Coupling between Nutrient Availability and Thyroid Hormone Activation.
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.
From the Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida 33136.
Lattoya J
LJ
Lartey
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.
João Pedro
JP
Werneck-de-Castro
the Jesse Brown Veterans Affairs Medical Center and the Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612.
InSug
I
O-Sullivan
the Jesse Brown Veterans Affairs Medical Center and the Department of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612.
Terry G
TG
Unterman
the Department of Internal Medicine, Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, Illinois 60612, abianco@deiodinase.org.
Antonio C
AC
Bianco
D000818:Animals; D005215:Fasting / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism*; D000097564:Iodothyronine Deiodinase Type II
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007453:Iodide Peroxidase; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II; C085126:FOXO1 protein, human
FOXO1; insulin; mTOR complex (mTORC); signal transduction; signaling; thyroid hormone; type 2 deiodinase