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Philip Reed Larsen, M.D.
Senior Physician, Brigham and Women's Hospital
Professor of Medicine, Harvard Medical School

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

Research Location: Harvard Institute of Medicine

Research Email:

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Research Narrative:

Research Summary:

Obesity and its complications, diabetes and cardiovascular disease, are major health issues for the US population. Obesity results from greater caloric intake than is required for maintaining metabolic homeostasis. Nonetheless, attempts at long-term dietary restriction as a treatment for obesity is only rarely successful and current efforts are devoted to develop methods which can also increase metabolic rate. Thyroid hormone excess can achieve this but adverse effects on cardiac function and bone health preclude its systemic administration. In humans, regulation of intracellular thyroid status is achieved largely through a balance between the activation of thyroxine (T4) to form triiodothyronine (T3) by type 2 deiodinase (D2) and the inactivation of T4 and T3 by the type 3 deiodinase (D3). Thus, manipulation of the activities of enzymes offers the potential for achieving tissue-specific increases in intracellular thyroid status independent of elevations in circulating thyroid hormone. We are using molecular and physiological approaches in mouse models to enhance our basic understanding of the rate-limiting steps in these T3-generating and inactivating pathways so that we can translate these approaches to humans. 

We are also exploring the role of thyroid hormone in skeletal muscle physiology, especially its roles in muscle regeneration and differentiation.  The thyroid hormone-skeletal muscle relationship is important for several reasons.  First, we easily recognize from patients with hypothyroidism or thyrotoxicosis that muscle is a thyroid hormone target.  Since thyroid dysfunction is one of the most common endocrine disorders, affecting 5-7% of the female population, understanding the pathophysiology of these relationships is of considerable medical interest.  Second, skeletal muscle contributes about 30% to resting energy expenditure.  If thyroid status could be enhanced in muscle, without causing systemic effects, one could increase total energy expenditure thus improving chances of weight control.  We have further shown that T4 activation by D2 is required for normal regeneration after muscle injury.  Although it was known that D2 was expressed in muscle, the critical role it and FoxO3, an important regulator of muscle D2, in these two events was entirely unknown.  We also found a marked, but transient, increase in D3 expression in skeletal muscle early after injury which may amplify satellite and myoblast precursor cell proliferation.  The factors regulating this increase and its consequences for muscle cell regeneration are being explored.  Atrophy of skeletal muscle, “sarcopenia”, is recognized as an important cause of accidental falls in the geriatric age group.  The disuse atrophy which occurs with a few weeks of bed-rest is an example of the rapidity with which muscle can deteriorate, especially in the elderly.  Thus, knowledge of how we might manipulate intracellular thyroid hormone concentrations to improve muscle regeneration has widespread public health applications.


Selected Original Publications:

1. Abrams GM, Larsen PR. Triiodothyronine and thyroxine in the serum and thyroid glands of iodine deficient rats. J Clin Invest 1973; 52:2522-2531. 


2. Silva JE, Larsen PR. Pituitary nuclear 3,5,3'-triiodothyronine and thyrotropin secretion: an explanation for the effect of thyroxine. Science 1977; 198:617-619. 


3. Visser TJ, Leonard JL, Kaplan MM, Larsen PR. Kinetic evidence suggesting two mechanisms for iodothyronine 5'-deiodination in rat cerebral cortex. Proc Natl Acad Sci 1982; 79:5080-5084. 


4. Berry MJ, Banu L, Larsen PR. Type I iodothyronine deiodinase is a selenocysteine-containing enzyme Nature 1991; 349:438-440. 


5. Berry MJ, Banu L, Chen Y, Mandel SJ, Kieffer JD, Harney JW, Larsen PR. Recognition of UGA as a selenocysteine codon in Type I deiodinase requires sequences in the 3' untranslated region. Nature 1991; 353:273-276. 

6. Salvatore D, Low SC, Berry MJ, Maia AL, Harney JW, Croteau W, St.Germain DL, Larsen PR.  Type 3 iodothyronine deiodinase:  cloning; in vitro expression; functional analysis of the placental selenoenzyme.  J Clin Invest 1995; 96:2421-2430.

7. Salvatore D, Tu H, Harney JW, Larsen PR.  Type 2 iodothyronine deiodinase is highly expressed in human thyroid.  J Clin Invest 1996; 98:962-968.


8. Steinsapir J, Harney J, Larsen PR.  Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes.  J Clin Invest 1998; 102:1895-1899.


9. Maia AM, Kim BW, Huang SA, Harney JW, Larsen PR.  Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans.  J Clin Invest 2005; 115:2524-2533.


10. Huang SA, Mulcahey MA, Crescenzi A, Chung M, Kim BW, Barnes C, Kuijt W, Turano H, Harney J, Larsen PR.  Transforming growth factor-b promotes inactivation of extracellular thyroid hormones via transcriptional stimulation of type 3 iodothyronine deiodinase.  Molecular Endo 2005; 19(12):3126-36. 


11. Dentice M, Luongo C, Huang S, Ambrosio R, Elefante A, Mirebeau-Prunier D, Zavacki AM, Fenzi G, Grachtchouk M, Hutchin M, Dlugosz AA, Bianco AC, Missero C, Larsen PR,  Salvatore D.  Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes.  PNAS 2007: 104(36): 14466-14471.


12. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FWJS, Crescenzi A, daSilva WS, Harney J, Engel EB, Obregon MJ, Larsen PR, Bianco AC, Huang SA.  Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease.  J Clin Invest 2008; 118(3):975-83. 


13. Dentice M, Marsili A, Ambrosio R, Guardiola O, Sibilio A, Paik J-H, Minchiotti G, DePinho RA, Fenzi G, Larsen, PR, Salvatore D.  The FoxO3/type 2 deiodinase pathway is required for normal mouse myogenesis and muscle regeneration.  J Clin Invest 2010; 120(11):4021-4030. 


14. Marsili A, Ramadan W, Harney JW, Mulcahey M, Castroneves LA, Goemann IM, Wajner SM, Huang SA, Zavacki AM, Maia Al, Dentice M, Salvatore D, Larsen PR.  Type 2 iodothyronine deiodinase levels are higher in slow-twitch than fast-twitch mouse skeletal muscle and are increased in hypothyroidism.  Endocrinology 2010; 151(12):5952-60.


15. Wajner SM, Goemann IM, Bueno AL, Larsen PR, Maia AL.  IL-6 promotes nonthyroidal illness syndrome by blocking thyroxine activation while promoting thyroid hormone inactivation in human cells.  J Clin Invest 2011; 121(5):1834-45. 


16. Marsili A, Aguayo-Mazzucato C, Chen T, Kumar A, Chung M, Lunsford EP, Harney JW, Van-Tran T, Gianetti E, Ramadan W, Chou C, Bonner-Weir S, Larsen PR, Silva JE, Zavacki AM.  Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet-induced obesity.  PLoS One 2011; 6(6):e20832. 


17. Marsili A, Tang D, Harney JW, Singh P, Zavacki AM, Dentice M, Salvatore D, Larsen PR.  Type 2 iodothyronine deiodinase provides intracellular 3,5,3' triiodothyronine to normal and regenerating mouse skeletal muscle.  Am J Physiol Metab 2011; Nov; 301(5):E818-24.


18. Marsili A, Sanchez E, Singru P, Harney JW, Zavacki AM, Lechan R, Larsen PR.  Thyroxine-induced induction of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase.  J Endocrinol 2011; Oct; 211(1):73-8.


19. Zhu B, Shrivastava A, Luongo C, Chen T, Harney JW, Marsili A, Tran TV, Bhadouria A, Mopala R, Steen AI, Larsen PR, Zavacki AM.  Catalysis leads to posttranslational inactivation of the type 1 deiodinase and alters its conformation.  J Endocrinol 2012; 214(1):87-94.


20. Dentice M, Luongo C, Ambrosio R, Sibilio A, Castillo A, Iaccarino A, Troncone G, Fenzi G, Larsen PR, Salvatore D.  Beta-catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells.  Gastroenterology 2012; 143(4):1037-47.


Selected Reviews:


1. Berry MJ, Larsen PR. The role of selenium in thyroid hormone action. Endocrine Review 1992;13:207-219.


2. Bianco AC, Salvatore D, Gereben B, Berry M, Larsen PR.  Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.  Endocrine Reviews 2002; 23:38-89. 


3. Marsili A, Zavacki AM, Harney JW, Larsen PR.  Physiological role and regulation of iodothyronine deiodinases: A 2011 update.  J. Endocrinol Invest 2011; 34:395-407. 




1992 Clinical Endocrinology Trust of United Kingdom: Medal for Distinguished Contributions to Endocrinology
1992 Merck Prize, European Thyroid Association
1992 Recognition Award for Distinguished Career in Clinical Investigation, Columbia Presbyterian Medical Center
2002 Edwin B. Astwood Lecture Award, The Endocrine Society
2004 William Silen Lifetime Achievement in Mentoring Award, Harvard Medical School
2008 Fred Conrad Koch Award in Recognition of Exceptional Contributions to Endocrinology, The Endocrine Society