Evidence for a compensated thermogenic defect in transgenic mice lacking the mitochondrial glycerol-3-phosphate dehydrogenase gene

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 (QO(2)) and food intake, and show signs of increased brown adipose tissue (BAT) stimulation, higher plasma T-4 and T-3 concentrations, as well as increased uncoupling protein 3 (UCP3) expression in muscle. When acclimated at thermoneutrality temperature (32 C), QO(2) decreased in both genotypes, but the difference between them widened to 16%, whereas BAT underwent atrophy, and plasma T-4 and T-3 levels and UCP3 mRNA decreased, yet T-3 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 them GPD(-/-) mice developed profound hypothermia (similar to28 vs. 34 C in wild-type mice; P<0.001). Thus, mGPD-deficient mice have, despite increased plasma T-4 and T-3, 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.