Depressed Thermogenesis but Competent Brown Adipose Tissue Recruitment in Mice Devoid of All Hormone-Binding Thyroid Hormone Receptors

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 18; no. 2; pp. 384 - 401
• Main Authors: Golozoubova, Valeria, Gullberg, Hjalmar, Matthias, Anita, Cannon, Barbara, Vennström, Björn, Nedergaard, Jan
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-02-2004; Oxford University Press
• Subjects: Adipose Tissue, Brown - cytology; Adipose Tissue, Brown - physiology; Adrenergic alpha-Agonists - pharmacology; Animals; Carrier Proteins - drug effects; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured - drug effects; Cells, Cultured - physiology; Cold Temperature; Female; Gene Expression Regulation - drug effects; Ion Channels; Male; Medicin och hälsovetenskap; Membrane Proteins - drug effects; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Mutant Strains; Mitochondrial Proteins; Norepinephrine - pharmacology; Receptors, Thyroid Hormone - genetics; Receptors, Thyroid Hormone - metabolism; Thermogenesis - drug effects; Thermogenesis - physiology; Thyroid Hormone Receptors alpha - genetics; Thyroid Hormone Receptors alpha - metabolism; Thyroid Hormone Receptors beta; Uncoupling Protein 1
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2003-0267

We have examined the metabolic role of hormone-binding nuclear thyroid hormone receptors (TRs). Mice devoid of all hormone-binding TRs [TRα1(−/−)β(−/−) (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.