Thyroid hormones and metabolic flexibility: tissue-specific control of energy homeostasis.

Thyroid Hormones (THs) are central regulators of energy metabolism, traditionally viewed as key determinants of Basal Metabolic Rate (BMR) and whole-body energy expenditure. Beyond their classical systemic effects, it is now evident that TH action is critically shaped by tissue-specific mechanisms that regulate intracellular hormone availability and signaling. These processes enable a fine-tuned and physiological state-specific control of metabolic activity. In this review, we synthesize current knowledge on the role of THs in energy homeostasis, with a particular focus on the mechanisms that govern local triiodothyronine (T3) signaling. We discuss how the integration of hormone transport, intracellular activation and inactivation by Deiodinases, and receptor-mediated transcriptional responses determine the intensity and timing of TH action in the target tissues. This spatiotemporal regulation supports metabolic flexibility, enabling coordinated control of substrate utilization, mitochondrial function, and energy expenditure under diverse physiological conditions. We further examine how TH signaling is modulated in response to key metabolic challenges, including physical exercise, changes in body weight and adiposity, and circadian rhythms. During exercise, local activation of TH signaling, particularly through type 2 Deiodinase (D2), facilitates mitochondrial adaptation, muscle remodeling, and improved metabolic efficiency. In the context of obesity, interactions between THs and adipose-derived signals such as leptin influence both central and peripheral pathways controlling energy balance, although these mechanisms may become impaired in leptin-resistant states. In parallel, circadian regulation of the Hypothalamic-Pituitary-Thyroid (HPT) axis and peripheral TH metabolism introduces an additional temporal dimension to metabolic control, allowing local tuning of TH action across the day. By integrating molecular, physiological, and systemic perspectives, this review highlights the concept of THs as context-dependent modulators of metabolic flexibility and underscores their potential as targets for interventions in metabolic disorders.