Email: enrique.silva@bhs.org
Silva's PVLSI Web Site

M.D.: University of Chile
Postdoctoral Training: Internal & Experimental Medicine, Hospital del Salvador, U Chile, 1968-1971

Thyroid hormone physiology, Thermogenesis, Temperature Homeostasis

Our laboratory has been for long time interested in how hormones, particularly the hormones of the thyroid gland (thyroid hormone, TH), regulate thermogenesis and energy balance. Homeothermic animals spend a large amount of energy generating heat (thermogenesis) to maintain body temperature. The fuel efficiency of the homeothermic “machine” is much lower than that of the poikilothermic machine for the sake of temperature homeostasis. Being a wasteful process, the need for thermogenesis has competed through evolution with food availability. Probably because of the variability of these competing pressures on our remote ancestors, thermogenesis is major source of variability of energy expenditure in humans. It is known that low metabolic rate (due to low thermogenesis) is a risk factor for obesity. Furthermore, thermogenesis is promptly turned down in starvation and caloric restriction, which limits the efficiency of low-calorie diets. TH acquired a new role with the advent of homeothermy in evolution, which is to stimulate and sustain thermogenesis. In the absence of TH, homeothermic species regress to a nearly poikilothermic status. Therefore, understanding how thyroid hormone controls thermogenesis and energy balance is likely to provide valuable insight to understand the variability of energy expenditure in humans and eventually may provide clues to medical interventions, and this knowledge is relevant to obesity and type-2 diabetes, two major health problems of our time.

Our laboratory spent many years unraveling the interaction of TH and the sympathetic nervous system in the regulation of brown adipose tissue thermogenesis( (1) for review). This is facultative thermogenesis, turned on in response to ambient cold. In recent years, our laboratory has turned into understanding the mechanisms leading to enhanced basal thermogenesis in mammals and taken a more global view on body temperature homeostasis. We have resorted to transgenic mouse models with deletion of genes likely to be involved in the control of thermogenesis and temperature homeostasis (2). The current focus is on mice with deletion of one the TH receptors (TR), the TRa (3). These mice have lower body temperature and are cold intolerant. To compensate, they recruit another form of facultative 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 severer cold (e.g. 4-10°C), so these mice would die during winter if leaving in the wild. Another model we have started to study lacks the mitochondrial glycerol phosphate dehydrogenase (mGPD) (4,5). The mGPD-/- mice have modestly reduced basal thermogenesis in spite of an elevation of blood levels of TH, and are more prone to diet-induced obesity and lose less weight when calorie-restricted. Interesting females are much more affected than males, who compensate better the lack of the gene.

Representative publications:

1. Silva JE, Rabelo R. Regulation of the Uncoupling Protein Gene Expression.1997 Eur J Endocrinol ; 136(3):251-264.

2. Silva JE. Thermogenic Mechanisms and Their Hormonal Regulation.2006 Physiol Rev ; 86:435-464.

3. 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.2005 Endocrinology ; 146(7):2872-2884.

4. 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.2004 Am J Physiol Regul Integr Comp Physiol ; 287(1):R147-R156.

5. 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.2003 Endocrinology ; 144(12):5469-5479.