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Type 2 diabetes mellitus (T2DM) is a pervasive metabolic syndrome that is characterized by insulin resistance, hyperglycemia and dyslipidemia. As full agonists of PPARγ, thiazolidinedione (TZD) drugs elicit antidiabetic effects by targeting PPARγ but is accompanied by weight gain, fluid retention and cardiovascular risk associated with their transcriptional agonism potency. We here identify a natural product chelerythrine as a unique selective PPAR modulator (SPPARM) with a potent PPARγ binding activity but much less classical receptor transcriptional agonism. Structural analysis reveals that chelerythrine exhibits unique binding in parallel with H3 of PPARγ. Unlike TZDs, chelerythrine destabilizes helix 12, especially residue tyrosine 473, resulting in a loose configuration of AF-2 and a selective cofactor profile distinct from TZDs, leading to a differential target gene profile in adipogenesis in db/db diabetic mice …