A novel specific peroxisome proliferator-activated receptor ? (PPAR?) modulator YR4-42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet-induced obese mice.

ABSTRACT: AIMS:To evaluate a novel tetrahydroisoquinoline derivative YR4-42 as a selective peroxisome proliferator-activated receptor ? (PPAR?) modulator (SPPARM) and explore its anti-diabetic effects in vitro and in vivo. MATERIALS AND METHODS:Using two standard full PPAR? agonists rosiglitazone and pioglitazone as controls, the PPAR? 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? was also assessed. The effects of YR4-42 on adipogenesis and glucose consumption and PPAR? 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? 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? of the coactivators thyroid hormone receptor-associated protein complex 220?kDa component (TRAP220) and PPAR? coactivator 1-? (PGC1?) compared to full agonists. In 3 T3-L1 adipocytes, YR4-42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor ?-mediated phosphorylation of PPAR? at Ser273, thereby upregulating the expression of the PPAR? 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? responses. This finding was supported by the gene expression analysis, which showed that YR4-42 selectively targets PPAR?-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? agonists. YR4-42 should be further investigated in preclinical and clinical studies.

SUBMITTER: Huan Y 

PROVIDER: S-EPMC6851555 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature