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J Biol Chem. 2015 Dec 18;290(51):30551-61. doi: 10.1074/jbc.M115.665505. Epub 2015 Oct 23.

Coupling between Nutrient Availability and Thyroid Hormone Activation.

Author information

1
From the Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
2
the Department of Internal Medicine, Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois 60612, the Carlos Chagas Filho Biophysics Institute and School of Physical Education and Sports, Federal University of Rio de Janeiro, Rio de Janeiro 21941-599, Brazil, and.
3
the Jesse Brown Veterans Affairs Medical Center and the Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612.
4
the Department of Internal Medicine, Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois 60612, abianco@deiodinase.org.

Abstract

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.

KEYWORDS:

FOXO1; insulin; mTOR complex (mTORC); signal transduction; signaling; thyroid hormone; type 2 deiodinase

PMID:
26499800
PMCID:
PMC4683275
DOI:
10.1074/jbc.M115.665505
[Indexed for MEDLINE]
Free PMC Article

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