Thyroid hormone--sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform--specific.
In newborns and small mammals, cold-induced adaptive (or nonshivering) thermogenesis is produced primarily in brown adipose tissue (BAT). Heat production is stimulated by the sympathetic nervous system, but it has an absolute requirement for thyroid hormone. We used the thyroid hormone receptor-beta--selective (TR-beta--selective) ligand, GC-1, to determine by a pharmacological approach whether adaptive thermogenesis was TR isoform--specific. Hypothyroid mice were treated for 10 days with varying doses of T3 or GC-1. The level of uncoupling protein 1 (UCP1), the key thermogenic protein in BAT, was restored by either T3 or GC-1 treatment. However, whereas interscapular BAT in T3-treated mice showed a 3.0 degrees C elevation upon infusion of norepinephrine, indicating normal thermogenesis, the temperature did not increase (<0.5 degrees C) in GC-1--treated mice. When exposed to cold (4 degrees C), GC-1--treated mice also failed to maintain core body temperature and had reduced stimulation of BAT UCP1 mRNA, indicating impaired adrenergic responsiveness. Brown adipocytes isolated from hypothyroid mice replaced with T3, but not from those replaced with GC-1, had normal cAMP production in response to adrenergic stimulation in vitro. We conclude that two distinct thyroid-dependent pathways, stimulation of UCP1 and augmentation of adrenergic responsiveness, are mediated by different TR isoforms in the same tissue.
Ribeiro
M O
MO
Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, California 90073, USA.
Carvalho
S D
SD
Schultz
J J
JJ
Chiellini
G
G
Scanlan
T S
TS
Bianco
A C
AC
Brent
G A
GA
D000085:Acetates / Q000494:pharmacology*; D000222:Adaptation, Physiological / Q000187:drug effects; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D003080:Cold Temperature; D000242:Cyclic AMP / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D005993:Glycerolphosphate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007037:Hypothyroidism / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D007473:Ion Channels; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008291:Malate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009638:Norepinephrine / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology*; D020033:Protein Isoforms / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology*; D014284:Triiodothyronine / Q000494:pharmacology / Q000627:therapeutic use; D000071256:Uncoupling Protein 1
D000085:Acetates; D002352:Carrier Proteins; C413355:GC 1 compound; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010636:Phenols; D020033:Protein Isoforms; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D014284:Triiodothyronine; D000242:Cyclic AMP; D005993:Glycerolphosphate Dehydrogenase; D008291:Malate Dehydrogenase; D009638:Norepinephrine