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

Division of Endocrinology (H.M., A.S., Z.S., J.E.S.), Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2; Montréal Heart Institute (M.-A.G., A.C.), Montréal, Québec, Canada H1T 1C8; Department of Medicine (R.E.W.), University of Chicago, Chicago, Illinois 60637; and Ecole Normal Superior (J.S.), 69364 Lyon Cadex 07, France

Address all correspondence and requests for reprints to: J. Enrique Silva, M.D., Jewish General Hospital, Division of Endocrinology, Room E-104, 3755 Cote-Ste-Catherine, Montréal, Québec, Canada H3T 1E2. E-mail: enrique.silva{at}staff.mcgill.ca.

We studied temperature homeostasis in male mice lacking all thyroid hormone receptor- gene products (TR-0/0). As other TR-deficient mice, TR-0/0 mice have lower core body temperature (T_C) than cognate wild-type controls. We found that obligatory thermogenesis is normal in TR-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, TR-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 T_C at RT, 9 C below thermoneutrality, yet TR-0/0 mice do not show signs of being cold stressed at 20–22 C. Instead, oxygen consumption is greater in TR-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 TR is necessary for T₃ 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.

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