Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo

Abstract

<p id="d10044991e592">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. </p><p class="first" id="d10044991e595">Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding–defective TRβ leads to disruption of the hypothalamic–pituitary–thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level. </p>