OR50-1 The thyroid hormone analog DITPA ameliorates metabolic parameters in Mct8 deficient mice

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR50-Novel Approaches to Diagnosis & Treatment of Thyroid Diseases
Translational
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:15 AM
Room 134 (Moscone Center)
Alfonso Massimilano Ferrara*, Xiao Hui Liao, Honggang Ye, Roy E Weiss, Alexandra M Dumitrescu and Samuel Refetoff
University of Chicago, Chicago, IL
Mutations in the monocarboxylate transporter 8 (MCT8) gene, coding for a specific thyroid hormone (TH) cell membrane transporter, causes a severe form of X-linked psychomotor retardation in young males. Typical are truncal hypotonia, poor head control and progressive spastic quadriplegia. Consequently, affected individuals are unable to walk and talk.  Affected subjects have also a characteristic thyroid phenotype combining high serum T3, low T4, and low reverse T3. While they suffer of thyroid hormone deprivation in brain, the elevated serum T3level is believed to produce peripheral tissue hypermetabolism responsible for the inability to maintain body weight.

Mct8 deficient (Mct8KO) mice replicate the thyroid phenotype and the peripheral tissue putative hyperthyroidism in humans and are, thus, suitable for direct metabolic studies that are not possible in affected humans.

We have shown that the thyroid hormone analog, diiodothyropropionic acid (DITPA), normalizes the thyroid test abnormalities of Mct8KO mice. To determine whether it produces an amelioration of the hypermetabolic state in Mct8KO mice, we measured metabolic parameters such as O2 consumption and CO2 production, food and water intake in 8 Mct8KO and 8 Wtmale mice, matched for age, by using an open circuit indirect calorimetry system (metabolic cages). Mice were, initially, acclimatized in metabolic cages for 5 days during which baseline data were recorded. Then, DITPA (0.3mg/100gBW) was injected intraperitoneously for 10 days and data were recorded during the last 5 days.

At baseline, Mct8KO mice compared to wild-type (Wt) mice have, in the active dark phase, significantly higher total energy expenditure (TEE) (7.88±0.13 vs 7.42±0.11 Kcal/h/Kg; P<0.05), respiratory exchange rate (RER) (1.00±0.01 vs 0.96±0.01; P<0.01), food (160±7.67 vs 133±8.97 g/mg BW/day; P<0.05) and water intake (150±6.55 vs120±6.38 ml/g BW/day; P<0.05) with a tendency for increased metabolic use of carbohydrates (5,140±191 vs 4,301±140 mg/h/kg BW; P< 0.01) but reduced use of lipids (109±65 vs 281±47 mg/h/kg BW; P< 0.05).

DITPA treatment improves the metabolic parameters in Mct8KO mice compared to Wt animals by normalizing TEE (7.21±0.05 vs 7.46±0.11 kcal/h/kg), RER (0.97±0.01 vs 0.96±0.01), food (143±9.27 vs 144±7.35 g/mg BW/day) and water (140±8.32 vs 130±6.39 ml/g BW/day) intake. Additionally, DITPA treatment normalizes glucose consumption (4,513±126 vs 4,249±146 mg/h/kg BW), whereas lipid oxidation remains lower in Mct8KO mice compared to Wt animals (133±45 vs293±66 mg/h/kg BW).

In conclusion, our study demonstrates the beneficial effect of DITPA in reducing the hypermetabolism in Mct8KO mice suggesting that it is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency.

Nothing to Disclose: AMF, XHL, HY, REW, AMD, SR

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH; Smile foundation; Sherman family
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