A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in Skeletal Muscle Cells via AMPK-Dependent Signaling

Introduction: Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are highly effective in treating insulin resistance. However, associated side effects such as weight gain due to increase in adipogenesis and lipogenesis hinder their clinical use. The aim of the study was to design and synthesize novel partial PPAR gamma agonists with weaker lipogenic effect in adipocytes and enhanced glucose transporter 4 (GLUT4) translocation stimulatory effect in skeletal muscle cells. Methods: Novel partial PPAR gamma agonists (GS1, GS2, and GS3) were designed and screened to predict their binding interactions with PPAR gamma by molecular docking. The stability of the docked ligand-PPAR gamma complex was studied by molecular dynamics (MD) simulation. The cytotoxicity of synthesized compounds was tested in 3T3-L1 adipocytes and L6 myoblasts by MTT assay. The lipogenic effect was investigated in 3T3-L1 adipocytes using oil red O staining and GLUT4 translocation stimulatory effect in L6-GLUT4myc myotubes by an antibody-coupled colorimetric assay. Results: The molecular docking showed the binding interactions between designed agonists and PPAR gamma. MD simulation demonstrated good stability between the GS2-PPAR gamma complex. GS2 and GS3 did not show any significant effect on cell viability up to 80 or 100 mu M concentration. Pioglitazone treatment significantly increased intracellular lipid accumulation in adipocytes compared to control. However, this effect was significantly less in GS2- and GS3-treated conditions compared to pioglitazone at 10 mu M concentration, indicating weaker lipogenic effect. Furthermore, GS2 significantly stimulated GLUT4 translocation to the plasma membrane in a dose-dependent manner via the AMPK-dependent signaling pathway in skeletal muscle cells. Conclusion: GS2 may be a promising therapeutic agent for the treatment of insulin resistance and type 2 diabetes mellitus without adiposity.

Automated summary

The study designed and synthesized a novel partial PPAR gamma agonist GS2, which showed weaker lipogenic effect in cell experiments and enhanced GLUT4 translocation stimulatory effect in skeletal muscle cells. GS2 may serve as a promising therapeutic agent for the treatment of insulin resistance and type 2 diabetes mellitus without adiposity.