The deiodinases initiate or terminate thyroid hormone (TH) action. Studies pioneered in my laboratory unveiled that the activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease TH signaling in a tissue- and temporal-specific fashion. In other words, D2 and D3 determine the intensity of thyroid signaling independently of plasma T3 (the biologically active TH. Our studies revealed that these mechanisms can be modulated by a wide variety of signaling molecules such as the hedgehog family of proteins, bile acids, HIF-1, NF-B, and a number of xenobiotic substances. These studies have indicated that deiodinases play a broad role in the control of metabolism and disease state, the understanding of which is the focus of this application. In this proposal, we focus on the role of inactivating deiodinase (D3) in three different tissues, brain, heart and pancreas (specifically beta cells). Our publications and preliminary data show that D3 plays a crucial role in these three tissues. For example, in brain, we have shown that D3 translocates into the nucleus to inactivate thyroid hormone (T3) to reduce metabolism in neurons. In addition, we have demonstrated that D3 plays a critical role in myocardial fibrosis and cardiac remodeling using paternally imprinted D3 heterozygous mouse models. Finally, we have published that a D3 knockout mouse has impaired glucose tolerance and has a defect in insulin secretion from pancreatic beta cells. These discoveries underlie a role of D3-controlled termination of TH signaling in brain, heart and pancreatic beta cells with repercussions for metabolic regulation in brain, adrenergic or angiotensin signaling in heart and insulin secretion mechanism in pancreatic beta cells. Our studies indicate that these novel D3 mediated adaptive mechanisms are operating in settings of three different tissues, such as brain, heart and pancreas. This proposal investigates the D3 paradigm from the perspective of various physiological or pathological contexts in different tissues, examining the effects of inactivating thyroid hormone signaling by D3 in the model of stroke, cardiac hypertrophy and diabetes. The novel findings that (i) D3 plays an important protective role in neuronal hypoxia/ischemia, (ii) myocardial D3 affects adrenergic and angiotensin signaling for myocardiac fibrosis, and that (iii) D3 is crucial n pancreatic beta cell development, expansion and insulin secretion, form the basis of this proposal.

Public Health Relevance

Tissue specific activation (D2) and inactivation (D3) of thyroid hormone by deiodinases is critical in metabolic regulation. This proposal is to investigate these pathways in brain stroke, cardiac hypertrophy, diabetes and obesity. The proposal is centered on our novel observation that ischemia/hypoxia leads to D3 expression and localized tissue hypothyroidism. This study will provide the scientific basis of therapeutic intervention of stroke heart disease and diabetes respectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077148-07
Application #
8700379
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2007-01-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
$332,775
Indirect Cost
$115,275
Name
Rush University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
McAninch, Elizabeth A; Bianco, Antonio C (2016) The History and Future of Treatment of Hypothyroidism. Ann Intern Med 164:50-6
Gereben, Balázs; McAninch, Elizabeth A; Ribeiro, Miriam O et al. (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642-52
Werneck de Castro, Joao Pedro; Fonseca, Tatiana L; Ueta, Cintia B et al. (2015) Differences in hypothalamic type 2 deiodinase ubiquitination explain localized sensitivity to thyroxine. J Clin Invest 125:769-81
Roberts, Simon C; Bianco, Antonio C; Stapleton, Heather M (2015) Disruption of type 2 iodothyronine deiodinase activity in cultured human glial cells by polybrominated diphenyl ethers. Chem Res Toxicol 28:1265-74
McAninch, Elizabeth A; Bianco, Antonio C (2015) New insights into the variable effectiveness of levothyroxine monotherapy for hypothyroidism. Lancet Diabetes Endocrinol 3:756-8
McAninch, Elizabeth A; Fonseca, Tatiana L; Poggioli, Raffaella et al. (2015) Epicardial adipose tissue has a unique transcriptome modified in severe coronary artery disease. Obesity (Silver Spring) 23:1267-78
McAninch, Elizabeth A; Jo, Sungro; Preite, Nailliw Z et al. (2015) Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. J Clin Endocrinol Metab 100:920-33
Fliers, Eric; Bianco, Antonio C; Langouche, Lies et al. (2015) Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3:816-25
Medina, Mayrin C; Fonesca, Tatiana L; Molina, Judith et al. (2014) Maternal inheritance of an inactive type III deiodinase gene allele affects mouse pancreatic β-cells and disrupts glucose homeostasis. Endocrinology 155:3160-71
Bianco, Antonio C; Anderson, Grant; Forrest, Douglas et al. (2014) American Thyroid Association Guide to investigating thyroid hormone economy and action in rodent and cell models. Thyroid 24:88-168

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