Drop in the "atypical" beta-adrenergic response and modification of the beta/alpha 2-adrenoceptor balance in fat cells from aging rabbits.
Previous studies have shown a strong reduction of catecholamine-induced lipolysis in perirenal white fat cells in aging rabbits. The molecular basis of this observation was explored on scapular and perirenal adipocytes from 45 and 300- to 500-day-old rabbits. ACTH and forskolin were used to define the maximal lipolytic potencies of the adipocytes. beta-Adrenergic responsiveness was explored with isoproterenol and specific agonists of the "atypical" beta-adrenoceptor (beta-AR) (BRL37344 and (+/-)CGP12177); beta 1/beta 2-ARs were identified with [125I]cyanopindolol. alpha 2-adrenergic responses were evaluated with the full alpha 2-agonist, UK14304. The alpha 2 AR number was determined with the alpha 2-antagonist radioligand [3H]RX821002. Whatever the fat deposit, the relative order of lipolytic potency of the beta-agonists was: isoproterenol greater than BRL37344 greater than (+/-)CGP12177. As previously reported for catecholamines, the maximal lipolytic response initiated by isoproternol decreased with aging; the stronger reduction was observed in perirenal adipocytes compared to subscapular adipocytes. The most striking observation concerns the parallel and complete disappearance of the lipolytic responses induced by the atypical beta-agonists (BRL37344 and (+/-)CGP12177) and the preservation of a residual action of isoproterenol (30% of that described in young animals) which was attributed to the stimulation of beta 1/beta 2-ARs. The number of beta 1/beta 2-AR binding sites was practically equivalent whatever the fat deposite and the age of the animals. alpha 2-Adrenergic responsiveness and alpha 2-adrenergic receptor number were increased with aging in the various deposits but the stronger changes were observed in the perirenal adipocytes where epineprine initiated a biphasic effect on lipolysis (antilipolytic and then lipolytic). To conclude, the reduction of catecholamine-induced lipolysis observed in the rabbit fat cells with aging can be explained by changes in the atypical beta-AR/alpha 2-AR balance. First, a loss of responsiveness to the atypical beta-adrenergic agents was observed (it is impossible for the moment to distinguish between the loss of atypical beta-AR binding sites and their putative uncoupling from the adenylate cyclase system) whereas beta 1/beta 2-AR-mediated responses were maintained. Second, an increment of alpha 2-adrenergic responsiveness and of the alpha 2-AR binding sites accompanied aging and fattening. In the absence of, or after a strong reduction of the atypical beta-AR component of the lipolytic response in fat cells of aged rabbits, epinephrine exerts a biphasic effect on lipolysis, demonstrating the changes occurring in the atypical beta-AR/alpha 2-AR balance.(ABSTRACT TRUNCATED AT 400 WORDS)
Langin
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D
Institut National de la Santé et de la Recherche Médicale (I.N.S.E.R.M.-U. 317), Institut Louis Bugnard, Faculté de Médecine, CHU Rangueil, Toulouse, France.
Portillo
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M
Dauzats
M
M
Lafontan
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M
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D000068438:Brimonidine Tartrate; D004837:Epinephrine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000032:analysis*; D011943:Receptors, Adrenergic, beta / Q000032:analysis*
D004983:Ethanolamines; D011412:Propanolamines; D011810:Quinoxalines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D000068438:Brimonidine Tartrate; C057368:BRL 37344; D000324:Adrenocorticotropic Hormone; D007545:Isoproterenol; C033394:CGP 12177; D004837:Epinephrine