It is estimated that somewhere between 34 and 61 million people in the US are obese and in much of the developing world incidence is increasing by about 1% per year. Obesity increases the likelihood of death from all causes by 20%, and more specifically death from coronary artery disease and stroke are increased by 25% and 10% respectively. In addition to these diseases, obese patients suffer an increased incidence of arthritis. We have recently published a full DiscoveryDossier giving an in depth analysis of what many consider to be one of the most promising target for obesity, ghrelin (Click here for dossier access). Another target that has also attracted considerable attention is the beta 3-adrenoreceptor, which is one of three beta-adrenergic receptor subtypes. While beta 1 and beta 2 adrenergic receptors are broadly expressed throughout the body, beta 3-adrenergic receptors are found predominantly in adipocytes. Stimulation of the beta adrenergic receptors leads to lipolysis in white adipocytes and non-shivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the beta adrenergic receptor system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, beta 3-adrenergic receptor agonists are able to prevent or reverse obesity in animal models. Despite these promising qualities, several pharmaceutical problems and theoretical concerns have slowed the development of these products as therapeutic agents in humans during the last 15 years. Up until now, the pharmaceutical industry has not been successful in developing a beta 3-adrenoceptor agonist for use in the treatment of human obesity or type 2 diabetes. Pharmaceutical problems in this area concern important differences between rodent and human beta 3-adrenoceptors and the difficulty in finding a compound with sufficient bioavailability that is a highly selective and full agonist at the human receptor. Some of these problems seem to have been solved with the cloning of the human beta 3-adrenoceptor, which has made it possible to develop novel compounds that act directly and specifically against the human receptor. However, several theoretical concerns still remain. These include the major question as to whether the number of biologically active beta 3-adrenoceptors in adult humans is sufficient to produce relevant metabolic effects and, if so, whether their long-term stimulation is safe and free of unwarranted side effects. These concerns have been addressed in part in recent studies wherein CL-316,243, a highly selective, albeit rodent specific beta 3-adrenoceptor agonist was observed to increase lipolysis, fat oxidation and insulin action in humans. Recently, a second beta3-adrenoceptor agonist, L-796568, directed at the human receptor has been shown to increase lipolysis and energy expenditure by about 8% in overweight men. This is the first study to show such an effect of beta 3-adrenergic receptor agonists in obese humans without significant evidence for beta 2-adrenergic receptor involvement. Whether this effect is sustainable when administered chronically remains to be fully investigated.

Link to journal abstract:

Adapted from Van Baak et al, Clin Pharmacol Ther 2002 Apr;71(4):272-9.

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