Role of β-Adrenergic Receptor Subtypes in Lipolysis

Abstract

In vitro lipolysis stimulated by low (-)-isopre-naline concentrations (≤30 nM) in epididymal white adipo-cytes from Sprague-Dawley rats was inhibited at least 60–80% by the specific β₁-antagonists LK 204-545 and CGP 20712A (1 μM), suggesting that at these low (10 nM) concentrations of (-)-isoprenaline lipolysis was primarily (80%) but not solely mediated via β₁-adrenergic receptors. Low concentrations (100 nM) of (-)-noradrenaline and formoterol also confirmed a role for β₁-adrenergic receptors in mediating lipolysis at low concentrations of these agonists. At higher agonist concentrations, β₃-adrenergic receptors were fully activated and were the dominant β-adrenergic receptor subtype mediating the maximum lipolytic response, and the maximum response was not affected by the β₁-antagonists, demonstrating that the β₃-receptor is capable of inducing maximum lipolysis on its own. Studies of lipolysis induced by the relatively β₂-selective agonist formoterol in the presence of β₁-blockade (1 μM CGP 20712A) demonstrated the inability of the β₂-selective antagonist ICI 118-551 to inhibit the residual lipolysis at concentrations of ICI 118-551 ≤ 1 μM. Higher concentrations of ICI 118-551 inhibited the residual formoterol-induced lipolysis competetively, but with low affinity (∼500-fold lower than its β₂-adrenergic receptor pA ₂, 7.80 ± 0.21), suggesting that formoterol was not acting via β₂-adrenergic receptors. These data are consistent with β₁-adrenergic receptors playing an important role in lipolysis at physiological but not pharmacological concentrations of catecholamines and that β₂-adrenergic receptors play no obvious direct role in mediating β-adrenergic receptor agonist-induced lipolysis in vitro. Finally, racemic-SR 59230A, unlike the pure (S, S)-isomer (a β₃-selective antagonist), was found to be a non-selective antagonist at the three β-adrenergic receptor subtypes, showing that the other enantiomers have different selectivity.