Regulation of beta3‐adrenoceptor expression in white fat cells*

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Abstract
Summary— Catecholamines (adrenaline and noradrenaline) stimulate adipocyte lipolysis via three beta-adrenoceptor subtypes β1, β2 and β3. β3-adrenoceptor-mediated lipolysis varies according to the species. Rodent adipocytes exhibit the strongest response to β3 agonists while human fat cells are poorly responsive. The species-related differences can partly be explained by lower β3-adrenoceptor mRNA levels in human adipocytes compared to rat adipocytes. Poor coupling efficiency of human adipocyte β3-adrenoceptors cannot, however, be ruled out. The regulation of β3-adrenoceptor gene expression has been studied in the adipocytes of the murine cell line 3T3-F442A which express high levels of β3-adrenoceptors. Insulin and glucocorticoids down-regulate β3-adrenoceptor expression through a trancriptional effect. The impairment of β3-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 β3-adrenergic responsiveness varies according to the anatomical location of the fat pad. There is a marked decrease in β3-adrenergic response in rabbit retroperitoneal fat cells during ageing. cAMP modulates the β3-adrenergic response in white adipocytes at different levels. Human β3-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 β-adrenoceptors that the β3-adrenoceptor is less prone to desensitization than the β1 and β2-subtypes. This observation is in agreement with the absence of desensitization of the β3-adrenoceptor response in isolated rat fat cells. Continuous infusion of noradrenaline for six days into hamsters does not lead to an alteration of the β-adrenergic response. A similar treatment undertaken in the guinea pig, a species, unlike the hamster, devoid of β3-adrenoceptor responsiveness, promoted strong desensitization of the β-adrenergic response through down-regulation of β1- and β2-adrenoceptors. From these observations, it could be hypothesized that the β3-adrenoceptor, that shows a low affinity for catecholamines, is the “emergency” β-adrenoceptor which is essential under conditions of strong and sustained sympathetic nervous system activation.