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.

中文翻译：

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左旋甲状腺素和非经典甲状腺激素TETRAC是PPARγ的有效激活剂。

甲状腺激素（THs）通过调节甲状腺甲状腺激素受体和其他几种蛋白质来执行许多生理过程。我们报告的核过氧化物酶体增殖物激活受体γ（PPARγ）和类维生素A X受体（RXR）的直接激活由经典和非经典THs作为THs的另一种分子活性。T4代谢物TETRAC是PPARγ上活性最强的TH，具有纳摩尔效价和结合亲和力。我们证明，TETRAC可以在无细胞，细胞和体内促进PPARγ/ RXR信号传导设置。异二聚体伴侣PPARγ和RXR的同时激活导致高二聚体激活功效。与作为PPARγ和RXR的已知天然配体的脂肪酸相比，TETRAC的分子结构显着不同，并且PPARγ-TETRAC复合物揭示了TH的独特结合方式。我们的观察结果表明，通过重叠的配体识别，TH和PPAR信号传导之间存在潜在联系，并可能对TH和PPAR药理学有影响。