Research Interests: Relationships Between Temperature Homeostasis and Energy Balance
Homeothermic animals such as humans and other mammals spend a large amount of energy generating heat to maintain body temperature, a process called thermogenesis. Our laboratory's long-time interest is in how hormones, particularly the hormones of the thyroid gland, regulate thermogenesis and energy balance. Fuel efficiency in mammals and birds is much lower than that of nonmammals for the sake of temperature homeostasis. Being a wasteful process, the need for thermogenesis has competed with food availability throughout evolutionary history.
Probably because of these competing pressures on our remote ancestors, thermogenesis is a major source of variability of energy expenditure in humans. It is known that a low metabolic rate due to low thermogenesis is a risk factor for obesity. Furthermore, thermogenesis is promptly reduced in starvation and caloric restriction, which limits the efficiency of low-calorie diets. Thyroid hormones acquired a new role with the advent of homeothermy in evolution. Homeothermy is a process that stimulates and sustains thermogenesis. In the absence of thyroid hormones, mammals and birds regress to a nearly nonmammalian status. Therefore, understanding how thyroid hormones control thermogenesis and energy balance is likely to provide valuable insight into the variability of energy expenditure in humans and eventually may provide clues to medical interventions. This knowledge is relevant to obesity and type 2 diabetes, two major health problems of our time.
Over recent years, our laboratory has turned to transgenic mouse models in which genes likely to be involved in the control of thermogenesis and temperature homeostasis have been deleted. Mice with deletion of one of the thyroid hormone receptors, the TRα, have lower body temperature and are cold intolerant. To compensate, they stimulate another form of thermogenesis, which is more energy demanding and makes them eat more and gain less weight. However, this mechanism is not sufficient to protect them from severe cold (eg, 4-10 degrees Celsius). Another model, lacking a mitochondrial enzyme, is more prone to diet-induced obesity and loses less weight when calorie-restricted. Interestingly, females are much more affected than males, who compensate better for the lack of the gene.
Silva JE. Facultative Non-Shivering Thermogenesis: Physiological Importance and Neuro-Hormonal Control. Invited Review, Frontiers in Biosciences, Scholar Edition. 2011;3:352-371.
Ramadan W, Marsili A, Larsen PR, Zavacki AM, Silva JE. Type-2 iodothyronine 5′deiodinase (D2) in skeletal muscle of C57Bl/6 mice. II. Evidence for a role of D2 in the hypermetabolism of thyroid hormone receptor alpha-deficient mice. Endocrinology. In press (2011).
Ramadan W, Marsili A, Wang S, Larsen PR, Silva JE. Type-2 iodothyronine 5′deiodinase in skeletal muscle of C57Bl/6 mice. I. Identity, subcellular localization and characterization. Endocrinology. In press (2011).
Marsili A, Ramadan W, Harney JW, Mulcahey M, Castroneves LA, Goemann IM, Wajner SM, Huang SA, Zavacki AM, Maia AL, Dentice M, Salvatore D, Silva JE, et al. 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):5952-5960.
Demetri C, Shoukri KC, Taylor SL, Silva JE. Postpartum granulomatous thyroiditis with sphenoid sinus involvement: a case study. Endocr Pract. 2010;16(2):264-269.
Hagobian TA, Sharoff GA, Stephens BR, Wade GN, Silva JE, et al. Effects of exercise on energy regulating hormones and appetite in men and women Am J Physiol Regul Integr Comp Physiol. 2009;296(2):R233-R242.
Silva JE, Carvalho-Bianco, SD. Thyroid-andrenergic interactions: Physiological and Clinical Implications. Thyroid. 2008,18(2):157-165.
Pelletier P, Gautier K, Sideleva O, Samarut J, Silva JE. Mice lacking the thyroid hormone receptor alpha gene spend more energy in thermogenesis, burn more fat and are less sensitive to high-fat diet-induced obesity. Endocrinology. 2008;149(12):6471-6486.
Silva JE. Thermogenic Mechanisms and Their Hormonal Regulation. Physiological Reviews. 2006;86:435-464.
Marrif H, Schifman A, Stepanyan Z, Gillis MA, Calderone A, Weiss RE, Samarut J, Silva JE. Temperature homeostasis in transgenic mice lacking thyroid hormone receptor alpha gene products. Endocrinology. 2005;146(7):2872-2884.
Alfadda A, DosSantos RA, Stepanyan Z, Marrif H, Silva JE. Mice with deletion of the mitochondrial glycerol-3-phosphate dehydrogenase gene exhibit a thrifty phenotype: effect of gender. Am J Physiol Regul Integr Comp Physiol. 2004;287(1):R147-R156.
DosSantos RA, Alfadda A, Eto K, Kadowaki T, Silva JE. Evidence for a compensated thermogenic defect in transgenic mice lacking the mitochondrial glycerol 3-phosphate dehydrogenase gene. Endocrinology. 2003; 144(12):5469-5479.