Printed by Introduction Conclusion Acknowledgements The Authors wish to thank Mark Proefke Manager Analytical Sciences and Amway.

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printed by Introduction Conclusion Acknowledgements The Authors wish to thank Mark Proefke Manager Analytical Sciences and Amway R&D for providing support for this research Glabridin modulates some PPARG responsive genes and not others Fatty Acid Binding Protein 1 (FABP1) is not activated by Glabridin in HepG2 cells Phosphoenolcarboxykinase 1 (PEPCK1, PCK1) is activated by Glabridin in HepG2 cells 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2) is inhibited by Glabridin in HepG2 cells Licorice Root Extract activates PPARG MODULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARG) BY GLYCYRRHIZA GLABRA John F Rebhun*, Kelly Glynn, Jeffrey D Scholten, Yingqin Li, and Stephen R Missler Amway Corporation, Ada MI Discovery process to screen thousands of botanical extracts to identify active plants and their phytochemicals Cell-based screens for PPARG and PPARA activation Describe a potential metabolic function of Glycyrrhiza glabra (Licorice root) as an insulin sensitizing botanical. PPARG and PPARA activators are known to modulate energy metabolism, glucose and lipid utilization. Figure 1. Licorice Root Extract Activates Peroxidosme Proliferator-Activated Receptor Gamma (PPARG). A. Methanol, chloroform or a mixed (1:1; ethanol:chloroform) extract of Licorice Root at 50 ug/ml were screened in PPARG or PPARA assays. The methanol extract was dose titrated in PPARG (B) activation assay. Chinese Hamster Ovary (CHO) cells stably transfected with a luciferase construct under the control of 9XUAS and a Gal4-PPAR LBD were serum starved for 24 hrs and treated for 18 hrs with Licorice root extracts. Data points represent mean values + Standard Deviations. Experiment was repeated 3 times Glabridin containing Fraction aligns with PPARG Activity LC-MS PPARG Glabridin Glabrene Glycyrrhizin Figure 2. Glabridin Containing Fraction Activates Peroxisome Proliferator-Activated Receptor Gamma (PPARG). Methanol extract was solubilized in 50% methanol to 50 mg/ml and fractionated using Reverse Phase HPLC. Fractions were tested for PPARG Activity. Red line represents MS/MS trace. Blue boxes represent PPARG activity. Glabridin Activates PPARG and is Inhibited by PPARG Antagonist, T Glabridin competes with Agonist for PPARG Ligand Binding Domain Figure 3. Purified Glabridin Activates Peroxisome Proliferator-Activated Receptor Gamma (PPARG). Glabridin activates PPARG in a dose dependent manner (A) and has little effect on PPARA (B). Glabridin activation of PPARG is antagonized by a specific PPARG inhibitor, T (C) and glabridin’s slight activation of PPARA is not affected by T (D). Figure 4. Glabridin Displaced Fluoromone™ binding to isolated PPARG Ligand Binding Domain (LBD). Lantha- Screen® (Invitrogen) was used to assess Glabridin and Glycyrrhizin binding to isolated PPARG LBD. Antagonist and Agonists were added to a terbidium labelled PPARG-LBD in the presence of Fluoromone™ a fluorescent Pan-PPARG ligand. Changes of Fluoromone™/LBD binding were assessed by 518 nm/488 nm time-resolved fluorescence resonance energy transfer (TR-FRET). Data points represent mean values + Standard Deviations. Experiment was repeated 2 times with similar results. Glabridin activates full length PPARG receptor in HepG2 Cells Figure 5. Glabridin Activates Full-length Peroxisome Proliferator-Activated Receptor (PPARG) and is Inhibited by T HepG2 cells were transfected with a full length PPARG receptor construct under the control of CMV and a luciferase reporter construct under the control of a 4X PPAR Response element. Cells were treated as described above. Data points represent mean values (triplicate responses) + Standard Deviations. Experiment was repeated 3 times with similar results. Figure 6. Glabridin Modulates Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Genes. HepG2 cells were treated with known agonist, Troglitazone, and Glabridin in the absence or presence of a known antagonist T for 24 hrs. Quantitative PCR was completed using gene-specific primer sets for PCK1, FABP1 and HMGCS2 to assess mRNA levels. Glabridin a phytochemical in Glycyrrhiza glabra appears to modulate PPARG activity by direct receptor interaction as well as through other signaling pathways to affect PPARG. Direct and indirect action of Glycyrrhiza glabra on PPARG activation may explain some of it’s insulin sensitization activity in vivo.