Noncanonical Thyroid Hormone Signaling Mediates Cardiometabolic Effects in Vivo.

Significance This study changes our understanding of how thyroid hormone acts. Thyroid hormone receptors are considered typical nuclear receptors that bind to DNA and, after binding, alter the expression of their target genes and regulate physiological responses. Nevertheless, we show that thyroid hormone still mediates important physiological effects in mice expressing mutant receptors that cannot bind DNA. These are predominantly linked to energy metabolism and include glucose and triglyceride concentrations, body temperature, locomotor activity, and heart rate. This study provides in vivo evidence that thyroid hormone receptors mediate physiologically relevant effects that are independent of DNA binding and direct activation of gene expression.