A novel specific peroxisome proliferator‐activated receptor γ (PPARγ) modulator YR4‐42 ameliorates hyperglycaemia and dyslipidaemia and hepatic steatosis in diet‐induced obese mice

Abstract

AimsTo evaluate a novel tetrahydroisoquinoline derivative YR4‐42 as a selective peroxisome proliferator‐activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti‐diabetic effects in vitro and in vivo.Materials and methodsUsing two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ 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 PPARγ was also assessed. The effects of YR4‐42 on adipogenesis and glucose consumption and PPARγ 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 PPARγ 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 PPARγ of the coactivators thyroid hormone receptor‐associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1‐α (PGC1α) compared to full agonists. In 3 T3‐L1 adipocytes, YR4‐42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α‐mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ 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 PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4‐42 selectively targets PPARγ‐regulated genes mapped to glucose and lipid metabolism in DIO mice.ConclusionsWe conclude that YR4‐42 is a novel anti‐diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4‐42 should be further investigated in preclinical and clinical studies.

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

“…A new drug class, selective PPAR modulators (SPPARM), is now under development (e.g. INT-131 besylate [CHS-131 [17]], MK-0533 [18], YR4-42 [19]). Preclinical data have shown that SPPARM, compared with thiazolidinedione PPAR-γ full agonists, exert similar effects of glucose and lipid lowering at smaller doses but without causing weight gain and fluid retention, thus reducing side effects and serious safety concerns [18,19].…”

Caffeic and Chlorogenic Acids Synergistically Activate Browning Program in Human Adipocytes: Implications of AMPK- and PPAR-Mediated Pathways

“…Repressive PPARγ modulators acting as inverse agonists are suggested as promising therapeutic options in obesity management and are associated with enhancement in bone formation and improved WAT metabolic functions [ 9 , 48 , 59 , 60 ]. Furthermore, recent insights into the structural mechanisms of the PPARγ repressive function [ 48 ] permit better understanding of the interpretation of the interactions between chemical ligands and PPARγ protein.…”

Co-delivery of EGCG and lycopene via a pickering double emulsion induced synergistic hypolipidemic effect

“…PPARγ, the peroxisome proliferator activated receptor (PPAR), is one of the subtypes of PPAR as an important nuclear receptor in cells responsible to regulate glycolipid metabolism key transcription factors of metabolic related genes. 46 PPARγ has adipose tissue specificity and can be activated by fatty acids and exogenous peroxisome proliferators to regulate the expression of enzymes involved in lipid metabolism. PPARγ is induced before the transcriptional activation of many adipocyte genes and plays an important role in fat cell differentiation.…”