title: The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency.
abstract: 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 of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Alfonso Massimiliano
authors: AM
authors: Ferrara
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Xiao-Hui
authors: XH
authors: Liao
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Honggang
authors: H
authors: Ye
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Roy E
authors: RE
authors: Weiss
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Alexandra M
authors: AM
authors: Dumitrescu
authors: Departments of Medicine (A.M.F., X.-H.L., H.Y., R.E.W., A.M.D., S.R.) and Pediatrics (R.E.W., S.R.) and the Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637.
authors: Samuel
authors: S
authors: Refetoff
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004104:Diiodothyronines / Q000008:administration & dosage / Q000494:pharmacology*; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D009123:Muscle Hypotonia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters; D013963:Thyroid Hormones / Q000097:blood; D013972:Thyrotropin / Q000097:blood
chemical_list: D004104:Diiodothyronines; D007527:Isoenzymes; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D011422:Propionates; C484257:Slc16a2 protein, mouse; D027981:Symporters; D013963:Thyroid Hormones; C082182:3,5-diiodothyropropionic acid; D013972:Thyrotropin; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+); D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha