The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency
Open accessAbstract
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.
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DITPA is a TH analog that can activate the T3 signaling cascade and has been tested in animal models and MCT8-deficient patients.
“As an example, DITPA is a TH analog that can activate the T3 signaling cascade and has been tested in animal models and MCT8-deficient patients (Ferrara et al., 2015; Verge et al., 2012).”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Ferrara et al., 2015
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- Authors
- Ferrara, A. M., Liao, X.-H., Ye, H., Weiss, R. E., Dumitrescu, A. M., & Refetoff, S.
- Affiliations
- University of Chicago (US)
- Corresponding author
- Refetoff, Samuel
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2015-08-31
- Volume
- 156
- Issue
- 11
- Pages
- 3889-3894
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC4606752
- OpenAlex
- W1952875124
- Cited by
- 32
- References
- 5
- Citations by year
- 2025: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 3
- FWCI
- 3.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R37-DK 15070, R37DK015070, DK020595, P60DK020595, P30DK020595)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- MCT8 deficiency, thyroid hormone transporters, thyrotoxicosis, hypermetabolism, energy expenditure, respiratory exchange ratio, food and water intake, liver, skeletal muscle
- MeSH terms
- Animals, Brain, Diiodothyronines, Drinking, Eating, Energy Metabolism, Glutathione Transferase, Humans, Injections, Intraperitoneal, Isoenzymes, Liver, Male, Mice, Inbred C57BL, Muscle Hypotonia, Muscular Atrophy, Propionates, Thyroid Hormones, Thyrotropin, Gene Expression, Mice, Knockout, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Membrane Transport Proteins, Monocarboxylic Acid Transporters, Symporters, Mental Retardation, X-Linked, X-Linked Intellectual Disability, Glycerol-3-Phosphate Dehydrogenase (NAD+)
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