The current proposal focuses on the concept that thyroid hormone activation (T4 to T3 conversion) via the type 2 deiodinase (D2)plays a critical role in fuel homeostasis and energy expenditure. This concept originated from studies in brown adipose tissue (BAT), the main thermogenic tissue in human newborns and other small mammals. Recently, the discovery of D2 activity in human skeletal muscle has generated considerable excitement as it has become clear that deiodination is a common mechanism for metabolic control (1).Given this background, we were immediately intrigued by fact that BAT D2 is up-regulated in a mouse model of resistance to diet-induced obesity. In this model, supplementation with 0.5% bile acids prevents animals from becoming overweight or insulin-resistant when placed on a high fat diet. Intense collaborative investigation resulted in the first recognition of an FXR-independent metabolic pathway through which bile acids interact with the G-protein coupled receptor TGR5 and thus stimulate D2 in metabolically relevant tissues including BAT and human skeletal myocytes. Our preliminary studies indicate that other; GPCRs also stimulate D2. These striking data suggest that the spectrum of metabolites controlling D2, and the range of target tissues in which this mechanism is operant may be even more extensive than previously thought. With this in mind, we have begun to search for novel D2-regulating substances, and have preliminary evidence supporting significant regulatory effects for xenobiotic compounds. Understanding how metabolic signals from rapidly fluctuating endogenous molecules and xenobiotic factors are integrated via the D2 pathway is the major goal of these studies. Ultimately, by understanding these novel mechanisms for thyroid-hormone dependent metabolic control, we hope to identify new targets and approaches for therapeutic intervention in metabolic disorders including type II diabetes, obesity, and the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK077148-04
Application #
7756670
Study Section
Special Emphasis Panel (ZRG1-EMNR-G (02))
Program Officer
Margolis, Ronald N
Project Start
2007-01-01
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$374,103
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Paolino, Bruno S; Pomerantzeff, Pablo M; Dallan, Luís Alberto O et al. (2017) Myocardial Inactivation of Thyroid Hormones in Patients with Aortic Stenosis. Thyroid 27:738-745
Ignacio, Daniele L; Silvestre, Diego H S; Anne-Palmer, Elena et al. (2017) Early Developmental Disruption of Type 2 Deiodinase Pathway in Mouse Skeletal Muscle Does Not Impair Muscle Function. Thyroid 27:577-586
McAninch, Elizabeth A; Bianco, Antonio C (2016) The History and Future of Treatment of Hypothyroidism. Ann Intern Med 164:50-6
Bocco, Barbara M L C; Louzada, Ruy A N; Silvestre, Diego H S et al. (2016) Thyroid hormone activation by type 2 deiodinase mediates exercise-induced peroxisome proliferator-activated receptor-? coactivator-1? expression in skeletal muscle. J Physiol 594:5255-69
Bocco, Barbara M L C; Werneck-de-Castro, João Pedro; Oliveira, Kelen C et al. (2016) Type 2 Deiodinase Disruption in Astrocytes Results in Anxiety-Depressive-Like Behavior in Male Mice. Endocrinology 157:3682-95
Gereben, Balázs; McAninch, Elizabeth A; Ribeiro, Miriam O et al. (2015) Scope and limitations of iodothyronine deiodinases in hypothyroidism. Nat Rev Endocrinol 11:642-652
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
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; 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
Fliers, Eric; Bianco, Antonio C; Langouche, Lies et al. (2015) Thyroid function in critically ill patients. Lancet Diabetes Endocrinol 3:816-25

Showing the most recent 10 out of 29 publications