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Ann Marie Zavacki, PhD, BS
Research Associate, Brigham and Women's Hospital
Assistant Professor of Medicine, Harvard Medical School

Brigham and Women's Hospital
Department of Medicine
Endocrinology
75 Francis Street
Boston, MA 02115

Research Location: Harvard Institute of Medicine

Phone: 617-525-5153
Research Email: azavacki@partners.org

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Research Narrative:

The iodothyronine deiodinases activate and inactivate thyroid hormone

80% of the daily thyroid hormone production in humans is in the form of the pro-hormone, thyroxine (T4), which must to be converted to the biologically active hormone 3,5,3’-triiodothyronine (T3). The iodothyronine deiodinase enzymes are key to thyroid hormone action, due to their ability to both activate and inactivate thyroid hormone. The type 1 and 2 deiodinases (D1 and D2) remove an outer-ring iodine from T4 to produce T3, whereas the type 3 deiodinase (D3) inactivates T3 and T4 viathe removal of an inner-ring iodine to generate T2 or reverse T3 (rT3). D1 primarily contributes to serum T3 levels, while coordinated changes in D2 and D3 can regulate the amount of T3 locally within a specific tissue/cell type, without changing circulating T3.

Physiological roles of the iodothyronine deiodinases

Our research addresses the many roles that the deiodinase enzymes play in a variety of physiological situations. To investigate the compensatory mechanisms by which the dediodinases maintain physiologically appropriate amounts of thyroid hormone in both the circulation and tissues we have developed a mouse model with minimal extra-thyroidal conversion of T4 to T3. When a targeted deletion of the Dio2 gene (D2KO) was backcrossed into a C3H background (C3H-D2KO mice) with impaired D1 activity (1/10 normal), thus eliminating most of the extrathyroidal conversion of T3 to T4, these mice were still able to maintain euthyroid serum T3 levels. However, C3H-D2KO mice had an increased serum T4 and TSH suggesting a central resistance to T4, and increased body fat when fed a high fat diet (~30%), indicative of other tissue-specific defects in thyroid hormone action.

Further studies of the D2KO mice in a C57 background (with “normal” D1 activity) allowed us to determine that the metabolic phenotype of the C3H-D2KO was a result of the loss of the Dio2 gene, and our recent work has determined that the D2KO mouse has increased body fat and liver steatosis on a high fat diet, and is insulin resistant even before increased weight gain. While D2KO mice show no changes in energy expenditure, they do exhibit an increased preference for carbohydrate usage. We are currently expanding these studies to further define the role that D2 may play in other aspects of metabolic regulation.

Cell biology of the iodothyronine deiodinases

We also study the cell biology of the deiodinases. Using 2 dimensional differential gel electrophoresis combined with mass spectrophotometry (2-D DIGE MS), we have identified a type 3 deiodinase interacting protein, peroxiredoxin 3, that is necessary for the regeneration of the oxidized D3 enzyme in vivo. We have also isolated D3 interacting proteins using the yeast two-hybrid system, and are further characterizing how these proteins regulate D3 activity. Our cell biology studies have further determined that catalysis of substrate leads to an alteration of D1-homodimers that results in enzyme inactivation.


Education:
Harvard University, 1996, PhD
Rochester Institute of Technology, 1988, BS