Sustained decreases in weight and serum insulin, glucose, triacylglycerol and cholesterol in JCR:LA-corpulent rats treated with D-fenfluramine.

1. The effects of D-fenfluramine were studied in the JCR:LA-corpulent rat that is grossly obese, hyperphagic, hyperlipidaemic, hyperinsulinaemic and atherosclerosis-prone. 2. Daily doses of 1, 2.5 and 5 mg kg-1 of D-fenfluramine produced sustained decreases in body weight and food intake over a period of 30 days in 6 month old female rats fed ad libitum. This was accompanied by decreases in the circulating concentrations of glucose, triacylglycerol, free cholesterol and insulin. 3. Food restriction imposed by meal feeding also decreased circulating glucose, triacylglycerols, cholesterol and insulin and diminished the effect of D-fenfluramine on these parameters in male and female rats. 4. Addition of D-fenfluramine to drinking water to give a dose of about 0.25 mg kg-1 daily produced a sustained decrease in body weight and food intake of male and female rats over a nine week period. 5. The results show that the JCR:LA-corpulent rat is very sensitive to the pharmacological effects of D-fenfluramine. These rats should provide an appropriate animal model for determining the mechanisms of action of this anti-obesity agent and whether apparently beneficial changes in metabolism translate into long-term protection against premature atherosclerosis.