TY - JOUR
T1 - The thyroid hormone analog DITPA ameliorates metabolic parameters of male mice with Mct8 deficiency
AU - Ferrara, Alfonso Massimiliano
AU - Liao, Xiao Hui
AU - Ye, Honggang
AU - Weiss, Roy E.
AU - Dumitrescu, Alexandra M.
AU - Refetoff, Samuel
N1 - Publisher Copyright:
© 2015 by the Endocrine Society.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2015/11
Y1 - 2015/11
N2 - Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism ofMct8KOmice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8deficiency, as suggested in limited preliminaryhumantrials.
AB - Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism ofMct8KOmice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8deficiency, as suggested in limited preliminaryhumantrials.
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U2 - 10.1210/en.2015-1234
DO - 10.1210/en.2015-1234
M3 - Article
C2 - 26322373
AN - SCOPUS:84946098237
VL - 156
SP - 3889
EP - 3894
JO - Endocrinology
JF - Endocrinology
SN - 0013-7227
IS - 11
ER -