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This version published online on April 21, 2005
Endocrinology, doi:10.1210/en.2004-1544
A more recent version of this article appeared on July 1, 2005
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Submitted on November 29, 2004
Accepted on April 12, 2005

Temperature Homeostasis in transgenic mice lacking thyroid hormone receptor alpha gene products

Husnia Marrif, Aria Schifman, Zaruhi Stepanyan, Marc-Antoine Gillis, Angelino Calderone, Roy E. Weiss, Jacques Samarut, and J. Enrique Silva*

Division of Endocrinology, Jewish General Hospital, McGill University, Montreal, QC, Canada; Montreal Heart Institute, Montreal, Canada.Department of Medicine, University of Chicago, Chicago, Ill; Ecole Normal Superior, Lyon, France

* To whom correspondence should be addressed. E-mail: enrique.silva{at}staff.mcgill.ca.

We studied temperature homeostasis in male mice lacking all thyroid hormone receptor-{alpha} gene products (TR{alpha}-0/0). As other TR{alpha}-deficient mice, TR{alpha}-0/0 mice have lower core body temperature (TC) than cognate wild-type (WT) controls. We found that obligatory thermogenesis is normal in TR{alpha}-0/0 and that the lower TC at room temperature (RT, 20-22 C) is caused by a down setting of the hypothalamic thermostat. However, TR{alpha}-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 T4 deiodinase respond normally to cold stimulation, as do serum T3, serum glycerol (marker of lipolysis) and heart rate. BAT normally contributes to maintain TC at RT, 9 C below thermoneutrality, yet TR{alpha}-0/0 mice do not show signs of being cold-stressed at 20-22 C. Instead, oxygen consumption is greater in TR{alpha}-0/0 than in WT 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 TR{alpha} is necessary for T3 to modulate the central control of TC 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.
Key words: temperature regulation • thermogenesis • thyroid hormone • thyroid hormone receptors • sympathetic nervous system




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