PHYSIOLOGICAL DESENSITIZATION OF BETA(3)-ADRENERGIC RESPONSES IN BROWN FAT-CELLS - INVOLVEMENT OF A POSTRECEPTOR PROCESS

To investigate a possible physiological desensitization process for be ta3-adrenergic responses, the effect of cold acclimation of hamsters o n adrenergically stimulated oxygen consumption of isolated brown fat c ells was investigated. Cells were prepared from control and from cold- acclimated hamsters. In agreement with earlier findings, cells isolate d from cold-acclimated hamsters responded to norepinephrine addition w ith a decreased sensitivity (approximately 10 times higher 50% effecti ve concentration) and a decreased maximal rate of oxygen consumption c ompared with cells from control hamsters. When cells were stimulated w ith the general beta-adrenergic agonist isoprenaline or with the beta3 -selective agonists BRL-37344 or CGP-12177, a similarly desensitized r esponse was observed, demonstrating that it was indeed a beta3-adrener gic response that was functionally desensitized. However, when the mit ochondria within the cells were directly stimulated with exogenous fre e fatty acids (palmitate or octanoate), no difference between cells fr om control and cold-acclimated animals was seen, indicating that a med iatory step must be desensitized. When the cells were stimulated with forskolin (to activate adenylyl cyclase) or with 8-bromoadenosine 3',5 '-cyclic monophosphate, the desensitized response was still observed. At post-adenosine 3',5'-cyclic monophosphate levels, a desensitization was not evident. Cyclic nucleotide phosphodiesterase activity was inc reased in cells from cold-acclimated animals. It is therefore suggeste d that this increased activity of phosphodiesterase could be (at least partly) responsible for the physiologically induced desensitized resp onses observed here. Thus, despite the fact that the beta3-receptor it self lacks most of the amino acid residues involved in the phosphoryla tion normally associated with beta-receptor desensitization mechanisms , a physiological desensitization process may be observed in beta3-sti mulated cells, with at least one component of the desensitization mech anism located to a site beyond the receptor itself.