Abstract
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 beta3-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. beta1-Adrenoreceptor mRNA abundance was slightly decreased by TNF-alpha treatment, while beta2-adrenoreceptor mRNA levels were potently induced (6-fold increase at 6 h). (-)-[125I]Iodocyanopindolol saturation and competition binding experiments indicated that TNF-alpha induced a 2-fold decrease in beta3-adrenoreceptor number, a nonsignificant reduction in beta1-subtype population, and a approximately 4.5-fold increase in beta2-adrenoreceptor density. This correlated with a lower EC50 value measured for epinephrine in stimulating adenylyl cyclase, whereas the EC50 value for norepinephrine increased. Nuclear run-on assays on isolated nuclei and mRNA stability measurements showed that TNF-alpha increased both beta2-adrenoreceptor gene transcription and beta2-adrenoreceptor mRNA half-life, while beta1- and beta3-adrenoreceptor gene expression was modulated only at the transcriptional level by the cytokine. These findings demonstrate a differential modulation by TNF-alpha of the three beta-adrenoreceptor subtypes in adipocytes, which may contribute to metabolic disorders induced by the cytokine in the adipocyte.
Highlights
Tumor necrosis factor-␣ (TNF-␣)1 is a multifunctional cytokine that was originally identified as a tumoricidal protein [1]
Differential Modulation by TNF-␣ of 1, 2- and 3-AR mRNA Levels—Since the 3-AR is the main -AR subtype expressed in rodent adipocytes [18, 19, 35], we first evaluated the effect of TNF-␣ on 3-AR gene expression. 3T3-F442A mature adipocytes were exposed or not to various TNF-␣ concentrations for 6 h, and total RNA was extracted
Since the 3-AR can be considered as a marker of adipose conversion of murine 3T3 cells [18, 19], it is questionable whether the potent downregulation of this receptor subclass by TNF-␣ reflects a dedifferentiation of 3T3-F442A cells
Summary
Tumor necrosis factor-␣ (TNF-␣) is a multifunctional cytokine that was originally identified as a tumoricidal protein [1]. It is documented that TNF-␣ decreases the synthesis and activity of several proteins essential for lipogenesis and triglyceride accumulation in adipocytes. These include lipoprotein lipase [5, 7,8,9], acetyl-coenzyme A carboxylase [4, 10, 11], acyl-coenzyme A synthetase [12], stearoyl-coenzyme A desaturase [12], and the insulin-sensitive glucose transporter GLUT4 [13, 14]. Through activation of three -AR subtypes, catecholamines exert a key role in the regulation of lipid metabolism in adipocytes. They modulate cAMP-dependent processes such as lipolysis and the genetic control of the lipogenic and thermogenic pathways. Using the model of the 3T3-F442A cell line that presents a coordinate expression of the three -AR subtypes in the mature adipose phenotype [18, 19], we demonstrate that TNF-␣ differentially regulates 1-, 2-, and 3-AR gene expression and responsiveness
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