DOWN-REGULATION OF BETA(3) ADRENOCEPTOR GENE-EXPRESSION IN BROWN FAT-CELLS IS TRANSIENT AND RECOVERY IS DEPENDENT UPON A SHORT-LIVED PROTEIN FACTOR

The regulation of the expression of the beta(3) adrenoreceptor gene wa s examined in the brown adipose tissue of intact mice and in murine br own fat primary cell cultures, Both in vivo and in vitro, high levels of beta(3) receptor mRNA were observed. Acute cold exposure of mice re sulted in a marked and rapid down-regulation of beta(3) gene expressio n; this down-regulation was, however, transient, Similarly, in brown f at cell cultures, norepinephrine addition led to down-regulation of be ta(3) gene expression, with a lag phase of 30 min and with an apparent half-life of beta(3) mRNA of similar to 30 min, This down-regulation was stimulated via the beta(3) receptors themselves and mediated via c AMP; the apparent affinity of norepinephrine was extremely high (<1 nM ), The degradation rate after actinomycin was identical to that after norepinephrine and was not affected by the presence of norepinephrine; thus, the down-regulation was due to cessation of transcription but n ot to an increased rate of degradation, Notably, inhibition of protein synthesis by cycloheximide also led to down-regulation. The norepinep hrine induced doum-regulation was transient; spontaneous recovery occu rred after similar to 18 h and was not due to depletion of adrenergic agent, Recovery did not occur in the presence of cycloheximide. After recovery, the cells showed a functional desensitization of the down-re gulation process itself (EC(50) now similar to 10 similar to 10 nM). I t is concluded that a down-regulated state cannot explain the function al desensitization of beta(3) adrenergic responsiveness observed in br own fat cells isolated from cold-acclimated animals (i.e. physiologica lly chronically adrenergically stimulated brown fat cells); since the beta(3) receptor is not subject to desensitization via phosphorylation processes, no satisfactory explanation for the functional desensitiza tion exists as yet, A model is presented for the down-regulation/recov ery process, involving the participation of a phosphorylatable short-l ived transcription factor.