Thyroid hormone, thyromimetics, and metabolic efficiency

Thyroid hormone (TH) has long been recognized as a major modulator of metabolic efficiency, energy expenditure, and thermogenesis. TH effects in regulating metabolic efficiency are transduced by controlling the coupling of mitochondrial oxidative phosphorylation and the cycling of extramitochondrial substrate/futile cycles. However, despite our present understanding of the genomic and nongenomic modes of action of TH, its control of mitochondrial coupling still remains elusive. This review summarizes historical and up-to-date findings concerned with TH regulation of metabolic energetics, while integrating its genomic and mitochondrial activities. It underscores the role played by TH-induced gating of the mitochondrial permeability transition pore (PTP) in controlling metabolic efficiency. PTP gating may offer a unified target for some TH pleiotropic activities and may serve as a novel target for synthetic functional thyromimetics designed to modulate metabolic efficiency. PTP gating by long-chain fatty acid analogs may serve as a model for such strategy.