Temperature Homeostasis in Transgenic Mice Lacking Thyroid Hormone Receptor-α Gene Products

Abstract

We studied temperature homeostasis in male mice lacking all thyroid hormone receptor-alpha gene products (TRalpha-0/0). As other TRalpha-deficient mice, TRalpha-0/0 mice have lower core body temperature (T(C)) than cognate wild-type controls. We found that obligatory thermogenesis is normal in TRalpha-0/0 and that the lower T(C) at room temperature (RT, 20-22 C) is caused by a down setting of the hypothalamic thermostat. However, TRalpha-0/0 mice are cold intolerant due to impaired facultative thermogenesis. Norepinephrine-induced brown adipose tissue (BAT) thermogenesis is blunted, even though BAT-relevant genes and T(4) deiodinase respond normally to cold stimulation, as do serum T(3), serum glycerol (marker of lipolysis), and heart rate. BAT normally contributes to maintain T(C) at RT, 9 C below thermoneutrality, yet TRalpha-0/0 mice do not show signs of being cold stressed at 20-22 C. Instead, oxygen consumption is greater in TRalpha-0/0 than in wild-type mice at RT, suggesting the recruitment of an alternate, cold-activated form of thermogenesis to compensate for the lack of BAT thermogenesis. These results indicate that TRalpha is necessary for T(3) to modulate the central control of T(C) and for an essential step in norepinephrine activation of BAT thermogenesis but not to sustain obligatory thermogenesis. In addition, the results provide evidence for an alternate form of facultative thermogenesis, which probably originates in skeletal muscle and that is less effective and more energy demanding than BAT thermogenesis.

Nonshivering thermogenesis and its adequate measurement in metabolic studies

“…In addition, mice that lack the thyroid hormone receptor  show an increased metabolism, etc. at 22°C but not at thermoneutrality (Marrif et al, 2005;Pelletier et al, 2008). The most probable explanation for this is again an insulation problem (although the authors propose another mechanism).…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…In homeothermic species, such as humans, T 3 has acquired a critical role in temperature homeostasis and is responsible for w30% of REE (11). The T 3 -induced thermogenic activity is exerted through the thyroid hormone receptor a (TRa) (12,13), while TRb is a key regulator of cholesterol metabolism (14). Mice lacking all TRs display a phenotype characterized by decreased basal metabolic rate, decreased body temperature, and cold intolerance (15).…”

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…A rather complex mix of information on the specific roles of the individual TR isoforms has resulted from work on mice with ablated and mutated variants of TR (Forrest et al, 1996a,b;Wikstrom et al, 1998;Marrif et al, 2005). Currently, at least seven mutant alleles for THRA and nine for THRB exist, either as knockout or knockin mutations (Flamant et al, 2006).…”

“…TRb-deficient mice show a defect in the feedback control exerted by TH on the hypothalamus-pituitary-thyroid axis; they have high thyrotropin-releasing hormone and TSH levels and consequent increased circulating TH levels (Forrest et al, 1996a,b;Wikstrom et al, 1998;Marrif et al, 2005). TRb-deficient mice also display auditory and visual defects, including deafness and colorblindness, goiter, and defective hepatic response to triiodothyronine, including inability to regulate cholesterol breakdown to bile acids (Forrest et al, 1996a,b;Wikstrom et al, 1998;Gullberg et al, 2000Gullberg et al, , 2002Marrif et al, 2005). Elevated TH is also found in mice lacking both TRa and TRb (Vennstrom et al, 2010).…”