Clinical pharmacology of beta(3)-adrenoceptors

1 An atypical non beta(1)/beta(2)-adrenoceptor (AR) subtype (beta(3)-AR) has been identified which is selectively stimulated by a group of ligands which mediate lipolytic and thermic responses in brown and white adipose tissue. 2 Molecular studies have shown that beta(3)-AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall-bladder and colon. In vitro studies with beta(3)-AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3 Regulation of beta(3)-AR may differ from beta(1)/beta(2)-AR subtypes in that continuous agonist exposure does not result in receptor down-regulation. 4 A polymorphism of the human beta(3)-AR gene (Trp64Arg) has been identified which is associated with obesity, insulin resistance and an earlier onset of non-insulin-dependent diabetes mellitus (NIDDM). Studies are required to establish whether expression of the mutant gene results in altered metabolic responses to beta(3)-AR stimulation in man. 5 There is accumulating evidence to support a therapeutic role of beta(3)-AR agonists in NIDDM because of anti-obesity and anti-diabetic activity, as a consequence of thermogenic effects as well as increased insulin sensitivity and glucose tolerance. 6 Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a beta(3)-AR mediated component to thermogenesis which is dissociated from beta(1)/beta(2)-mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional beta(3)-AR mediating cardiac but not airway responses in humans. An evaluation of beta(3)-AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.