Hormone-induced homologous and heterologous desensitization in the rat adipocyte

We examined the process of desensitization in the isolated rat adipocyte. When adipocytes were exposed to isoproterenol (10(-7) or 10(-5) M) or ACTH (250 mU/ml) for 2 h, there was a marked decline of as much as 77% in response upon restimulation by hormone, as measured by glycerol release or cAMP levels. This desensitization was both heterologous as well as homologous. Thus, for example, exposure of adipocytes to isoproterenol desensitized them to further stimulation by both isoproterenol and ACTH. The process was time dependent, since augmentation rather than desensitization was seen if cells were initially exposed to hormone for 30 min rather than 2 h. No desensitization was seen when the cells were restimulated with the nonhormonal lipolytic agent dibutyryl cAP. Similarly, no desensitization was seen when cells were first exposed to dibutyryl cAMP and then restimulated with hormone. We draw the following conclusions. First, desensitization in the adipocyte is a time- and dose-dependent process that is specific for adenylate cyclase-activating hormones. Secondly, the process is heterologous as well as homologous. Initial exposure of the adipocyte to one adenylate cyclase-activating hormone reduces its adenylate cyclase or lipolytic response upon reexposure to either the same or a different adenylate cyclase-activating hormone. Finally, the reduction in the end result of hormone activation, lipolysis, is due in part to a decrease in inducible levels of cAMP.