Metabolic abnormalities linked to obesity: Effects of dexfenfluramine in the corpulent rat

Abstract

The JCR:LA-corpulent rat is a useful experimental model for the obese-diabetic-dyslipidemic syndrome that mimics the human condition and exhibits spontaneous development of atherosclerosis and myocardial lesions. A 30-day treatment of 6-month-old rats with dexfenfluramine 1, 2.5, and 5 mg per kilogram decreased body weight through loss of adipose tissue mass. The effect is caused primarily by the ability of dexfenfluramine to reduce food intake. The maximum depression of food intake and greatest weight loss is seen during the first 10 days of treatment in this experimental model; thereafter, body weight stabilizes. However, during this period, there is a marked decrease in serum concentrations of triglycerides, cholesterol, and insulin. Corpulent male rats were also treated from 6 to 37 weeks of age with dexfenfluramine 2.5 mg/kg. This also produces a sustained decrease in body weight and a decrease in circulating insulin concentrations. Preliminary evidence demonstrates a substantial decrease in the incidence of necrotic myocardial lesions produced by ischemic events. This study establishes that dexfenfluramine treatment can decrease the severity of associated risk factors for cardiovascular disease, namely obesity, diabetes, and dyslipidemias. Furthermore, we report the first evidence that long-term treatment with dexfenfluramine can largely prevent the occurrence of myocardial lesions and end-stage cardiovascular disease in this animal model prone to atherosclerosis.