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Desensitization of the ß-Adrenergic Response in Human Brown Adipocytes¹

CNRS-UPR 0415 and Université Paris VII, Institut Cochin de Génétique Moléculaire, F-75014 Paris, France

Address all correspondence and requests for reprints to: Dr. Ralf Jockers, Laboratoire d’Immuno-Pharmacologie Moléculaire, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, F-75014 Paris, France. E-mail: jockers{at}icgm.cochin.inserm.fr

Activation of adenylyl cyclase by ß-adrenergic receptors (ßARs) plays a major role in adipose tissue homeostasis. The increase in cAMP promotes lipolysis in white adipose tissue, activates both thermogenesis and lipolysis in brown adipose tissue (BAT), and induces BAT hypertrophy. Previous studies indicated that among the three ßAR subtypes present in adipose tissue, ß₃AR could be a potential target for antiobesity treatments in humans. We studied immortalized human brown adipocytes (PAZ6 adipocytes) as a model of ß-adrenergic response in human BAT. PAZ6 adipocytes and freshly isolated mature human brown adipocytes display the same proportions of ßAR subtypes, with ß₃AR being the most abundant (80% of the total). However, ß₃AR was poorly coupled to the adenylyl cyclase pathway in PAZ6 cells, contributing to only 10% of the isoproterenol-induced accumulation of cAMP, whereas 20% and 70% of the signal depended on ß₁- and ß₂-subtypes, respectively. Upon isoproterenol stimulation, ß₁- and ß₂AR down-regulated with a half-life of about 3 h and the ß₃AR with a half-life of 30–40 h. Long term stimulation with both saturating (micromolar) and nonsaturating (nanomolar) concentrations of ß-adrenergic agonists caused a complete desensitization of the ß-adrenergic response at the adenylyl cyclase level and loss of stimulated protein kinase A activity and CREB phosphorylation. These results suggest that cAMP-dependent processes will be desensitized upon permanent treatment with ß₃AR agonists. Further studies should establish whether the ß₃AR is coupled to other signaling pathways in human brown adipocytes and whether these may contribute to BAT hypertrophy and/or thermogenesis.

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