Physiological desensitization of beta 3-adrenergic responses in brown fat cells: involvement of a postreceptor process.

To investigate a possible physiological desensitization process for beta 3-adrenergic responses, the effect of cold acclimation of hamsters on adrenergically stimulated oxygen consumption of isolated brown fat cells was investigated. Cells were prepared from control and from cold-acclimated hamsters. In agreement with earlier findings, cells isolated from cold-acclimated hamsters responded to norepinephrine addition with a decreased sensitivity (approximately 10 times higher 50% effective concentration) and a decreased maximal rate of oxygen consumption compared with cells from control hamsters. When cells were stimulated with the general beta-adrenergic agonist isoprenaline or with the beta 3-selective agonists BRL-37344 or CGP-12177, a similarly desensitized response was observed, demonstrating that it was indeed a beta 3-adrenergic response that was functionally desensitized. However, when the mitochondria within the cells were directly stimulated with exogenous free fatty acids (palmitate or octanoate), no difference between cells from control and cold-acclimated animals was seen, indicating that a mediatory 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 increased in cells from cold-acclimated animals. It is therefore suggested that this increased activity of phosphodiesterase could be (at least partly) responsible for the physiologically induced desensitized responses observed here.(ABSTRACT TRUNCATED AT 250 WORDS)