Relationship between lipolysis and cyclic AMP generation mediated by atypical β‐adrenoceptors in rat adipocytes

Abstract

1 The nature of the fi-adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (-)-isoprenaline and the lipolytically selective fi-adrenoceptor agonist, BRL 37344, was investigated by use of the fli-selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes.2 While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (-)-isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62. 3 With CGP 20712A small rightward shifts of the (-)-isoprenaline concentration-response curve (CRC) were observed at concentrations up to 10pM, while at 100pM and 1 mm clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10pM. Only at 100pM and 1mM CGP 20712A were rightward shifts observed.4 CGP 20712A concentrations of 1OpM and 100pM depressed the maximum of the (-)-isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (-)-isoprenaline). Only at 1 mm CGP 20712A, was the CRC of BRL 37344 depressed, while the (-)-isoprenaline maximum was diminished further. 5It was concluded that as with lipolysis, (-)-isoprenaline acts both through typical f1-and atypical 63-adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical f3-adrenoceptors.6 The results also demonstrate that the relationship between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (-)-isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (-)-isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.

Characteristics of the α2/β‐adrenoceptor‐coupled adenylate cyclase system and their relationship with adrenergic responsiveness in hamster fat cells from different anatomical sites

“…However, the Kd values in Table 3 are very similar to those recently reported in 3T3F442A cells by Feve et al [32] who demonstrated, on the basis of both pharmacological and mRNA studies, the large predominance of the newly discovered b3-adrenoceptor subtype [33] in these cells. Our results thus provide further support to recent suggestions that rodent adipocytes possess the b3-adrenoceptor subtype [34,351. However, comparison of the lipolytic potency of the selective f13-adrenergic agonist BRL37344 failed to reveal any significant difference between epididymal and femoral subcutaneous deposits.…”

“…The half-maximal stimulation (EC,,) for (-)-epinephrine was reached at about 0.2 0.06 pM in the two anatomical sites. The same was true when the ECso values for (-)-isoproterenol and BRL37344, a selective agonist for the fat cell atypical P-adrenoceptor [20], were compared. However, BRL37344 was more potent with epididymal and femoral subcutaneous adipocytes (EC50, 0.49 & 0.17 nM and 0.83 f 0.15 nM, respectively) than (-)-isoproterenol (EC,,, 1.68 f 0.38 nM and 3.11 & 0.64 nM, respectively).…”

Classical and atypical binding sites for β‐adrenoceptor ligands and activation of adenylyl cyclase in bovine skeletal muscle and adipose tissue membranes

“…The most extensive studies of P3-adrenoceptor-mediated cyclic AMP responses are those which have been conducted on rat adipose tissue (Granneman, 1990;Hollenga et al, 1991a,b). This tissue can be stimulated by BRL 37344 and in the presence of (-)-isoprenaline, gives a bi-phasic response which is resistant to blockade by either CGP 20712A or ICI 118551, yielding pA2 values of 4.53 (Hollenga et al, 1991b) and 5.49 (Hollenga & Zaagsma, 1989) respectively. None of these features were observed in the present study, suggesting that P3-adrenoceptors are not expressed at a functional level in either bovine skeletal muscle or adipose tissue membranes.…”

α1-Adrenergic Stimulation Potentiates the Thermogenic Action of β3-Adrenoreceptor-generated cAMP in Brown Fat Cells

“…Ref. 37), often under conditions where, for example, forskolin-derived cAMP and cAMP derived from hormonal stimulation apparently do not induce the final cellular response with the same potency, i.e. a situation akin to the one described here for brown fat cells.…”