Regulation of beta 3-adrenoceptor expression in white fat cells.

Abstract

Catecholamines (adrenaline and noradrenaline) stimulate adipocyte lipolysis via three beta-adrenoceptor subtypes beta 1, beta 2 and beta 3. beta 3-adrenoceptor-mediated lipolysis varies according to the species. Rodent adipocytes exhibit the strongest response to beta 3 agonists while human fat cells are poorly responsive. The species-related differences can partly be explained by lower beta 3-adrenoceptor mRNA levels in human adipocytes compared to rat adipocytes. Poor coupling efficiency of human adipocyte beta 3-adrenoceptors cannot, however, be ruled out. The regulation of beta 3-adrenoceptor gene expression has been studied in the adipocytes of the murine cell line 3T3-F442A which express high levels of beta 3-adrenoceptors. Insulin and glucocorticoids down-regulate beta 3-adrenoceptor expression through a transcriptional effect. The impairment of beta 3-adrenoceptor gene expression in adipocytes of congenitally obese ob/ob mice could be related to the higher glucocorticoid plasma levels when compared to lean littermates although the direct involvement of glucocorticoids remains to be demonstrated. In the rat and the rabbit, the beta 3-adrenergic responsiveness varies according to the anatomical location of the fat pad. There is a marked decrease in beta 3-adrenergic response in rabbit retroperitoneal fat cells during ageing. cAMP modulates the beta 3-adrenergic response in white adipocytes at different levels. Human beta 3-adrenoceptor expression seems to be up-regulated by cAMP through an interaction with the promoter of the gene. It has been shown in cells transfected with cDNAs for the different beta-adrenoceptors that the beta 3-adrenoceptor is less prone to desensitization than the beta 1 and beta 2-subtypes. This observation is in agreement with the absence of desensitization of the beta 3-adrenoceptor response in isolated rat fat cells. Continuous infusion of noradrenaline for six days into hamsters does not lead to an alteration of the beta-adrenergic response. A similar treatment undertaken in the guinea pig, a species, unlike the hamster, devoid of beta 3-adrenoceptor responsiveness, promoted strong desensitization of the beta-adrenergic response through down-regulation of beta 1- and beta 2-adrenoceptors. From these observations, it could be hypothesized that the beta 3-adrenoceptor, that shows a low affinity for catecholamines, is the "emergency" beta-adrenoceptor which is essential under conditions of strong and sustained sympathetic nervous system activation.