Coupling between Nutrient Availability and Thyroid Hormone Activation*
| Autor: | Joao Pedro Werneck-de-Castro, InSug O-Sullivan, Terry G. Unterman, Lattoya J. Lartey, Antonio C. Bianco |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Deiodinase DIO2 Mechanistic Target of Rapamycin Complex 2 Biochemistry Iodide Peroxidase Thyroid hormone receptor beta Mice Phosphatidylinositol 3-Kinases Internal medicine medicine Animals Muscle Skeletal Molecular Biology Mice Knockout Thyroid hormone receptor Triiodothyronine biology Forkhead Box Protein O1 TOR Serine-Threonine Kinases Forkhead Transcription Factors Cell Biology Fasting Insulin receptor Thyroxine Endocrinology Metabolism Hormone receptor Multiprotein Complexes biology.protein Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists Hormone Signal Transduction |
| Popis: | The activity of the thyroid gland is stimulated by food availability via leptin-induced thyrotropin-releasing hormone/thyroid-stimulating hormone expression. Here we show that food availability also stimulates thyroid hormone activation by accelerating the conversion of thyroxine to triiodothyronine via type 2 deiodinase in mouse skeletal muscle and in a cell model transitioning from 0.1 to 10% FBS. The underlying mechanism is transcriptional derepression of DIO2 through the mTORC2 pathway as defined in rictor knockdown cells. In cells kept in 0.1% FBS, there is DIO2 inhibition via FOXO1 binding to the DIO2 promoter. Repression of DIO2 by FOXO1 was confirmed using its specific inhibitor AS1842856 or adenoviral infection of constitutively active FOXO1. ChIP studies indicate that 4 h after 10% FBS-containing medium, FOXO1 binding markedly decreases, and the DIO2 promoter is activated. Studies in the insulin receptor FOXO1 KO mouse indicate that insulin is a key signaling molecule in this process. We conclude that FOXO1 represses DIO2 during fasting and that derepression occurs via nutritional activation of the PI3K-mTORC2-Akt pathway. |
| Databáze: | OpenAIRE |
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