Application of agents active at the alpha 2-adrenoceptor of fat cells to the treatment of obesity--a critical appraisal

Abstract

The extent of cyclic AMP (cAMP) mediated lipolysis in adipose tissue cells of man and several other animal species is regulated by the interplay of alpha- and beta-adrenoceptors modulating adenyl cyclase activity. Although the naturally-occurring catecholamines, and isoprenaline, are thought to act at the same pro-lipolytic beta-adrenoceptor antilipolytic agents, working through the alpha 2-adrenoceptor moiety of adenyl cyclase, appear to act at separate sites for: true alpha 2-agonists such as clonidine, for adenosine and for prostaglandins. Further, such antilipolytic agents are conspicuously more potent against lipolysis stimulated by methyl-isobutylxanthine (MIX) than against that stimulated by catecholamines. The nature of the dual character of adenyl cyclase remains to be elucidated. alpha 2 Adrenoceptor antagonists which promote lipolysis, and may possibly serve a therapeutic role in the treatment of obesity, may also provoke inappropriate insulin release which is contraindicated. Thus a problem in chemotherapy exists which may be resolved by new agents with differential tissue specificities. An example of this chemotherapeutic dilemma is possibly provided by the body weight accruing actions of tricyclic antidepressant compounds whose mechanism of action involves also (central) alpha 2-adrenoceptors.