Endocrinology, Vol 125, 2502-2509, Copyright © 1989 by Endocrine Society

ARTICLES

Alpha 1- and beta-adrenergic agents cause synergistic stimulation of the iodothyronine deiodinase in rat brown adipocytes

A Raasmaja and PR Larsen
Howard Hughes Medical Institute Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.

Previous studies have shown that norepinephrine causes a marked increase in the iodothyronine 5'-deiodinase activity in dispersed brown adipocytes. This stimulation required mRNA and protein synthesis and was 3- to 4-fold greater in cells from hypothyroid than in those from euthyroid rats. To investigate the cause of this differential response, we incubated dispersed brown adipocytes with catecholamines, a specific alpha 1-agonist, forskolin, and (Bu)2cAMP alone and in combination. Our results show a synergistic effect of alpha 1- and beta-adrenergic catecholamines to increase the deiodinase, which leads to 2-fold (euthyroid) to 4-fold (hypothyroid) higher enzyme activities in the presence of both agonists than can be accounted for by additive effects of the two agents. Since alpha 1-agonists cause minimal stimulation alone, this response is due to an enhancement of the cAMP effect. The alpha 1 effect is mimicked by the calcium ionophore A23187, but not by phorbol ester alone. After 2-h exposure to beta-adrenergic agents or forskolin, hypothyroid cells had a reduced cAMP response, but alpha 1- agonists did not reverse this. These results demonstrate a complex interrelationship between alpha 1- and beta-adrenergic agonists and thyroid status in the regulation of deiodinase in the brown adipocyte. The increase in intracellular calcium due to an alpha 1-agonist markedly enhances the effects of cAMP on deiodinase activation, permitting a beta-adrenergic effect despite the impaired cAMP generation characteristic of hypothyroid adipocytes. This unexpected enhancement of the beta-adrenergic pathway in the hypothyroid state may be especially relevant for maintaining maximum T3 production, which is required for the normal thermogenic function of this tissue.

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