DIFFERENTIAL REGULATION BY TUMOR-NECROSIS-FACTOR-ALPHA OF BETA(1)-ADRENORECEPTOR, BETA(2)-ADRENORECEPTOR, AND BETA(3)-ADRENORECEPTOR GENE-EXPRESSION IN 3T3-F442A ADIPOCYTES

Modulation of beta-adrenoreceptor expression by tumor necrosis factor- alpha (TNF-alpha) was investigated in murine 3T3-F442A adipocytes. TNF -alpha treatment of mature adipocytes decreased beta(3)-adrenoreceptor mRNA content in a time-and concentration-dependent manner, with a 8.5 -fold decrease observed after a 6-h exposure to 300 pM TNF-alpha. beta (1)-Adrenoreceptor mRNA abundance was slightly decreased by TNF-alpha treatment, while beta(2)-adrenoreceptor mRNA levels were potently indu ced (6-fold increase at 6 h), (-)-[I-125]Iodocyanopindolol saturation and competition binding experiments indicated that TNF-alpha induced a 2-fold decrease in beta(3)-adrenoreceptor number, a nonsignificant re duction in beta(1)-subtype population, and a similar to 4.5-fold incre ase in beta(2)-adrenoreceptor density, This correlated with a lower EC value measured for epinephrine in stimulating adenylyl cyclase, where as the EC50 value for norepinephrine increased. Nuclear run-on assays on isolated nuclei and mRNA stability measurements showed that TNF-alp ha increased both beta(2)-adrenoreceptor gene transcription and beta(2 )-adrenoreceptor mRNA half-life, while beta(1)- and beta(3)-adrenorece ptor gene expression was modulated only at the transcriptional level b y the cytokine. These findings demonstrate a differential modulation b y TNF-alpha of the three beta-adrenoreceptor subtypes in adipocytes, w hich may contribute to metabolic disorders induced by the cytokine in the adipocyte.