A Novel Specific Peroxisome Proliferator‐activated Receptor Γ (pparγ) Modulator YR4‐42 Ameliorates Hyperglycaemia and Dyslipidaemia and Hepatic Steatosis in Diet‐induced Obese Mice

Aims To evaluate a novel tetrahydroisoquinoline derivative YR4-42 as a selective peroxisome proliferator-activated receptor gamma (PPAR gamma) modulator (SPPARM) and explore its anti-diabetic effects in vitro and in vivo. Materials and methods Using two standard full PPAR gamma agonists rosiglitazone and pioglitazone as controls, the PPAR gamma binding affinity and transactivation action of YR4-42 were evaluated using biochemical and cell-based reporter gene assays. The capacity of YR4-42 to recruit coactivators of PPAR gamma was also assessed. The effects of YR4-42 on adipogenesis and glucose consumption and PPAR gamma Ser273 phosphorylation were investigated in 3T3-L1 adipocytes. The effects of YR4-42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high-fat diet-induced obese (DIO) C57BL/6J mice. The expression of PPAR gamma target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo. Results In vitro biochemical and cell-based functional assays showed that YR4-42 has much weaker binding affinity, transactivation, and recruitment to PPAR gamma of the coactivators thyroid hormone receptor-associated protein complex 220 kDa component (TRAP220) and PPAR gamma coactivator 1-alpha (PGC1 alpha) compared to full agonists. In 3 T3-L1 adipocytes, YR4-42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor alpha-mediated phosphorylation of PPAR gamma at Ser273, thereby upregulating the expression of the PPAR gamma Ser273 phosphorylation-dependent genes. Furthermore, in DIO mice, oral administration of YR4-42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4-42 also improved hyperlipidaemia-associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4-42 appeared to selectively modulate PPAR gamma responses. This finding was supported by the gene expression analysis, which showed that YR4-42 selectively targets PPAR gamma-regulated genes mapped to glucose and lipid metabolism in DIO mice. Conclusions We conclude that YR4-42 is a novel anti-diabetic drug candidate with significant advantages compared to standard PPAR gamma agonists. YR4-42 should be further investigated in preclinical and clinical studies.