Uncoupling Proteins and the Molecular Mechanisms of Thyroid Thermogenesis

Homoeothermic species engage thermogenic components of cellular metabolism to both maintain and raise core body temperature (Tc) when exposed to cold, feeding, infection, and certain classes of drugs (sympathomimetics). Body heat production stems from two main thermogenic mechanisms: 1) obligatory thermogenesis, or the heat produced as a collective byproduct of the inefficiency of all cellular metabolic reactions, and 2) facultative thermogenesis (also referred to as adaptive or nonshivering thermogenesis [NST]), the additional heat generation required along with obligatory thermogenesis to rapidly increase body temperature. Thyroid hormone (TH) is the well-established principal endocrine regulator of both obligatory and facultative thermogenesis. Here we aim to provide a brief overview of the mechanisms by which TH regulates facultative thermogenesis and to highlight recent studies describing a role for TH in the regulation of thermogenic mitochondrial uncoupling proteins. For a broader overview of the role of the endocrine control of thermoregulation, we would refer readers to the excellent review by Silva (1). Facultative thermogenesis is controlled by both a temporary shivering (muscle contraction) component and by more sustained nonshivering mechanisms. NST is regulated primarily by both the circulating levels of TH and the acute activity of the sympathetic nervous system (SNS) and mainly occurs in brown adipose tissue (BAT) and skeletal muscle (2). The primary role of TH in NST regulation is a permissive one; it chronically sets the capacity of thermogenic and metabolic responses to SNS stimulation through its transcriptional regulation of a vast repertoire of metabolic genes (3–5). In contrast, the SNS mainly controls the acute activity of thermogenic signaling pathways culminating in the activation of heat-generating proteins downstream of -adrenergic receptors (6, 7). Owing to the fundamental importance of TH in human thermoregulation, hyperand hypothyroid patients are heat and cold intolerant, respectively (8). Similarly, hypothyroid animal models demonstrate that the TH is absolutely required for a normal thermogenic response to both cold and sympathomimetic stimulation (9). TH is synthesized in the thyroid gland and controlled by thyroid peroxidase activity that regulates the iodination, coupling, and ultimately proteolysis of tyrosine residues on thyroglobulin to release the THs, T4 and T3, into the bloodstream (10). The lesser active T4 is released from the thyroid gland at higher concentrations than the more active T3 and is locally converted to T3 in target tissues by the actions of tissue-specific deiodinases (11–13). Two genes, THRA and THRB, are responsible for the expression of distinct thyroid hormone receptors (TRs), each of which are alternatively spliced to produce multiple isoforms, TR 1, TR 2, TR 1, and TR 2, respectively (14–16). With the exception of TR 2, which does not bind T3 and functions to repress T3 actions, TR isoforms mediate distinct functions (both stimulatory and repressive) in response to and in the absence of T3 (2). Integral to their functions as transcriptional regulators, TRs bind other nuclear hormone receptors, coactivators, and corepressors, the details of which have been reviewed elsewhere (2). In addition to its transcriptional regulation, recent work has also revealed that TH may regulate cell signaling