3,5-Diiodo-L-thyronine (3,5-T2) vs GW-0742

Metabolic

Metabolic

Research Only

Research Only

3,5-T2 acts largely independently of classical nuclear thyroid hormone receptor (THRβ) genomic signaling, with substantially lower THRβ affinity than T3. The primary mechanism is direct, non-genomic action at mitochondria: 3,5-T2 binds cytochrome-c oxidase subunit Va and abolishes the allosteric inhibition of respiration by ATP, rapidly increasing oxygen consumption. In rodent studies, it activates the AMPK–ACC–malonyl-CoA signaling pathway, increasing mitochondrial fatty-acid oxidation and redirecting lipid partitioning toward oxidation.

GW-0742 is a high-affinity, highly selective agonist of human PPARδ (EC50 = 1.1 nM for hPPARδ transactivation vs ~1.1 µM for hPPARα and ~2 µM for hPPARγ), conferring ~1000-fold selectivity for PPARδ over the other PPAR subtypes. Upon activation, PPARδ heterodimerizes with RXR and binds PPAR-response elements (PPREs) to alter transcription of genes governing fatty-acid oxidation, glucose utilization, and inflammatory signaling. In mice, however, GW-0742-induced hepatomegaly, hepatic/skeletal-muscle peroxisome proliferation, and skeletal myopathy were shown to be predominantly mediated by off-target PPARα cross-activation rather than PPARδ—a mechanism-based toxicity concern at animal-study exposures.