The thermogenic effect of thyroid hormone and its clinical implications.

Clinical Principles There is a popular belief, even among physicians, that weight changes are frequent manifestations of thyroid dysfunction. Thyrotoxicosis is usually associated with weight loss and heat intolerance. Cold intolerance, but not weight gain, is a prominent feature of hypothyroidism. Pathophysiologic Principles Thyroid hormones increase heat production only in homeothermic species. Thermogenesis is energy dissipation as heat. The thermogenic effect of thyroid hormones is closely linked to increased appetite and lipogenesis to ensure fuel availability and avoid wasting. Major thermogenic mechanisms include increased turnover of adenosine triphosphate (ATP) and programmed reduction in the efficiency of ATP synthesis. Reduced efficiency in ATP synthesis is relatively more important than increased ATP turnover in the transition from hypothyroidism to euthyroidism. Clinicians are very familiar with cold or heat intolerance in patients with altered thyroid function. While nonspecific, these symptoms have some predictive value in the diagnosis of thyroid dysfunction. Involuntary changes in weight are also perceived as indicators of abnormal thyroid function, often prompting laboratory testing of thyroid gland function. Most of the clinical manifestations of thyroid dysfunction in adults are directly or indirectly derived from the stimulating effect of thyroid hormone on thermogenesis and energy turnover. Even so, the relationship between these effects and energy balance and body weight is not simple. This review examines the thermogenic effect of thyroid hormone and how it affects some of the manifestations of hypo- and hyperthyroidism, energy balance, and body weight. Basic Definitions of Homeothermy and Poikilothermy Evolutionary development of homeothermy was an important biological advance because it allowed animal life to expand into environments with temperatures markedly different from those of the body. Tight control of body temperature homeostasis required the selection of several different mechanisms in the course of evolution that are activated whenever the body's basal heat production is insufficient or excessive. This maintains the core temperature at its setting. Reflecting the fact that the habitat is usually colder than the body, a mainstay of homeothermy is the inherent capacity of homeothermic species to constantly generate more heat than poikilothermic animals. Heat production, or thermogenesis, is customarily divided into two types: obligatory and facultative. Obligatory thermogenesis can be viewed as the constitutive heat production of homeothermic species (Figure 1). Obligatory thermogenesis is well reflected in the so-called basal metabolic rate or the less strict but more practical resting energy expenditure, which are measured under conditions that eliminate the energy cost of physical activity, emotional distress, temperature adaptation, and food processing. Two components can be distinguished in obligatory thermogenesis. As machines involved in energy transformations, and as a result of the fundamental laws of thermodynamics, living organisms generate some heat. This is the heat derived from the minimal energy cost of living and is not sufficient to maintain body temperature in cold environments. Homeothermic species need to produce more heat than poikilotherms, and they do so. When it results from basal metabolic activity, this excess heat is known as basal thermogenesis. Figure 1. The various forms of thermogenesis in homeothermic species. As illustrated in Figure 1, basal thermogenesis is independent of ambient temperature. Two differences between homeothermic and poikilothermic machines explain basal thermogenesis. First, homeothermic species have a more active metabolism, that is, they sustain a higher number of energy transactions per unit of time (1). Second, a larger fraction of energy involved in these transactions is dissipated as heat, that is, the homeothermic machine has a lower thermodynamic efficiency. For example, for the same amount of mechanical work, the mammalian muscle generates more heat than its reptilian or amphibian counterpart (2). If obligatory thermogenesis becomes insufficient to maintain body temperature, the body activates heat-conserving mechanisms (cutaneous vasoconstriction, piloerection) and recruits additional thermogenic mechanisms. These latter mechanisms constitute what is called adaptive thermogenesis. Skeletal muscle shivering is the most immediate thermogenic response to a cold environment. If cold is sustained, this form of adaptive thermogenesis is rapidly replaced by so-called nonshivering facultative thermogenesis, or simply facultative thermogenesis. Facultative thermogenesis is in essence extra heat, produced on demand from the metabolic activity in certain tissues (for example, brown adipose tissue, skeletal muscle). Facultative thermogenesis of brown adipose tissue is stimulated by the sympathetic nervous system (by mechanisms explained later), which is activated in the hypothalamus in response to signals originating from temperature sensors in the skin. The magnitude of facultative thermogenesis increases steeply as the environment turns colder (Figure 1). On the other hand, as ambient temperature becomes warmer, a point is reached at which obligatory thermogenesis is sufficient to maintain body temperature without facultative thermogenesis or ancillary heat-conserving or heat-dissipating mechanisms. This is called thermoneutrality temperature (Figure 1). It follows from this concept that the lower obligatory thermogenesis is, the higher thermoneutrality temperature will be, while if obligatory thermogenesis is high, colder environments will be needed to activate facultative thermogenesis. Thus, by having higher basal thermogenesis and hence higher obligatory thermogenesis, homeothermic species could stay in environments much colder than the body temperature without needing to activate thermoregulatory mechanisms to maintain their core temperature. Size, which affects the body surface area-to-volume ratio, also helps determine thermoneutrality temperature. Thus, while thermoneutrality temperature is 23 C in an adult man, it is 28 C in rats. Likewise, human newborns and infants have higher thermoneutrality temperatures than adults, which explains why brown adipose tissue is so important for temperature homeostasis at this age. Smaller size and immaturity of thermoregulatory mechanisms explain why risk for hypothermia is higher in premature babies than in full-term newborns (3). In addition to being activated by cold, facultative thermogenesis can be activated by food, providing a mechanism to dissipate excess calories. Dumping excess food calories as heat may be a later acquisition in evolution. Thyroid Hormone Acquires a New Role with the Advent of Homeothermy Strong evidence supports an essential role for thyroid hormone in the thermogenesis of warm-blooded species. It has been proposed that the greater thermogenic capacity of the homeothermic biological machine is the result of more active thyroid glands than those in poikilothermic species (4). However, as discussed later, the difference is more qualitative than quantitative (5). The thyroid gland is present in all vertebrates, and thyroid hormone receptors are found in species as primitive as the sea lamprey (6). Throughout the vertebrate spectrum, thyroid hormone plays an essential role in coordinating development and specific cell functions. However, only in homeothermic species does it acquire a role in metabolic regulation. Only in these species can thyroid hormone increase oxygen consumption and stimulate the activity of certain enzymes involved in metabolic regulation (6). The effect of thyroid hormone on basal metabolic rate was recognized more than a century ago (7). In the complete absence of thyroid hormone, basal metabolic rate or resting energy expenditure could be reduced by 30% or more, a change associated with markedly reduced cold tolerance. This indicates that as much as 30% of obligatory thermogenesis depends on thyroid hormone and that this fraction of obligatory thermogenesis is essential for temperature homeostasis. In addition, thyroid hormone is important for facultative thermogenesis; in the absence of this hormone, the thermogenic response of brown adipose tissue, the major site of facultative thermogenesis in mammals, is substantially reduced (8, 9). The reduced obligatory thermogenesis in hypothyroidism is partially compensated by cutaneous vasoconstriction (10, 11), which is perceived as cold and causes increased sympathetic stimulation of brown adipose tissue. Yet, despite showing signs of increased sympathetic stimulation in chronically hypothyroid rats (12), brown adipose tissue fails to produce sufficient heat to maintain body temperature, so that hypothyroid animals rapidly develop hypothermia in cold environments (9). Another evidence of the importance of thyroid hormone for thermogenic function of brown adipose tissue is the abundant presence of type II 5 iodothyronine deiodinase (D2). This enzyme is stimulated by the sympathetic nervous system when brown adipose tissue thermogenesis is needed, increasing the intracellular concentration of triiodothyronine (T3) to receptor-saturating levels. These high levels of T3 are needed to realize the thermogenic potential of brown adipose tissue (9, 13). In addition, D2 activity is increased in hypothyroxinemia. This, along with the increased sympathetic stimulation of brown adipose tissue in hypothyroidism, protect the brown adipose tissue T3 content in hypothyroidism, which must be severe to deplete brown adipose tissue of T3 (14). Together, this clinical and experimental evidence supports an essential role for thyroid hormone in both obligatory thermogenesis and facultative thermogenesis. However, two major questions remain unanswered: 1) How did thyroid hormone acquire this thermogenic role du