Desensitization of beta-1 and beta-2, but not beta-3, adrenoceptor-mediated lipolytic responses of adipocytes after long-term norepinephrine infusion

Abstract

The beta-3 adrenoceptor protein lacks most of the potential phosphorylation sites for beta adrenoceptor kinase and protein kinase A. In addition, it exhibits a lower affinity toward norepinephrine than beta-1 or beta-2 adrenoceptors. It is thus expected that beta-3 adrenoceptors could be less implicated in desensitization processes than the beta-1 or beta-2 adrenoceptors. An attempt to demonstrate the physiological relevance of this prediction was performed by using fat cells having a beta-3 adrenergic responsiveness or not (hamster and guinea pig). The influence of prolonged in vivo exposure to norepinephrine on the beta adrenoceptor-mediated lipolytic responses was investigated in both species. In control guinea pigs, isoproterenol, norepinephrine and epinephrine were fully lipolytic, whereas BRL 37344 [(R',R')-4-2[2-((2[(3-chlorophenyl)-2-hydroxyethyl]amino] propyl)phenyl]phenoxyacetic acid], CGP 12177](+-)-4-(3-tertiarybutylamino-2-hydroxypropoxy)- benzimidazole-2-on hydrochloride] and other beta-3 agonists were inefficient, whereas hamster adipocytes exhibited maximal response to the beta-3 agonists. Blockade of the lipolytic effect of isoproterenol in the guinea pig gave a rank order of beta antagonists [CGP 20712A (1-[2-(3-carbamoyl-4-hydroxyphenoxy)ethylamino]-3-4-(1-methyl-4-tr i-fluoro-methyl-1H-imidazol-2-yl)phenoxy-2-propanol methanesulfonate] > bupranolol > or = propranolol >> ICI 118551 [erythrodl-1-(7- methylindan-4-yloxy)-3-isopropylaminobutan-2-ol)] in agreement with that of a beta-1 effect. In contrast, the selective beta-1 antagonist CGP 20712A did not counteract the effect of BRL 37344 in hamsters and bupranolol was the best beta antagonist tested; a result arguing for the predominance of a beta-3 component in the adrenergic activation of lipolysis, as in rat fat cells. In treated guinea pigs (6-day treatment with osmotic minipumps delivering norepinephrine at the rate of 5 micrograms/min/kg), the adrenocorticotropic hormone dose-response curve was identical to that of controls, but the curves for isoproterenol, norepinephrine and epinephrine were flattened and shifted to the right. A down-regulation of beta-1 and beta-2 adrenoceptors was evidenced by a reduction in [3H]CGP 12177 high-affinity binding sites. In treated hamsters, compared to the controls, there was no change in the lipolytic response to the beta adrenergic agonists. Other protocols of chronic exposure to norepinephrine (e.g., daily injections) at different doses were also unable to reduce the beta-lipolytic effect in the hamster fat cells.(ABSTRACT TRUNCATED AT 400 WORDS)