Alpha 1- and beta-adrenergic agents cause synergistic stimulation of the iodothyronine deiodinase in rat brown adipocytes.
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.
Raasmaja
A
A
Howard Hughes Medical Institute Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Larsen
P R
PR
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015016:Yohimbine / Q000494:pharmacology
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D007093:Imidazoles; D005576:Colforsin; D010656:Phenylephrine; D015016:Yohimbine; D003994:Bucladesine; D000526:Alprenolol; D000242:Cyclic AMP; D007453:Iodide Peroxidase; D007545:Isoproterenol; C014282:cirazoline; D009638:Norepinephrine; D011224:Prazosin