The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes.
Brown adipose tissue (BAT) thermogenesis increases when uncoupling protein-1 (UCP1) is activated adrenergically and requires T3. In humans, UCP1 activation in BAT seems involved in body weight maintenance. BAT type 2 deiodinase (D2) increases in response to adrenergic agents, producing the T3 required for UCP1 expression. T3 actions are mediated by thyroid hormone nuclear T3 receptors (TR), TRα and TRβ. Studies in mice suggest that TRβ is required for UCP1 induction, whereas TRα regulates body temperature and adrenergic sensitivity. In the present study, we compare the effects of T3 vs. specific TRβ1 and TRα1 agonists [GC-1 and CO23] on the adrenergic induction of UCP1 and D2 in cultured rat brown adipocytes. T3 and GC-1 produced similar increases on UCP1, whereas CO23 increased UCP1 only at high doses (50 nm). GC-1 at low doses (0.2-10 nm) was less potent than T3, increasing the adrenergic stimulation of D2 activity and mRNA. At higher doses, GC-1 further stimulated whereas T3 inhibited D2 activity but not D2 mRNA, suggesting posttranscriptional effects. CO23 had no effect on D2 activity but increased D2 mRNA. T3, GC-1, or CO23 by themselves did not increase UCP1 or D2 mRNA. High T3 doses shortened D2 half-life and increased D2 turnover via proteasome, whereas GC-1 did not change D2 stability. The α1- and α2-adrenergic D2 responses increased using high T3 doses. In summary, T3 increases the adrenergic stimulation of UCP1 and D2 expression mostly via the TRβ1 isoform, and in brown adipocytes, D2 is protected from degradation by the action of T3 on TRβ1.
Martinez de Mena
Raquel
R
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain.
Scanlan
Thomas S
TS
Obregon
Maria-Jesus
MJ
D000085:Acetates / Q000494:pharmacology; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006827:Hydantoins / Q000494:pharmacology; D007453:Iodide Peroxidase / Q000235:genetics* / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D037042:Thyroid Hormone Receptors beta / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II
D000085:Acetates; D018663:Adrenergic Agents; D006827:Hydantoins; D007453:Iodide Peroxidase; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009638:Norepinephrine; D010636:Phenols; D020033:Protein Isoforms; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D000071256:Uncoupling Protein 1; D000097564:Iodothyronine Deiodinase Type II; C517607:5-(3,5-diiodo-4-(3-isopropyl-4-hydroxyphenoxy)benzyl)imidazolidine-2,4-dione; C413355:GC 1 compound; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat