Triiodothyronine causes rapid reversal of alpha 1/cyclic adenosine monophosphate synergism on brown adipocyte respiration and type II deiodinase activity.

Previous studies have shown that thyroid status affects the response of brown adipose tissue (BAT) to the sympathetic nervous system. For example, hypothyroidism is associated with the development of a marked synergism between alpha 1- and beta-adrenergic pathways to stimulate type II iodothyronine 5'-deiodinase activity. Hypothyroidism also attenuates the respiratory response (thermogenesis) of isolated brown adipocytes to norepinephrine. To explore the interactions of the sympathetic nervous system and thyroid status in these cells, we compared the thermogenic and 5'-deiodinase responses to adrenergic agonists in isolated brown adipocytes from hypothyroid rats during treatment with 3,5,3'-triiodothyronine (T3). The fivefold synergism of alpha 1- and beta-adrenergic catecholamines to increase the deiodinase activity was progressively reduced, reaching a control euthyroid value of unity after 5 days of T3 treatment. Hypothyroidism reduced both the O2max (twofold to threefold) and increased the concentration of agonist required for 50% stimulation (10-fold) for both norepinephrine and forskolin. In hypothyroid cells, there was a twofold synergism between the alpha 1-agonist cirazoline and forskolin to increase respiration, which was blocked by prazosin and reproduced by the calcium ionophore, A23187. This synergistic effect of the alpha 1-agonist was lost within 2 days of T3 administration. These studies identify a second Ca(2+)-dependent intra-adrenergic synergism, which functions to ameliorate the reduced cyclic adenosine monophosphate (cAMP) responsiveness of the hypothyroid brown adipocyte.

Effect of thyroid status on catecholamine stimulation of thyroxine 5'-deiodinase in brown adipocytes.

We examined type II 5'-iodothyronine deiodinase activation by adrenergic agonists in dispersed brown adipocytes from euthyroid and hypothyroid rats. In euthyroid cells, basal deiodinase activity was 30-100 fmol I-.h-1.10(6) cells-1 and increased four- to fivefold during exposure to norepinephrine, an effect that was enhanced by alprenolol. In cells from hypothyroid rats, norepinephrine caused a three- to fourfold greater deiodinase stimulation than occurred in euthyroid cells but alprenolol inhibited the response. In euthyroid cells, phenylephrine caused greater stimulation than did norepinephrine, but this was inhibited by alprenolol. Isoproterenol and 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) inhibited the phenylephrine response but were modestly stimulatory alone. Although both alpha 1- and beta-adrenergic agonists increased deiodinase activity modestly in hypothyroid cells, in combination they caused a marked synergistic stimulation. This synergism was induced by 8-BrcAMP and forskolin, as well as by isoproterenol. The stimulation of deiodinase in both cell types was due to an increase in Vmax without an alteration in the Km and required mRNA synthesis. The markedly greater deiodinase response of the hypothyroid brown adipocyte to catecholamines may serve to enhance the impaired thermogenic response of this tissue to cold exposure.