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 ( approximately 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.

By definition, homeothermic species maintain their core temperature (T c ) regulated within narrow limits. In most of these species, the hypothalamic thermostat is set somewhere between 36 and 38°C, and T c is tightly kept there, in spite of highly variable ambient temperatures. Several mechanisms to maintain body temperature have been selected during evolution. Vasoconstriction and piloerection are mechanisms to save heat, while vasodilatation, sweating and perspiration are mechanisms to rapidly dissipate heat. To maintain temperature in environments usually colder than T c , homeothermic species need to produce more heat than poikilothermic species. Energy transformations generate heat simply by virtue of the laws of thermodynamics and so the energy transformations inherent to life generate heat. Such heat, generated as byproduct of cell vital functions, is called obligatory thermogenesis (OT) and is expectedly higher in homeothermic species, as a consequence of which metabolic rate is substantially higher in these species than in poikilothermic species (Else and Hulbert, 1981). In addition to having a higher OT, homeothermic species can also activate specific mechanisms to produce extra heat in cold environments, which is called facultative thermogenesis (Gordon, 1993). Muscle shivering is the most immediate form of facultative thermogenesis, but it is energy consuming and disruptive for activity, and is rapidly replaced by metabolic heat production or non-shivering facultative thermogenesis (for simplicity we will call the former ''shivering'' and the latter ''facultative thermogenesis'', FT). There is an ambient temperature range, called thermoneutral zone, where OT is sufficient per se to maintain body temperature, without the need of FT or heat saving or heat dissipating mechanisms (Gordon, 1993). Such ambient temperature zone is quite narrow, but empirically it is possible to define a lower and an upper boundary (Gordon, 1993). In this discussion, I will talk rather of thermoneutrality temperature, T N , which corresponds to the low end of the thermoneutral zone and is defined as the minimal ambient temperature where OT can alone maintain body temperature.

We have investigated the effects of modifying the dose of thyroxine on resting energy expenditure (REE) and on the thermic effect of glucose (TEG) in 9 randomly recruited patients on chronic treatment with this hormone. The initial dose was changed twice in each patient at 6-8 wk intervals, aiming to have a normal, a slightly reduced, and a slightly elevated serum TSH concentration. A total of 27 dose points for each measured variable (3 per patient) were gathered. Dose changes were monitored with serum free T4, T3, and TSH. At the end of each dose period, low density lipoprotein and high density lipoprotein cholesterol, triglycerides, angiotensin converting enzyme, and sex hormone binding globulin were also measured, along with a systematic assessment of symptoms and signs. The investigators involved in the measurements were blinded to the dose of T4. Serum free T4 and TSH significantly correlated to the dose in each patient and in the whole group, whereas serum T3 levels were minimally affected by the dose and did not correlate with it, with free T4 or with TSH. This latter was below normal on 9 occasions, normal in 12, and above normal in 6. Serum free T4 and T3 remained within the normal range on all except 2 occasions. REE and TEG were normalized to fat-free mass (FFM). In each patient there was a significant negative correlation between REE and TSH. This correlation was maintained when all data were pooled (r2 = 0.64; P < 0.001). Also, initial REE and its change between the highest and the lowest thyroxine dose were significantly correlated with, respectively, initial serum TSH (r2 = 0.85; P < 0.001) and the change in serum TSH between the highest and the lowest dose of T4 (r2 = 0.67; P < 0.0065). REE decreased approximately 15% when TSH increased between 0.1 and 10 mU/L. In 6 of the 9 patients, TEG increased with the reduction of the dose, and higher values were associated with higher TSH levels but without reaching statistical significance (F = 2.852, P = 0.077). None of the other indices were significantly affected by the changes in dose. These results indicate that, in patients on chronic treatment with thyroxine, REE is significantly influenced by the dose of this hormone in a dose range encompassing serum TSH concentrations that are considered acceptable in the management of hypothyroid patients. In the absence of physiological or behavioral compensations, these changes in REE may be clinically relevant.