DESENSITIZATION OF BETA-1 AND BETA-2, BUT NOT BETA-3, ADRENOCEPTOR-MEDIATED LIPOLYTIC RESPONSES OF ADIPOCYTES AFTER LONG-TERM NOREPINEPHRINE INFUSION

The beta-3 adrenoceptor protein lacks most of the potential phosphoryl ation sites for beta adrenoceptor kinase and protein kinase A. In addi tion, it exhibits a lower affinity toward norepinephrine than beta-1 o r 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 r elevance 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 spe cies. In control guinea pigs, isoproterenol, norepinephrine and epinep hrine were fully lipolytic, whereas BRL 37344 )-4-2[2-(12[(3-chlorophe nyl)-2-hydroxyethyl]amino} propyl)phenyl]phenoxyacetic acid}, CGP aryb utylamino-2-hydroxypropoxy)-benzimidazole-2-on hydrochloride} and othe r beta-3 agonists were inefficient, whereas hamster adipocytes exhibit ed maximal response to the beta-3 agonists. Blockade of the lipolytic effect of isoproterenol in the guinea pig gave a rank order of beta an tagonists [CGP 20712A i-fluro-methyl-1H-imidazol-2-yl)phenoxy-2-propan ol methanesulfonate} > bupranolol greater-than-or-equal-to propranolol much greater than ICl 118551 -methylindan-4-yloxy)-3-isopropylaminobu tan-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 t ested; a result arguing for the predominence of a beta-3 component in the adrenergic activation of lipolysis, as in rat fat cells. In treate d guinea pigs (6-day treatment with osmotic minipumps delivering norep inephrine at the rate of 5 mug/min/kg), the adrenocorticotropic hormon e dose-response curve was identical to that of controls, but the curve s for isoproterenol, norepinephrine and epinephrine were flattened and shifted to the right. A down-regulation of beta-1 and beta-2 adrenoce ptors was evidenced by a reduction in [H-3]CGP 12177 high-affinity bin ding sites. In treated hamsters, compared to the controls, there was n o change in the lipolytic response to the beta adrenergic agonists. Ot her protocols of chronic exposure to norepinephrine (e.g., daily injec tions) at different doses were also unable to reduce the beta-lipolyti c effect in the hamster fat cells. The results indicate that the beta- 3 adrenoceptor-mediated lipolysis, which is the major component of adr energic lipolysis in hamster adipocytes, was not modified after long-t erm exposure to norepinephrine. So, desensitization of the overall bet a adrenergic responsiveness was not detectable, although down-regulati on of the beta-1 and beta-2 adrenoceptors was observed.