Thyroid Hormone Action and Energy Expenditure

1. Energy Expenditure: Definition and Components

In sedentary individuals, resting EE (REE) accounts for the majority (60% to 80%) of total EE (TEE) [10]. The term REE is often used interchangeably with BMR, and it is defined as the minimum amount of energy necessary to maintain the individual alive awake in a steady state of energy balance. Of interest, in dynamic states of energy balance such as prolonged fast, REE can decrease substantially [10]. Substrate oxidation (respiration) is required to maintain the basic functions of the organism, which include delivery of substrate and oxygen to the tissues, cellular structural integrity and functions, among them the maintenance of gradients between intracellular and extracellular compartments.

Voluntary physical activity, also called exercise activity–related thermogenesis (EAT), and non–exercise activity–related thermogenesis (NEAT), spontaneous fidgeting, are likely the most important modifiable variables in the TEE in most people and can vary significantly between individuals [11] and within the same subject on a day-to-day basis in relation to the physical activity [11].

An additional lesser-known component of EE is the thermic effect of food (alternatively defined as postprandial thermogenesis), which represents the energy loss following food intake above and beyond the requirements for absorption, storage, and digestion. The thermic effect of food is considered an energy metabolism homeostatic short loop directed to dissipate acute calorie loads, that generally ranges between 8% and 15% of energy intake, and the variance has been associated with nutrient composition and energy content of consumed foods [12].

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Finally, adaptive thermogenesis is defined as the energy dissipation required to maintain the core temperature when individuals are exposed to environmental temperatures below the thermoneutral zone, which is estimated to be 28°C in humans [13]. Adaptive thermogenesis is also subdivided in shivering thermogenesis, due to muscle fasciculation and involuntary contraction, and nonshivering thermogenesis, which results from direct conversion of chemical energy into heat, mostly by the shunting of the proton gradient in the mitochondrial membrane by the uncoupling protein-1 (UCP-1) predominantly expressed in brown and beige fat [14]. Adaptive thermogenesis was thought to be relevant only in small and hibernating mammals, but over the last decade, observational and intervention studies have demonstrated that adaptive thermogenesis can account for a substantial fraction of human TEE, up to 15% via nonshivering, and greater during intense shivering thermogenesis [15]. The components of EE and their relative contribution to TEE are shown in Fig. 1.

Remarkably, all of the components of TEE are modulated by TH (reviewed in detail by Vaitkus et al. [16]). Briefly, TH exerts a pervasive role on REE by directly regulating (and thus promoting ATP utilization) metabolic cycles such as the lipolysis/lipogenesis, glycogenolysis/gluconeogenesis, phosphofructokinase/fructose 1,6-diphosphatase, hexokinase/glucose-6-phosphatase, and protein synthesis and catabolism [17]. Additionally, TH action accelerates ion leaks across the cell membrane, most notably via the Na+/K+ ATPase, and sarcoendoplasmic calcium ATPase, requiring additional ATP consumption to maintain the ion gradients [18].

Moreover, the inotropic and chronotropic actions of TH on the myocardium are well described and account for a demonstrable change in oxygen consumption as a result of changes in the TH status, both in vitro and in vivo [19].

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TH action also has a remarkable modulatory effect on mitochondrial respiration by promoting mitochondrial biogenesis directly [20] and by stimulating the transcription of PGC-1α [21], which is considered the master regulator of aerobic respiration. Additionally, TH action has the ability of shunting the proton gradient in the inner membrane of the mitochondria, effectively diverting chemical energy into heat. Aside from UCP-1, TH decreases the efficiency of oxidative phosphorylation of the mitochondrial respiration by activating the mitochondrial permeability transition pore and by modulating the ADP/ATP translocase [22].

The exquisite local, tissue-specific modulation of the TH action resulting from the interaction of circulating levels of TH with local conversion of T4 into T3, its transport within the target cell, and the interaction with the receptor isoforms and transcription apparatus enables a remarkable variability of the TH signaling (and as a result a modulation of oxygen consumption) at a cellular level [23]. This is exemplified by the effects of cold exposure on brown adipose tissue (BAT) by which the activation of the β3-adrenergic pathway promotes a transient state of “cellular hyperthyroidism” driven by the action of the type 2 deiodinase, which in turn results in a local stimulation of transcription of UCP-1, and mitochondrial membrane permeability, ultimately promoting a dissociation between mitochondrial respiration and ATP production, generating an extremely efficient and timely generation of heat to maintain the core temperature [24]. At the cellular level, TH action is modulated by a group of enzymes containing selenoproteins. Among these three enzymes, type 1 and 2 deiodinase convert T4 (inactive or prohormone) to active TH T3, allowing local concentration changes and regulation of hormone action in certain tissues without showing considerable variation on serum levels. Type 2 deiodinase has a high affinity for T4 and is primarily found in brain, pituitary gland, thyroid, muscle, and brown fat and particularly important in the time- and tissue-specific regulation of TH action in thermogenesis.

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Collectively, TH action plays a critical role in the modulation of EE in vertebrates, and it has a unique role in the maintenance of core temperature in warm-blooded animals. These effects are mostly permissive, and in physiologic states, the local modulation of the hormonal signaling rather than changes in circulating levels of TH is responsible for the cellular specificity of TH on respiration and ultimately on EE.


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About the Author: Tung Chi