l-Thyroxin and the Nonclassical Thyroid Hormone TETRAC are Potent Activators of PPARg

Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation of the nuclear peroxisome proliferator-activated receptor gamma (PPARg) and retinoid X receptor (RXR) by classical and nonclassical THs as another molecular activity of THs. The T4 metabolite TETRAC was the most active TH on PPARg with nanomolar potency and binding affinity. We demonstrate that TETRAC promotes PPARg/RXR signaling in cell-free, cellular, and in vivo settings. Simultaneous activation of the heterodimer partners PPARg and RXR resulted in high dimer activation efficacy. Compared to fatty acids as known natural ligands of PPARg and RXR, TETRAC differs markedly in its molecular structure and the PPARg-TETRAC complex revealed a distinctive binding mode of the TH. Our observations suggest a potential connection of TH and PPAR signaling through overlapping ligand recognition and may hold implications for TH and PPAR pharmacology.