Jockers R, Issad T, Zilberfarb V, de Coppet P, Marullo S, Strosberg A D
CNRS-UPR 0415 and Université Paris VII, Institut Cochin de Génétique Moléculaire, France.
Endocrinology. 1998 Jun;139(6):2676-84. doi: 10.1210/endo.139.6.6050.
Activation of adenylyl cyclase by beta-adrenergic receptors (betaARs) 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 betaAR subtypes present in adipose tissue, beta3AR could be a potential target for antiobesity treatments in humans. We studied immortalized human brown adipocytes (PAZ6 adipocytes) as a model of beta-adrenergic response in human BAT. PAZ6 adipocytes and freshly isolated mature human brown adipocytes display the same proportions of betaAR subtypes, with beta3AR being the most abundant (approximately 80% of the total). However, beta3AR 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 beta1- and beta2-subtypes, respectively. Upon isoproterenol stimulation, beta1- and beta2AR down-regulated with a half-life of about 3 h and the beta3AR with a half-life of 30-40 h. Long term stimulation with both saturating (micromolar) and nonsaturating (nanomolar) concentrations of beta-adrenergic agonists caused a complete desensitization of the beta-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 beta3AR agonists. Further studies should establish whether the beta3AR is coupled to other signaling pathways in human brown adipocytes and whether these may contribute to BAT hypertrophy and/or thermogenesis.
β-肾上腺素能受体（βARs）激活腺苷酸环化酶在脂肪组织稳态中起主要作用。环磷酸腺苷（cAMP）的增加促进白色脂肪组织中的脂肪分解，激活棕色脂肪组织（BAT）中的产热和脂肪分解，并诱导BAT肥大。先前的研究表明，在脂肪组织中存在的三种βAR亚型中，β3AR可能是人类抗肥胖治疗的潜在靶点。我们研究了永生化的人棕色脂肪细胞（PAZ6脂肪细胞）作为人类BAT中β-肾上腺素能反应的模型。PAZ6脂肪细胞和新鲜分离的成熟人棕色脂肪细胞显示出相同比例的βAR亚型，其中β3AR最为丰富（约占总数的80%）。然而，β3AR在PAZ6细胞中与腺苷酸环化酶途径的偶联较差，仅占异丙肾上腺素诱导的cAMP积累的10%，而20%和70%的信号分别依赖于β1和β2亚型。在异丙肾上腺素刺激下，β1和β2AR以约3小时的半衰期下调，β3AR以30 - 40小时的半衰期下调。用饱和（微摩尔）和非饱和（纳摩尔）浓度的β-肾上腺素能激动剂进行长期刺激，导致在腺苷酸环化酶水平上β-肾上腺素能反应完全脱敏，刺激的蛋白激酶A活性和CREB磷酸化丧失。这些结果表明，用β3AR激动剂进行长期治疗会使cAMP依赖性过程脱敏。进一步的研究应确定β3AR是否与人棕色脂肪细胞中的其他信号通路偶联，以及这些通路是否可能导致BAT肥大和/或产热。
