Effects of thyroid hormone deficiency on cyclic adenosine 3':5'-monophosphate and control of lipolysis in fat cells.

Isolated fat cells from hypothyroid rats, in contrast with those from normal animals, lack ability to give a lipolytic response to epinephrine or glucagon. However, activation of triglyceride lipolysis was induced with (N6,02’-dibutyryl cyclic adenosine 3’ :5’-monophosphate), or a combination of epinephrine and phosphodiesterase inhibitors. Adenylyl cyclase was activated by catecholamines or glucagon in membrane ghosts prepared from fat cells obtained from hypothyroid rats. The characteristics of the enzyme, and its activation by hormones and fluoride were similar to those observed in fat cell membrane ghosts from normal animals. Thus, adenylyl cyclase appears to be functional in the hypothyroid state, although lipolysis is blocked. Whole fat cells were incubated in the presence and absence of epinephriue or theophylline, and accumulation of cyclic AMP over 10 min was measured. Basal, unstimulated levels were found to be similar in cells from normal and hypothyroid animals. In the presence of theophylline alone, similar levels of cyclic AMP were again observed. An increase in cyclic AMP accumulation in response to epinephrine stimulation, however, was not obtained in cells from hypothyroid rats except in the presence of the phosphodiesterase inhibitor. Cyclic nucleotide phosphodiesterase activities were fractionated by discontinuous sucrose gradient centrifugation. The soluble, low a%lnity form of phosphodiesterase activity did not difIer in the normal and hypothyroid states. The particulate, high affinity forms of cyclic AMP phosphodiesterase activity were elevated in fat cells from hypothyroid rats. Thyroid hormones may thus exert a modulating effect on cyclic AMP-mediated responses by regulating the activity of a membrane associated, high afZnity, cyclic AMP phosphodiesterase.