is increasing in incidence in both youth and adult populations. Despite the prevalence of obesity as a childhood disease and its consequences, treatment of obesity in children and adolescents is complicated both by the lack of standards for appropriate body weight and body composition and by the need to maintain an increase in lean mass as a part of normal growth and developmental maturation, while normalizing body fat. Currently, 15% to 20% of children in the United States are considered to be obese, with the greatest increase in those with extreme obesity (1). The risks and comorbidities of obesity in adults have been well-documented and many of the complications of obesity seen in adults also occur in children. Moreover, most obese children and adolescents remain obese as adults. The short-term risks of childhood obesity are similar to those of adults and include hypertension, elevated cholesterol, and triglycerides as well as pulmonary, gastroenterological, and endocrine disorders (1, 2). Longer-term risks include increased cardiovascular disease and the likelihood of the persistence of obesity into adulthood. Few studies have addressed the consequences of drug therapy of obese adolescents compared with those in adults.

In adults, sibutramine, a reuptake inhibitor of norepinephrine and serotonin (3, 4), has demonstrated efficacy in decreasing body weight (5, 6). Mechanistically, sibutramine is believed to affect energy balance via reduction in food intake as well as by modulating energy expenditure. Sibutramine reduces food intake in humans both acutely (7) and after 1 or 2 weeks of treatment (8). Two studies, 8 and 12 weeks in length, in humans, have shown that sibutramine blocks the decline in energy expenditure associated with decreased body weight (9, 10). In contrast, a related study in humans given sibutramine treatment for 8 weeks found no difference in resting energy expenditure between treated and placebo-treated groups either during active weight loss or during a period of maintenance of the initial weight loss (11). In rats, sibutramine reduces food intake in a dose-dependent manner after a single treatment (12, 13). Additionally, sibutramine decreases body weight in diet-induced obese rats (14) and in monosodium glutamate-induced obese rats (15).

Dexfenfluramine, an anorectic agent believed to act via inhibition of 5HT reuptake and promotion of 5HT release, has increased efficacy in rats that are fatter and fed cafeteria diets compared with chow-fed counterparts (16). Six-month-old diet-induced obese rats given dexfenfluramine (7 mg/kg per day, intraperitoneally) for 60 days had a larger body weight decrease than did chow-fed rats compared with their respective controls (16). In a similar study, Rowland and Carlton (17), using continuous infusion of dexfenfluramine, demonstrated a greater suppression of body weight in 3-month-old cafeteria-fed than in 3-month-old chow-fed rats. In both these studies that show differential dexfenfluramine effects, diet was used to generate the difference in the experimental groups (16, 17). To generate obesity, rats are often placed on a high-fat or cafeteria-style diet. However, in such studies, suppression of food intake by pharmacological agents may be related to their ability to suppress appetite for particular macronutrients that are not represented similarly in control diets (18, 19). One study by Blundell and Hill (20) suggests that the dexfenfluramine effects are more likely to be driven by adiposity rather than by diet composition. They found that dexfenfluramine had similar efficacy on body weight in female Wistar rats during the early developmental stage of cafeteria diet-induced obesity compared with chow-fed controls, yet 3 months later in the same rats, there was a markedly greater effect of dexfenfluramine on suppression of body weight gain in the cafeteria diet-fed rats than the chow-fed rats. The caveat remains, however, of whether the change in efficacy is related to age and body weight or composition.

In this study, we sought to evaluate whether sibutramine, similar to dexfenfluramine, has increased efficacy in rats with dietary-induced obesity. We eliminated the potential confound of dietary composition by feeding rats the same high-energy diet that contains moderately high levels both of sucrose and of fat for different periods. Clearly, to obtain differences in adiposity with the same diet, one set of rats remained on the diet longer; thus, there was a 2-month age difference between the rats. This led to the question of whether lean mass growth was inhibited in young rats on a steep growth curve. We found that older rats with higher carcass fat content were more sensitive to sibutramine than were younger rats with a lower carcass fat content with respect to efficacy in food intake reduction and total body weight and percentage of body weight loss. However, rats at both levels of body fat had similar deceases in percentage of fat loss in response to sibutramine treatment.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Animals

Male Sprague–Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). Rats were fed a moderate high-fat diet(pelleted D12266B; Research Diets, Inc., New Brunswick, NJ) from 3 to 7 weeks of age, while at the Charles River Laboratories facility, after which they were brought into the Merck (Rahway, NJ) facility and maintained on the D12266B diet until they were ∼8 or 16 weeks of age. At that point, body fat, based on DXA-scan analysis, was ∼15% or 25%, respectively, of total body mass. This dietary regimen causes all rats to become obese compared with those fed only low-fat, chow diet from 3 weeks of age (21). Rats were housed individually in a temperature-controlled room (26 °C) with a 12:12-hour light/dark cycle and were given free access to food and water throughout the duration of the study. All experimental protocols were approved by Merck Research Laboratories Institutional Animal Care and Use Committee.

Diet

D12266B, a defined diet from Research Diets, contains 16.8% protein (percentage by kilocalories), 51.4% carbohydrate, and 31.8% fat; with a caloric density of 4.5 kcal/g. Rats were raised on a pelleted form of D12266B; before the studies commenced, rats were switched to a milled version of the diet for measurement purposes.

Food Intake

Rats were individually housed in plastic shoe-box cages with Nalgene metabolism cage feeders (Minimitter Corp., Sunriver, OR). Each feeder has an aperture through which the animal can reach the food cup below which sits on a balance external to the feeder. Each balance is connected to a central computer, which records weight of food remaining at predetermined intervals. Rats were acclimated in the feeding set up for at least 2 days before initiating experiments.

Body Composition

Body composition was measured using DXA-scan analysis. A Hologic QDR 4500A (Hologic, Waltham, MA) with a software program adapted for small animals was used to obtain body composition data (22, 23). Rats were anesthetized with ketamine/xylazine (45 and 6.5 mg/kg, respectively) for the procedure. To allow for recovery of food intake and body weight after anesthesia, initial scans were performed 6 days before the start of the experiment. A final scan was performed at the termination of the experiment.

Statistical Analyses

One-way measures ANOVAs were used to calculate the dose-related efficacy of sibutramine on end-points of daily food intake and cumulative body weight gain. Repeated measures ANOVAs were used to assess food intake and weight gain. Differences in pre- and post-DXA-scan data were calculated for analysis and one-way ANOVAs performed on the differences generated by sibutramine treatment. Post hoc differences were determined using Dunnett's analysis.

Experimental Protocols

Rats were grouped to ensure that starting body weight and the percentage of body fat were equivalent. Dosing and weighing of the rats was done daily 1 hour before lights out and food intake was measured daily. At the end of the study, after DXA-scan analyses, animals were euthanized and epididymal, mesenteric and retroperitoneal fat pads were removed and weighed. Sibutramine HCl was prepared by Merck Medicinal Chemistry.

Rats were dosed orally for 14 days with either vehicle (0.5% methycellulose, 2 mL/kg) or sibutramine (0.6 or 2 mg/kg). The 2-mg/kg dose was previously determined to be effective in suppressing acute overnight food intake in the 15%-fat rats. Group sizes were n = 6 except for the vehicle and 2-mg/kg group of the 25%-fat rats wherein each group had n = 12. The 15%-fat rats (n = 6 per group), ∼2 months of age, weighed 387 ± 6 g at the start of the study. The 25%-fat rats, 4 months of age, weighed 555 ± 6 g.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Fourteen-Day Food Intake

In the younger, 15%-fat rats, food intake was not significantly decreased by sibutramine for the 14 days (vehicle, 294 ± 18 g; 0.6 mg/kg, 278 ± 15 g; 2.0 mg/kg, 258 ± 14 g). In contrast, in the older, 25%-fat rats, sibutramine decreased food intake in a dose-dependent manner; cumulative food intake decreased significantly over the 14-day period (vehicle, 275 ± 8 g; 0.6 mg/kg, 201 ± 13 g; 2 mg/kg, 198 ± 7 g; F(2) 30.3; p < 0.0001).

Figure 1 shows the daily food intake across the 14-day period. In the younger, 15%-fat rats, overnight food intake in the sibutramine-treated rats was suppressed only during the first 2 days of dosing (day 1, ∼20 and 25% for the 0.6 and 2.0-mg/kg doses, respectively; day 2, 14% and 23%, respectively); thereafter, food consumption overlapped that of the vehicle group (Figure 1A). In contrast, in the older, 25%-fat rats, sibutramine produced a more sustained inhibition of food intake that was greatest initially and declined at later time-points. Suppression was significant in the 0.6-mg/kg group for all days except day 11 and on all days in the 2-mg/kg group (Figure 1B).

image

Figure 1. Sibutramine effects on 14-day food intake in (A) rats with 15% body fat and (B) rats with 25% body fat with 14 days of dosing. A. In the 15%-fat rats, there was an effect of the day of dosing and an interaction between day and sibutramine, despite no direct effect of sibutramine (drug: not significant; day: F(13) 3.3, p = 0.0001; interaction: F(26) 1.6, p = 0.043). (B) In the 25%-fat rats, food intake was significantly decreased throughout the study. Significance of the individual groups (p < 0.05 by Dunnett's post hoc analysis) is denoted by the asterisk.

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Patterns of Food Intake

In both groups of animals, the profile of food intake in the presence of sibutramine (2 mg/kg) was examined in 4-hour intervals on days 1, 7, and 14 (Figure 2). Vehicle data from days 1, 7, and 14 were analyzed and found to be similar, and thus, data reported for vehicle treatment represent the average of those 3 days. In the younger, 15%-fat rats (Figure 2A), food intake in these intervals was significantly affected both by the treatment day and the time of day (treatment day: F(3) 2.9, p = 0.04; time interval: F(3) 19.8, p < 0.001; interaction: F(9) 2.1, p = 0.04). The greatest decrease in food intake from vehicle occurred during the first 4-hour time block after dosing on day 1 (p < 0.05) and was absent on days 7 and 14.

image

Figure 2. Food intake in the vehicle and 2-mg/kg groups measured in 4-hour intervals starting at the onset of dosing, 1 hour before lights out on days 1, 7, and 14. (A) In 15%-fat rats, food intake was significantly affected by the treatment day and time of day (treatment day: F(3) 2.9, p = 0.04; time interval: F(3) 19.8, p < 0.001; interaction: F(9) 2.1, p = 0.04). (B) In 25%-fat rats, food intake was significantly affected both by the treatment day and the time of the interval (treatment day: F(3) 27.5, p < 0.0001; time interval: F(3) 27.6, p < 0.0001; interaction: F(9) 4.0, p < 0.0001). Differences of each group are shown by the asterisk (p < 0.05 by Dunnett's post hoc analysis).

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As in the younger, 15% fat rats, the data of the vehicle-treated older, 25% fat rats from days 1, 7, and 14 were analyzed and found to be similar, and, thus, data reported for vehicle treatment represent the average of those 3 days. The older, 25% fat rats had larger and more prolonged decreases in food intake than younger, 15% fat rats when sibutramine effects were examined by interval (Figure 2B). Food intake in these intervals was significantly affected both by the treatment day and the time of the interval (treatment day: F(3) 27.5, p < 0.0001; time interval: F(3) 27.6, p < 0.0001; interaction: F(9) 4.0, p < 0.0001). The 4-hour interval food intake analyses showed that feeding was uniformly decreased at each time-interval throughout the first night of dosing, whereas on day 7, food intake was suppressed only during the first 4 hours post-dose. By day 14, food intake during each interval was not significantly suppressed despite a statistically significant decrease of total food intake for that night.

Body Weight

In the younger, 15%-fat rats, sibutramine decreased daily body weight gain across time (Figure 3A; repeated measures ANOVA: drug: F(2) 3.8, p = 0.047; time: F(13) 2.9, p = 0.0008; interaction: not significant). The 0.6-mg/kg dose did not decrease body weight gain. However, the body weight gain in the 2-mg/kg group was significantly less (Dunnett's, p < 0.05) than both the vehicle and the 0.6-mg/kg groups. The percentage change in total body weight compared with day 0 for each group was +17 ± 1%,+18 ± 1%, and +13 ± 1% for rats receiving vehicle, 0.6 mg/kg, and 2 mg/kg sibutramine, respectively.

image

Figure 3. Body weight change during 14 days of sibutramine administration in (A) adolescent, 2-month-old rats with 15% body fat, and (B) 4-month-old rats with 25% body fat. (A) On all days, there was a dose-related decrease of body weight change. (B) Body weight gain of all sibutramine-treated groups was significantly decreased in a dose-dependent manner. Differences of each group are shown by the asterisk (p < 0.05 by Dunnett's post hoc analysis).

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The daily body-weight gain in the older, 25%-fat rats was decreased by sibutramine in a dose-dependent manner over the entire 14-day treatment period (Figure 3B; repeated measures ANOVA: drug: F(2) 33.4, p < 0.0001; time: F(13) 8.8, p < 0.0001; interaction: F(26) 3.0, p < 0.0001). Cumulative body-weight gain at day 14 was significantly less with sibutramine treatment (F(2) 33.4, p < 0.0001). Both groups were less than vehicle by Dunnett's analysis (p < 0.01). The percentage change in total body weight compared with day 0 was +10 ± 1%,+3 ± 2%, and +1 ± 1% for rats receiving vehicle, 0.6 mg/kg, and 2 mg/kg sibutramine, respectively.

Body Composition

In the younger, 15%-fat rats, there were no differences among the three groups in the initial DXA-scan measures of carcass composition taken 6 days before the onset of treatment. Values for the combined groups are shown in Table 1. Differences between initial and terminal body composition measures were then examined (Figure 4). Fat mass (Figure 4A) was significantly decreased by sibutramine treatment (F(2) 5.7, p = 0.017) as was change in the percentage of body fat (Figure 4B; F(2) 5.7, p = 0.014). As in the 14-day body weight gain, the effect is only seen in the 2-mg/kg dose. Lean mass (Figure 4C) was unaltered with sibutramine treatment.

Table 1.  Initial body composition of 15%- and 25%-fat rats
 BMC (grams)Fat massLean massTotal mass% BMC% Lean% Fat
  1. Measurements made by DXA scan analysis 6 days before sibutramine administration.

  2. BMC, bone mineral content.

15%-Fat       
Average9.160.7304.3374.22.481.516.0
SEM0.24.34.97.90.00.80.8
25%-Fat       
Average14.3142.2409.6566.12.572.824.7
SEM0.38.46.212.40.00.90.9
image

Figure 4. Change in body composition as measured by DXA-scan analysis after 14 days of sibutramine dosing. Two- or 4-month-old rats had body fat levels at the start of the study of 15% or 25%, respectively. (A) Both groups of rats had decreased fat mass. (B) There was a decrease in the percentage of body fat in both groups of rats. (C) Lean mass was not changed in the 15%- or 25%-fat groups with sibutramine treatment. Each set of variables is compared by one-way ANOVA. Asterisks represent change from vehicle by Dunnett's analysis.

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In the older, 25%-fat rats, there were also no differences between the experimental groups at the start of the study. Initial values are shown in Table 1. Fat mass (Figure 4A) decreased with sibutramine treatment (F(2) 7.2, p = 0.003), resulting in a concomitant reduction in the percentage of body fat (Figure 4B; F(2) 7.3, p = 0.003). No differences were seen in lean mass gain(Figure 4C).

Adipose Depot Weights

In the younger, 15%-fat rats, retroperitoneal white adipose tissue weight was decreased by sibutramine treatment (Table 2). Epididymal and mesenteric white adipose depots were not different in weight, although there was a strong trend for reduced weights in those depots. In the older, 25%-fat rats, sibutramine decreased retroperitoneal and mesenteric fat weight, but not epididymal fat pad weight, producing an overall reduction in total fat pad weights(Table 2).

Table 2.  Body fat depots after 14-day administration of sibutramine
 RetroperitonealMesenteric (mg/100 g body weight)EpididymalTotal
  • NS, not significant.

  • *

    Different from vehicle treatment by Dunnett's post hoc analysis.

15%-Fat rats (Expt. 1)    
Vehicle1.5740.9840.7883.340
 0.1610.1450.0210.218
Sibutramine    
0.6 mg/kg1.1561.0260.6922.871
 0.1600.0880.0700.287
2 mg/kg0.827*0.9350.7772.537
 0.0840.0410.0550.135
ANOVA0.005NSNS0.055
25%-Fat rats (Expt. 2)    
Vehicle1.8291.2451.2074.279
 0.1010.0550.0850.204
Sibutramine    
0.6 mg/kg1.5971.1221.3274.047
 0.1360.1140.0850.307
2 mg/kg1.3190.937*1.0413.297*
 0.1190.0660.0750.172
ANOVA0.0090.009NS0.004

Caloric Efficiency

Caloric efficiency, as calculated by the amount of weight gain per gram amount of food intake over the 14-day dosing period, decreased with sibutramine treatment in both groups of rats that had 15% or 25% body fat (Figure 5). The evoked decrease in caloric efficiency was greater and evident at a lower dose in the older, 25%-fat rats than in the younger, 15%-fat rats. In the 15%-fat rats (F(2) 5.5, p = 0.0162), whereas there was a group effect, neither dose was significantly less than vehicle treatment. In the older, 25%-fat rats (F(2) 16.9, p < 0.0001) both the 0.6-mg/kg and the 2-mg/kg groups were less than vehicle.

image

Figure 5. Caloric efficiency decreases with sibutramine treatment in both the (A) younger, 15%-fat and (B) older, 25%-fat rats. The magnitude is greater and efficacious at a lower dose in the 25%-fat rats. Data were calculated from total food intake and body weight change over the 14-day sibutramine administration. Differences of each group are shown by the asterisk (p < 0.05 by Dunnett's post hoc analysis).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We have shown that 14 days of sibutramine treatment decreased body weight and carcass fat in rats with a starting adiposity of 15% or 25% of total body weight. Although efficacious in decreasing body fat, sibutramine did not compromise accrual of lean mass. The effect on body weight was greater in the fatter rats, but the proportional loss of fat mass did not differ from that in rats with less body fat. Sibutramine also decreased food intake in both groups; however, the effect was more pronounced and sustained in the fatter rats. The differences seen in the responsiveness of these two groups may be a function of the differential adiposity; however, it may also be affected by the 2-month age difference between the groups. The age difference resulted from the decision to examine adiposity differences in rats on the same diet, thus eliminating the effect resulting from differences in dietary composition. Consequently, all rats were started on a moderately high-fat diet at the same age and then tested experimentally when they reached particular levels of adiposity, at 2 and 4 months of age.

With respect to the age differences, the younger, 15%-fat rats were on a steeper portion of their growth curve as is seen in the rate of weight gain increase in the vehicle-treated rats during the experimental period. They showed a body weight increase of 67 ± 6 g, 17% increase over their starting weight. In contrast, the older, 25%-fat rats showed a 54 ± 3 g increase, a net change of 10% over 14 days. Thus, it is not unexpected that the younger, 15%-fat rats exhibited smaller decreases in food intake and body weight. It seems adaptive that compensatory mechanisms may occur to the greatest extent in these rats so that appropriate growth is sustained. In fact, rats maintained lean mass growth at both sibutramine doses; only loss of fat mass contributed to the body weight decreases.

There is precedence for greater efficacy of anti-obesity agents in animals with increased adiposity, most notably fenfluramine (16, 17, 18, 19, 20). In our experiments, 2 mg/kg per day of sibutramine given to the younger, 15%-fat rats resulted in a 3.6% decrease in total body weight compared with vehicle control rats; in contrast, the same dose in the older, 25%-fat rats resulted in an 11.5% decrease in total body weight compared with their corresponding vehicle control group. Like body weight, food intake suppression was greatest in the older, 25%-fat rats. The initial food intake suppression is consistent with other reports of acute effects of sibutramine (13). However, body-weight decrease mediated by sibutramine probably reflects more than mere suppression of appetite. When examined over the 2-week period, the older, 25%-fat rats have a decreased caloric efficiency (Figure 5). This effect is minimal in the leaner rats. Sibutramine treatment of diet-induced obese rats has previously been shown to cause an increase in sympathetic nervous system activity. High doses of acutely administered sibutramine increase Vo2 by ∼30%. Similarly, glucose use studies suggest that this effect occurs through activation of thermogenesis in brown adipose tissue (24). When sibutramine is chronically given to diet-induced obese Sprague–Dawley rats, urinary catechols, another measure of general sympathetic activation, are increased (14). Thus, the decrease in caloric efficiency we see most likely results from an increase in sympathetic mechanisms, probably driving thermogenesis. Why this effect is smaller in the younger, 15%-fat rats than in older, 25%-fat rats is not clear, but is most likely driven by the compensatory mechanisms minimizing suppression of food intake. It would be of interest to find whether the sympathetic nervous system in rats with greater adiposity is more responsive to sibutramine than that of leaner rats.

Compensatory Mechanisms

The maximal effectiveness of sibutramine with respect to both food intake and body weight suppression occurred with the initial drug administration. The apparent desensitization of the effects of sibutramine could result from either a molecular desensitization (i.e., at the level of the serotonergic or adrenergic receptors proximally activated as a consequence of sibutramine action) or the activation of compensatory pathways to counteract the effects of sibutramine to ensure appropriate caloric supply to the body or maintenance of body weight.

5HT1B and 5HT2C receptors have been implicated both pharmacologically (25, 26) and genetically (27, 28, 29) in the anorectic action of serotonin. Effects at 5HT1B or 5HT2C receptors may account for some, but, seem to be insufficient to explain all the actions of sibutramine. Both Jackson et al. (4) and Grignaschi et al. (12) demonstrated that the acute anorectic effects of sibutramine were only partially blocked using a variety of serotonin 1B-, 2C-, or nonselective-receptor antagonists. Thus, down-regulation of either receptor could play a part in the desensitization of serotonin-mediated responses. Jackson et al. (4) attenuated the effects of sibutramine by α- andβ-adrenoreceptor blockade. Sibutramine-mediated down-regulation of the α2 and β1 adrenoreceptors has been observed (30, 31). Thus, alterations in noradrenergic systems seem more likely to account for the decreased responsiveness of sibutramine across time. By contrast, Fone et al. (32) demonstrated that 14-day infusion of the moderately selective 5HT2C receptor agonist, m-chlorophenylpiperazine (mCPP), only partially decreases 5HT2C receptor number in the cortex and the hypothalamus; in this study, there is a maintained suppression of feeding as a result of the mCPP. This suggests that the component of feeding that remains decreased in our study may well result from suppression of appetite by the 5HT2C receptor. Part of the difference in the absolute body weight effects between the two groups of rats in our study may occur as a result of greater contribution by metabolic rate in the response to sibutramine. Previously, significant effects on metabolic rate that have been published have only shown effects at higher doses, which gave effects similar to that seen in the older, 25%-fat rats of this study.

In characterizing the decrease in food intake seen with repeated sibutramine administration (Figure 1), it is apparent that sibutramine still is effective in suppressing appetite in the early part of the night (Figure 2B). These early effects suggest that the molecular mechanisms through which sibutramine exerts its effects, at least in the older, fatter rat, are intact and consequently, the decrease in sibutramine's action may result from other counter-regulatory pathways that are recruited to counter the anorectic effects of sibutramine and ensure maintenance of caloric supply and a recovery of body weight. That such a shift in food intake exists with long term dosing of sibutramine has been previously demonstrated (14). The stabilization of an intermediate food intake allows the animal to defend its new, lower set-point established by sibutramine's influence on neural pathways. Mechanistically, prolonged sibutramine treatment lowers the defended body weight in association with normalization of neuropeptide Y and pro-opiomelanocortin mRNA expression in the hypothalamic arcuate nucleus (14, 33). This suggests that such neurochemical adjustments might contribute to compensatory mechanisms and limit the efficacy of chronic sibutramine treatment.

In summary, although we saw greater efficacy of sibutramine to prevent body-weight gain in older rats with a higher starting adiposity, sibutramine had a similar efficacy in decreasing body fat in both groups of rats. These data suggest that sibutramine decreases body weight by specific activity on adipose tissue. The caveat in interpretation of these data is that the two groups of rats used were 2 months different in age, and, consequently, age-related differences may contribute to the observed effects. Because the 8-week-old rats are on a steeper growth curve than the 16-week-old rats, the differential magnitude of body weight loss may be due to the brain's recognition of a greater need to preserve lean mass. Regardless, the contrasting effects on lean mass and fat mass suggest that sibutramine may be well-suited to the treatment of overweight adolescents where there is still a need for unimpeded lean growth in the presence of excess fat mass.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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