Mct8-Deficient Mice Have Increased Energy Expenditure and Reduced Fat Mass That Is Abrogated by Normalization of Serum T3 Levels

Children with monocarboxylate transporter 8 (MCT8) deficiency lose weight, even when adequately nourished. Changes in serum markers of thyroid hormone (TH) action compatible with thyrotoxicosis suggested that this might be due to T-3 excess in peripheral tissues. Mct8-deficient mice (Mct8KO) replicate the human thyroid phenotype and are thus suitable for metabolic studies so far unavailable in humans. In the current work, compared with wild-type (Wt) mice, Mct8KO mice were leaner due to reduced fat mass. They tended to use more carbohydrates and fewer lipids during the dark phase. Mct8KO mice had increased total energy expenditure (TEE) and food and water intake, with normal total activity, indicating hypermetabolism. To determine whether this is due to the high serum T-3, we studied mice deficient in both Mct8 and deiodinase 1 (Mct8D1KO) with serum T-3 similar to Wt mice and Wt mice given L-T-3 to raise their serum T-3 to the level of Mct8KO mice. Contrary to Mct8KO, Mct8D1KO mice had similar fat mass, TEE, and food intake as their D1KO littermates, whereas T-3-treated Wt mice showed increased food intake and TEE, similar to Mct8KO mice. In skeletal muscle, Mct8KO mice had increased T-3 content and TH action and increased glucose metabolism, which improved in Mct8D1KO mice. These studies indicate that the high serum T-3 in MCT8 deficiency increases the TEE and fails to maintain weight despite adequate calorie intake. This is mediated by tissues that are not predominantly MCT8 dependent for TH transport, including skeletal muscle. Normalizing serum T-3 level by deleting deiodinase 1 corrects body composition and the metabolic alterations caused by the MCT8 deficiency.