Chronic treatment with either dexfenfluramine or sibutramine in diet-switched diet-induced obese mice.
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.
Bush
Eugene N
EN
Department R4CY, Metabolic Disease Research Division, Abbott Laboratories Global Pharmaceutical Research, Abbott Park, IL 60064-6126, USA. gene.bush@abbott.com
Shapiro
Robin
R
Brune
Michael E
ME
Knourek-Segel
Victoria E
VE
Droz
Brian A
BA
Fey
Thomas
T
Lin
Emily
E
Jacobson
Peer B
PB
D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003503:Cyclobutanes / Q000494:pharmacology*; D020372:Dexfenfluramine / Q000494:pharmacology*; D018752:Diet, Fat-Restricted; D054439:Ghrelin; D013006:Growth Hormone / Q000097:blood; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D036361:Peptide Hormones / Q000097:blood; D013851:Thinness / Q000097:blood; D015430:Weight Gain / Q000187:drug effects
D019440:Anti-Obesity Agents; D003503:Cyclobutanes; D054439:Ghrelin; D036361:Peptide Hormones; D013006:Growth Hormone; D020372:Dexfenfluramine; C058254:sibutramine