Metabolic mechanism of the anorectic and leptogenic effects of the serotonin agonist fenfluramine.

The purpose of these experiments was to investigate the action of a 5HT-agonist, D-fenfluramine (D-FF) upon energy expenditure in addition to its known anorectic action. Experiment 1 showed that body weight (BW) loss was more than predicted by the anorectic action of D-FF. In pair pattern feeding, D-FF induced a similar BW loss in treated and untreated partners despite the sedation of the former and agitation of the latter. Metabolic measurements (oxygen, carbon dioxide, respiratory quotient and locomotor activity (LA] revealed that D-FF enhances mobilization and intense utilization of endogenous fat reserves during anorexia. Energy expenditure (EE) increased via exaggerated cost of muscular effort which induced high glycolytic-lipogenetic reactions indicative of futile biochemical cycles leading to waste of energy. These locomotion and lipolysis-lipogenesis associated reactions varied as a function of basal body weight, food composition, intensity of LA, ambient temperature and dose of treatment. These data demonstrate that serotonin agonists like D-FF are more than anorectics since they enhance EE and therefore should be referred to as "leptogenic" (leptos = lean) agents since their end effect is the reduction of BW. They also suggest how leptogenic pharmacotherapy could be optimized by acting upon modulatory factors which have been studied in this work, and for example by encouraging LA in treated subjects.