KMUP-1, a GPCR Modulator, Attenuates Triglyceride Accumulation Involved MAPKs/Akt/PPARγ and PKA/PKG/HSL Signaling in 3T3-L1 Preadipocytes

Molecules. 2018 Sep 23;23(10):2433. doi: 10.3390/molecules23102433.


Xanthine-based KMUP-1 was shown to inhibit phosphodiesterases (PDEs) and modulate G-protein coupled receptors (GPCRs) to lower hyperlipidemia and body weight. This study further investigated whether KMUP-1 affects adipogenesis and lipolysis in 3T3-L1 preadipocytes. KMUP-1 (1⁻40 µM) concentration-dependently attenuated Oil Red O (ORO) staining and decreased triglyceride (TG) accumulation, indicating adipogenesis inhibition in 3T3-L1 cells. In contrast, the β-agonist ractopamine increased ORO staining and TG accumulation and adipogenesis. KMUP-1 (1⁻40 µM) also reduced MAPKs/Akt/PPARγ expression, PPARγ1/PPARγ2 mRNA, and p-ERK immunoreactivity at the adipogenesis stage, but enhanced hormone sensitive lipase (HSL) immunoreactivity at the lipolysis stage. Addition of protein kinase A (PKA) or protein kinase G (PKG) antagonist (KT5720 or KT5728) to adipocytes did not affect HSL immunoreactivity. However, KMUP-1 did increase HSL immunoreactivity and the effect was reduced by PKA or PKG antagonist. Simvastatin, theophylline, caffeine, and sildenafil, like KMUP-1, also enhanced HSL immunoreactivity. Phosphorylated HSL (p-HSL) was enhanced by KMUP-1, indicating increased lipolysis in mature 3T3-L1 adipocytes. Decreases of MAPKs/Akt/PPARγ during adipogenesis contributed to inhibition of adipocyte differentiation, and increases of PKA/PKG at lipolysis contributed to HSL activation and TG hydrolysis. Taken together, the data suggest that KMUP-1 can inhibit hyperadiposity in 3T3-L1 adipocytes.

Keywords: MAPK; PPARγ; adipogensis; lipolysis; phosphorylated HSL; protein kinases.

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipogenesis / drug effects*
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Lipolysis / drug effects
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Piperidines / pharmacology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects*
  • Sterol Esterase / metabolism
  • Triglycerides / metabolism*
  • Xanthines / pharmacology*


  • PPAR gamma
  • Piperidines
  • Triglycerides
  • Xanthines
  • KMUP 1
  • Proto-Oncogene Proteins c-akt
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Sterol Esterase