Thermogenic Mechanisms and Their Hormonal Regulation

Abstract

Increased heat generation from biological processes is inherent to homeothermy. Homeothermic species produce more heat from sustaining a more active metabolism as well as from reducing fuel efficiency. This article reviews the mechanisms used by homeothermic species to generate more heat and their regulation largely by thyroid hormone (TH) and the sympathetic nervous system (SNS). Thermogenic mechanisms antecede homeothermy, but in homeothermic species they are activated and regulated. Some of these mechanisms increase ATP utilization (same amount of heat per ATP), whereas others increase the heat resulting from aerobic ATP synthesis (more heat per ATP). Among the former, ATP utilization in the maintenance of ionic gradient through membranes seems quantitatively more important, particularly in birds. Regulated reduction of the proton-motive force to produce heat, originally believed specific to brown adipose tissue, is indeed an ancient thermogenic mechanism. A regulated proton leak has been described in the mitochondria of several tissues, but its precise mechanism remains undefined. This leak is more active in homeothermic species and is regulated by TH, explaining a significant fraction of its thermogenic effect. Homeothermic species generate additional heat, in a facultative manner, when obligatory thermogenesis and heat-saving mechanisms become limiting. Facultative thermogenesis is activated by the SNS but is modulated by TH. The type II iodothyronine deiodinase plays a critical role in modulating the amount of the active TH, T(3), in BAT, thereby modulating the responses to SNS. Other hormones affect thermogenesis in an indirect or permissive manner, providing fuel and modulating thermogenesis depending on food availability, but they do not seem to have a primary role in temperature homeostasis. Thermogenesis has a very high energy cost. Cold adaptation and food availability may have been conflicting selection pressures accounting for the variability of thermogenesis in humans.

Thermoneutrality, Mice, and Cancer: A Heated Opinion

“…Thyroid hormone also plays a crucial role in adaptive thermogenesis. The full thermogenic response of BAT requires ligation of nuclear thyroid hormone receptors (transcription factors) which increases the sensitivity of BAT cells to adrenergic stimulation allowing UCP-1 expression [16,17].…”

“…Thyroid hormone also plays a crucial role in adaptive thermogenesis. The full thermogenic response of BAT requires ligation of nuclear thyroid hormone receptors (transcription factors) which increases the sensitivity of BAT cells to adrenergic stimulation allowing UCP-1 expression [16,17].While it is obvious that mice have a very large body surface area to volume ratio compared to humans, it is not generally realized that this results in rapid heat loss to their environment whenever ambient temperature falls below thermoneutrality. In addition, because of their small size, mice cannot bear enough fur or fat insulation to prevent heat loss to their environment.…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…The classical theory of thyroid hormone regulation of metabolism is that T4 is activated in the peripheral tissues such as muscle or liver, thus stimulating energy expenditure through mitochondrial uncoupling or acceleration of the turnover of ATP-utilizing enzymes (55). A recent study suggests that there may be a direct effect of T3 to inhibit AMP kinase in the ventro-medial hypothalamus leading to upregulation of de novo lipogenesis in the hypothalamus.…”

Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions

“…Conversely, hypothyroid patients often suffer from weight gain and bradycardia (3). While most of the cardiovascular and metabolic effects of thyroid hormone have been attributed to direct actions in the corresponding peripheral tissues, such as heart (4) or skeletal muscle and fat (5,6), recent studies have demonstrated that the hormone modulates these processes also through the brain (7): injections of thyroid hormone into different brain regions stimulate energy expenditure (8), and thyroid hormone signaling is required to establish the metabolic set point during embryonal development (9,10).…”