Reversal of obesity in the genetically obese fa/fa Zucker rat with an ephedrine/methylxanthines thermogenic mixture.

Administration of a thermogenic mixture of ephedrine, caffeine and theophylline to grossly obese (11-12 mo old) fa/fa Zucker rats led to a rapid decline in their body weight, which reached lean levels within 9-10 wk, and this postobese weight was maintained for another 5-6 wk. Compared to the no-drug obese controls (O-ND), food intake was reduced by 70% during the dynamic phase of weight loss and by 50% during the postobese period in the food-restricted animals (O-FR) and by about 40% during both phases in the ephedrine/methylxanthines (O-E/Mx) animals. Energy expenditure in the O-FR group was lower than in the O-E/Mx group by 25-33%. Analysis of body composition showed that body fat in both O-FR and O-E/Mx groups was much lower than in the O-ND group, by 2.5- and 4-fold, respectively, and body protein was lower by 50 and 28%, respectively. Thus, compared to the O-ND group, the fat:protein ratio was only 25% lower in the O-FR animals but was three times less in the O-E/Mx group. These findings demonstrate that in the fa/fa rat a mixture of ephedrine and methylxanthines reduces food intake but also minimizes the fall in metabolic rate that usually accompanies such an energy deficit, effects that led to a reversal of their gross obesity. The ability of ephedrine alone or in combination with methylxanthines to reverse obesity in animal models with dietary and hypothalamic etiologies is thus extended to the obesity resulting from the inheritance of a single-gene recessive defect.