Depressed thermogenesis but competent brown adipose tissue recruitment in mice devoid of all hormone-binding thyroid hormone receptors.
We have examined the metabolic role of hormone-binding nuclear thyroid hormone receptors (TRs). Mice devoid of all hormone-binding TRs [TR alpha 1(-/-)beta(-/-) (TR-ablated mice)] had slightly decreased body temperature and much decreased basal metabolic rate, were still able to markedly increase metabolic rate in the cold, but were cold intolerant due to inadequate total heat production at low temperatures. A standard norepinephrine test showed that adrenergically induced thermogenesis could not be activated normally in the TR-ablated mice. This was not due to inadequate recruitment of brown adipose tissue, nor to the absence, decreased recruitment or dysfunction of the uncoupling protein-1. However, isolated brown fat cells were 10-fold desensitized, explaining the lack of response to standard adrenergic stimuli; cell culture experiments demonstrated that this desensitization was not an innate effect. Thus, the cold intolerance was probably not due to inadequate sympathetically induced nonshivering thermogenesis. Additionally, the results indicated that no metabolic effects of thyroid hormones could become manifest in the absence of nuclear TRs, that ligand-bound TRs were needed for euthermia and eumetabolism, but that TRs per se were not required for brown adipose tissue recruitment and uncoupling protein-1 gene expression.
Golozoubova
Valeria
V
The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91, Stockholm, Sweden.
Gullberg
Hjalmar
H
Matthias
Anita
A
Cannon
Barbara
B
Vennström
Björn
B
Nedergaard
Jan
J
D002001:Adipose Tissue, Brown / Q000166:cytology / Q000502:physiology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D003080:Cold Temperature; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D024101:Mitochondrial Proteins; D009638:Norepinephrine / Q000494:pharmacology; D011988:Receptors, Thyroid Hormone / Q000235:genetics* / Q000378:metabolism; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta; D000071256:Uncoupling Protein 1
D000316:Adrenergic alpha-Agonists; D002352:Carrier Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011988:Receptors, Thyroid Hormone; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D009638:Norepinephrine