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Evidence for a Compensated Thermogenic Defect in Transgenic Mice Lacking the Mitochondrial Glycerol-3-Phosphate Dehydrogenase Gene

Division of Endocrinology (R.A.D., A.A., J.E.S.), Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Québec, Canada H3T 1E2; Department of Metabolic Diseases (K.E., T.K.), Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan; and Core Research for Evolutional Science and Technology of Japan Science and Technology Corp. (K.E., T.K.), Saitama 332-0012, Japan

Address all correspondence and requests for reprints to: J. Enrique Silva, M.D., Jewish General Hospital, 3755 Chemin de la Côte-Ste-Catherine, Room E104, Montréal, Québec, Canada H3T 1E2. E-mail: enrique.silva{at}staff.mcgill.ca.

A role for mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) in thermogenesis was investigated in transgenic mice lacking the mGPD gene (mGPD^-/-). Reared and studied at 22 C, these mice have a small, but significant, reduction (7–10%) in energy expenditure, as evidenced by oxygen consumption (QO₂) and food intake, and show signs of increased brown adipose tissue (BAT) stimulation, higher plasma T₄ and T₃ concentrations, as well as increased uncoupling protein 3 (UCP3) expression in muscle. When acclimated at thermoneutrality temperature (32 C), QO₂ decreased in both genotypes, but the difference between them widened to 16%, whereas BAT underwent atrophy, and plasma T₄ and T₃ levels and UCP3 mRNA decreased, yet T₃ and UCP3 persisted at significantly higher levels in mGPD^-/- mice. Such differences disappeared when the mice were rendered hypothyroid. A compensatory role for the observed changes in BAT, thyroid hormone levels, and UCP3 was investigated with a 2-h cold challenge of 12 C in euthyroid and hypothyroid mice. No hypothermia ensued if the mice had been acclimated at 22 C, but when acclimated at 32 C, euthyroid mGPD^-/- mice became significantly more hypothermic than the wild-type controls. When rendered hypothyroid, this difference was accentuated, and the mGPD^-/- mice developed profound hypothermia (28 vs. 34 C in wild-type mice; P < 0.001). Thus, mGPD-deficient mice have, despite increased plasma T₄ and T₃, a small, but distinct, reduction in obligatory thermogenesis, which is compensated by increased BAT facultative thermogenesis and by thyroid hormone-dependent mechanisms using other proteins, possibly UCP3. The results support a role for mGPD in thyroid hormone thermogenesis.

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