Chronic treatment with either dexfenfluramine or sibutramine in diet-switched diet-induced obese mice
Eugene N Bush1, Robin Shapiro, Michael E Brune
1Department R4CY, Metabolic Disease Research Division, Abbott Laboratories Global Pharmaceutical Research, Abbott Park, IL 60064-6126, USA. gene.bush@abbott.com
Abstract:
Dexfenfluramine (DEX) and sibutramine (SIB) are effective antiobesity agents. Their effects on weight control and hormone profile have not been previously studied in diet-switched diet-induced obese (DIO) mice, in which treatment is initiated upon cessation of a low-fat diet and resumption of a high-fat diet. Furthermore, their effects on circulating ghrelin in obese humans or in animal models of obesity have not yet been reported. Male C57Bl/6J DIO mice after 16 wk on a high-fat diet (HF, 60 kcal% fat) were switched to a low-fat diet (LF, 10 kcal% fat) for 50 d. HF diet resumed concurrently with treatment for 28 d with DEX 3 and 10 mg/kg, twice a day (BID); SIB 5 mg/kg BID; or vehicle. Rapid weight regain ensued in vehicle-treated DIO mice. DEX or SIB treatment significantly blunted the body weight gain. Caloric intake was decreased acutely by DEX or SIB vs vehicle during the first 2 d treatment, but returned to control after 5 d. At the end of study, epididymal fat weight and whole body fat mass determined by DEXA scan were decreased by DEX 10 mg/kg, and whole body lean mass decreased with DEX 3 mg/kg treatment. Circulating ghrelin on d 28 was increased with either DEX 3 or 10 mg/kg treatment, while growth hormone and insulin were decreased. Leptin was also decreased in the DEX 10 mg/kg group. SIB did not significantly affect fat mass, ghrelin, growth hormone, insulin, or leptin. Mice chronically fed LF diet maintained a lower caloric intake, gained less weight and fat mass than diet-switched mice, and had higher ghrelin and lower insulin and leptin. In summary, weight regain in diet-switched DIO mice is delayed with either DEX or SIB treatment. DEX treatment of diet-switched DIO mice decreased growth hormone, insulin, leptin, fat mass, lean mass, and increased ghrelin, while SIB only decreased body weight.
Insights
Dexfenfluramine (DEX) and sibutramine (SIB) delay weight regain in diet-induced obese mice. DEX decreased fat and lean mass, while increasing ghrelin, but SIB only reduced body weight.
Area of Science:
- Metabolic research
- Obesity studies
- Pharmacology
Background:
- Diet-induced obesity (DIO) mouse models are crucial for studying weight management strategies.
- The effects of dexfenfluramine (DEX) and sibutramine (SIB) on weight control and hormone profiles in diet-switched DIO mice are not well-documented.
- Circulating ghrelin levels in response to these agents in obesity models remain largely unreported.
Purpose of the Study:
- To investigate the effects of DEX and SIB on weight control in diet-switched DIO mice.
- To analyze the impact of these antiobesity agents on circulating ghrelin, growth hormone, insulin, and leptin levels.
- To compare the efficacy of DEX and SIB in preventing weight regain and altering body composition.
Main Methods:
- Male C57Bl/6J mice were fed a high-fat (HF) diet for 16 weeks, then switched to a low-fat (LF) diet for 50 days.
- Following the diet switch, mice received DEX (3 or 10 mg/kg BID), SIB (5 mg/kg BID), or vehicle concurrently with a resumed HF diet for 28 days.
- Body weight, caloric intake, body composition (DEXA scan), and circulating hormone levels (ghrelin, growth hormone, insulin, leptin) were measured.
Main Results:
- Both DEX and SIB significantly blunted body weight regain in diet-switched DIO mice compared to vehicle controls.
- Caloric intake was acutely reduced by DEX and SIB but returned to control levels after 5 days.
- DEX (10 mg/kg) reduced epididymal fat and whole-body fat mass, and DEX (3 mg/kg) reduced lean mass. DEX increased circulating ghrelin and decreased growth hormone and insulin. SIB did not significantly alter fat mass or hormone levels.
- Mice maintained on an LF diet exhibited lower caloric intake, less weight and fat gain, and higher ghrelin with lower insulin and leptin compared to diet-switched mice.
Conclusions:
- Dexfenfluramine and sibutramine treatments delay weight regain in diet-switched DIO mice.
- DEX treatment impacts body composition (fat and lean mass) and alters key metabolic hormones (ghrelin, growth hormone, insulin, leptin) in this model.
- Sibutramine primarily reduced body weight without significant effects on body composition or the measured hormones in this study.
