l‑Thyroxin and the Nonclassical Thyroid Hormone TETRAC Are Potent Activators of PPARγ

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 (PPARγ) 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
PPARγ with nanomolar potency and binding affinity. We demonstrate
that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular,
and in vivo settings. Simultaneous activation of
the heterodimer partners PPARγ and RXR resulted in high dimer
activation efficacy. Compared to fatty acids as known natural ligands
of PPARγ and RXR, TETRAC differs markedly in its molecular structure
and the PPARγ-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.