The high incidence of obesity, its multifactorial nature, the complexity and lack of knowledge of the bodyweight control system, and the scarcity of adequate therapeutics have fuelled anti-obesity drug development during a considerable number of years. Irrespective of the efforts invested by researchers and companies, few products have reached a minimum level of effectiveness, and even fewer are available in medical practice. As a consequence of anti-obesity research, our knowledge of the bodyweight control system increased but, despite this, the pharmacological approaches to the treatment of obesity have not resulted yet in effective drugs. This review provides a panoramic of the multiple different approaches developed to obtain workable drugs. These approaches, however, rely in only four main lines of action: control of energy intake, mainly through modification of appetite;control of energy expenditure, essentially through the increase of thermogenesis;control of the availability of substrates to cells and tissues through hormonal and other metabolic factors controlling the fate of the available energy substrates; andcontrol of fat reserves through modulation of lipogenesis and lipolysis in white adipose tissue. A large proportion of current research is centred on neuropeptidic control of appetite, followed by the development of drugs controlling thermogenic mechanisms and analysis of the factors controlling adipocyte growth and fat storage. The adipocyte is also a fundamental source of metabolic signals, signals that can be intercepted, modulated and used to force the brain to adjust the mass of fat with the physiological means available. The large variety of different approaches used in the search for effective anti-obesity drugs show both the deep involvement of researchers on this field and the large amount of resources devoted to this problem by pharmaceutical companies. Future trends in anti-obesity drug research follow closely the approaches outlined; however, the increasing mass of information on the molecular basis of bodyweight control and obesity will in the end prevail in our search for effective and harmless anti-obesity drugs.
