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A Novel Partial PPARγ Agonist Has Weaker Lipogenic Effect in Adipocytes and Stimulates GLUT4 Translocation in

Bhavimani Guru1, Akhilesh K Tamrakar2, Subhankar P Mandal3

  • 1Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India.

Pharmacology
|November 4, 2021
PubMed
Abstract

Insights

New partial peroxisome proliferator-activated receptor gamma (PPARγ) agonists were developed. Compound GS2 shows reduced fat accumulation and enhanced glucose uptake, offering a potential treatment for insulin resistance without weight gain.

Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Molecular Biology

Background:

  • Peroxisome proliferator-activated receptor gamma (PPARγ) agonists effectively treat insulin resistance.
  • However, clinical use is limited by side effects like weight gain due to increased adipogenesis and lipogenesis.

Purpose of the Study:

  • To design and synthesize novel partial PPARγ agonists.
  • To develop compounds with reduced lipogenic effects in adipocytes and improved glucose transporter 4 (GLUT4) translocation in skeletal muscle cells.

Main Methods:

  • Novel partial PPARγ agonists (GS1, GS2, GS3) were designed and screened using molecular docking and dynamics simulations.
  • Cytotoxicity, lipogenic effects in 3T3-L1 adipocytes, and GLUT4 translocation in L6 myotubes were assessed.

Main Results:

  • Molecular docking and MD simulations confirmed interactions and stability of the GS2-PPARγ complex.
  • GS2 and GS3 exhibited weaker lipogenic effects compared to pioglitazone.
  • GS2 significantly stimulated GLUT4 translocation in skeletal muscle cells via an AMPK-dependent pathway.

Conclusions:

  • GS2 demonstrates potential as a therapeutic agent for insulin resistance and type 2 diabetes.
  • It may offer benefits without the adverse effect of adiposity.
Keywords:
AMPKGLUT4 translocationInsulin resistanceLipogenesisPPARγ

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