Clinical pharmacology of β₃‐adrenoceptors

Abstract

1An atypical non β1/β2‐adrenoceptor (AR) subtype (β3‐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. 2Molecular studies have shown that β3‐AR in man are mainly expressed in visceral adipocytes, and to a lesser extent in gall‐bladder and colon. In vitro studies with β3‐AR agonists have shown activity at other sites including skeletal muscle and myocardium. 3Regulation of β3‐AR may differ from β1/β2‐AR subtypes in that continuous agonist exposure does not result in receptor down‐regulation. 4A polymorphism of the human β3‐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 β3‐AR stimulation in man. 5There is accumulating evidence to support a therapeutic role of β3‐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. 6Selectivity studies with BRL35135 and isoprenaline in humans have demonstrated a β3‐AR mediated component to thermogenesis which is dissociated from β1/β2‐mediated effects on carbohydrate and fat metabolism. Similar studies have suggested a functional β3‐AR mediating cardiac but not airway responses in humans. An evaluation of β3‐AR agonists in irritable bowel syndrome may be warranted in view of colonic antimotility properties in vitro.

Effects of Trecadrine®, a β3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes

“…Activation of b3-adrenoceptors stimulates lipolysis in adipose tissue. 24,38 An increase in the activity of hormone sensitive lipase, the enzyme that catalyzes the hydrolysis of triglyceride to glycerol and fatty acids, 39 has Figure 3 Effects of Trecadrine on basal (A) and insulin-stimulated (B) glucose utilization by isolated rat adipocytes over 96 h in culture. Data are mean AE s.e.…”

Impact of aging on myocardial metabolic response to dobutamine

“…The impairment in MGU and lack of impairment in MFAU and MFAO may be related to the differential ␤-adrenergic receptor response to aging. Both ␤ 1 -and ␤ 2 -receptor sensitivity decrease with age, but ␤ 3 -receptor sensitivity does not decline (24,27,36). The ␤ 1 -and ␤ 2 -receptors play a key role in myocardial glucose uptake, and a decline in sensitivity with age would result in a reduction in MGU (11,17).…”

“…In contrast, MFAU and MFAO are driven to a large extent by plasma fatty acid levels. Plasma fatty acid levels in turn are determined by the degree of lipolysis in peripheral adipocytes, a process that is modulated by ␤ 3 -receptors in adipose tissue (27). Thus the response of MFAU and MFAO to dobutamine infusion may be less affected by age.…”

Anti-Obesity Effects of Selective Agonists to the .BETA.3-Adrenergic Receptor in Dogs. II. Recruitment of Thermogenic Brown Adipocytes and Reduction of Adiposity after Chronic Treatment with a .BETA.3-Adrenergic Agonist.

“…In companion animals, however, it often seems difficult to achieve effective treatments, largely because owners often feel uncomfortable with them and do not follow the prescribed regimen. Recently, pharmacological treatment of obesity using specific β-adrenergic receptor (β-AR) agonists has attracted much attention in human obesity [14]. This is based on the findings that β3-AR, an isoform of mammalian β-ARs, is expressed in adipocytes but not in other types of cells [7,17,19].…”