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 predisposition to obesity have impaired appetite control when diets are fat-rich and energy dense. They also exhibit a lower than expected resting metabolic rate (RMR). A low RMR, in concert with a sedentary lifestyle, contributes to a low total energy output, which may lead to obesity if continued over a period of years. A low metabolic rate seems to be genetically determined, and is partly caused by low sympathetic nervous system activity. Classical treatment programmes for obesity do not provide a satisfactory long-term outcome for the majority of patients. Patients who achieve only a small weight loss during dietary therapy, and have a tendency to weight regain, are characterised by lower energy expenditure, 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 supporting the dietary approach with pharmacological manipulation of central and peripheral pathways. Agents which stimulate adrenergic neurons are particularly suitable because they offer mechanisms for inhibiting hunger and for stimulating energy expenditure, lipolysis and fat oxidation. Sympathomimetic compounds can reduce appetite and increase energy expenditure. Energy expenditure can be increased by 5-10% via stimulation of a combination of beta-adrenoceptors; beta3-adrenoceptors may predominate during chronic therapy. This increased energy expenditure increases the relative proportion of fat oxidation; as this is not fully compensated by increased energy intake, a negative energy balance occurs. This mechanism may be responsible for the long-term weight loss efficiency of agents like ephedrine/caffeine and sibutramine. Pharmacotherapy 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 weight loss, compared with patients treated with conventional programmes alone. Pharmacotherapy which stabilises the size of fat stores at a lower level contributes indirectly to a pronounced improvement of risk factors, leading to a decreased potential for cardiovascular disease, type 2 diabetes and associated morbidity.