WHAT DO PHARMACOLOGICAL APPROACHES TO OBESITY MANAGEMENT OFFER - LINKING PHARMACOLOGICAL MECHANISMS OF OBESITY MANAGEMENT AGENTS TO CLINICAL-PRACTICE

Obesity is characterised by pathophysiological defects affecting both sides of the energy balance equation. Individuals with a predispositio n to obesity have impaired appetite control when diets are fat-rich an d energy dense. They also exhibit a lower than expected resting metabo lic rate (RMR). A low RMR, in concert with a sedentary lifestyle, cont ributes to a low total energy output, which may lead to obesity if con tinued over a period of years. A low metabolic rate seems to be geneti cally determined, and is partly caused by low sympathetic nervous syst em activity. Classical treatment programmes for obesity do not provide a satisfactory long-term outcome for the majority of patients. Patien ts who achieve only a small weight loss during dietary therapy, and ha ve a tendency to weight regain, are characterised by lower energy expe nditure, lower sympathetic activity, and a reduced ability to mobilise fat stores, compared with patients who are more successful at losing weight. It is reasonable to improve or normalise these traits by suppo rting the dietary approach with pharmacological manipulation of centra l and peripheral pathways. Agents which stimulate adrenergic neurons a re particularly suitable because they offer mechanisms for inhibiting hunger and for stimulating energy expenditure, lipolysis and fat oxida tion. Sympathomimetic compounds can reduce appetite and increase energ y expenditure. Energy expenditure can be increased by 5-10% via stimul ation of a combination of beta-adrenoceptors; beta(3)-adrenoceptors ma y predominate during chronic therapy. This increased energy expenditur e increases the relative proportion of fat oxidation; as this is not f ully compensated by increased energy intake, a negative energy balance occurs. This mechanism may be responsible for the long-term weight lo ss efficiency of agents like ephedrine/caffeine and sibutramine. Pharm acotherapy can be used to support short-term induction of weight loss or long-term weight maintenance. In the latter case, adrenergic agents enable a greater proportion of patients to maintain a satisfactory we ight loss, compared with patients treated with conventional programmes alone. Pharmacotherapy which stabilises the size of fat stores at a l ower level contributes indirectly to a pronounced improvement of risk factors, leading to a decreased potential for cardiovascular disease, type 2 diabetes and associated morbidity.