title: N-Acetylfarnesylcysteine is a novel class of peroxisome proliferator-activated receptor γ ligand with partial and full agonist activity in vitro and in vivo.
abstract: The thiazolidedione (TZD) class of drugs is clinically approved for the treatment of type 2 diabetes. The therapeutic actions of TZDs are mediated via activation of peroxisome proliferator-activated receptor γ (PPARγ). Despite their widespread use, concern exists regarding the safety of currently used TZDs. This has prompted the development of selective PPARγ modulators (SPPARMs), compounds that promote glucose homeostasis but with reduced side effects due to partial PPARγ agonism. However, this also results in partial agonism with respect to PPARγ target genes promoting glucose homeostasis. Using a gene expression-based screening approach we identified N-acetylfarnesylcysteine (AFC) as both a full and partial agonist depending on the PPARγ target gene (differential SPPARM). AFC activated PPARγ as effectively as rosiglitazone with regard to Adrp, Angptl4, and AdipoQ, but was a partial agonist of aP2, a PPARγ target gene associated with increased adiposity. Induction of adipogenesis by AFC was also attenuated compared with rosiglitazone. Reporter, ligand binding assays, and dynamic modeling demonstrate that AFC binds and activates PPARγ in a unique manner compared with other PPARγ ligands. Importantly, treatment of mice with AFC improved glucose tolerance similar to rosiglitazone, but AFC did not promote weight gain to the same extent. Finally, AFC had effects on adipose tissue remodeling similar to those of rosiglitazone and had enhanced antiinflammatory effects. In conclusion, we describe a new approach for the identification of differential SPPARMs and have identified AFC as a novel class of PPARγ ligand with both full and partial agonist activity in vitro and in vivo.
authors: Marlene and Stewart Greenebaum Cancer Center, Harvard University Medical School, Boston, Massachusetts 02215.
authors: Kavita
authors: K
authors: Bhalla
authors: Department of Biochemistry and Molecular Biology, Harvard University Medical School, Boston, Massachusetts 02215.
authors: Bor Jang
authors: BJ
authors: Hwang
authors: Dana-Farber Cancer Institute, Harvard University Medical School, Boston, Massachusetts 02215.
authors: Jang Hyun
authors: JH
authors: Choi
authors: Marlene and Stewart Greenebaum Cancer Center, Harvard University Medical School, Boston, Massachusetts 02215.
authors: Ruby
authors: R
authors: Dewi
authors: Marlene and Stewart Greenebaum Cancer Center, Harvard University Medical School, Boston, Massachusetts 02215.
authors: Lihui
authors: L
authors: Ou
authors: Department of Endocrinology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: John
authors: J
authors: Mclenithan
authors: Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: William
authors: W
authors: Twaddel
authors: Department of Pharmaceutical Sciences, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors: Edwin
authors: E
authors: Pozharski
authors: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08554.
authors: Jeffry
authors: J
authors: Stock
authors: Marlene and Stewart Greenebaum Cancer Center, Harvard University Medical School, Boston, Massachusetts 02215; Department of Biochemistry and Molecular Biology, Harvard University Medical School, Boston, Massachusetts 02215. Electronic address: ggirnun@som.umaryland.edu.
authors: Geoffrey D
authors: GD
authors: Girnun
mesh_terms: D041721:3T3-L1 Cells; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011485:Protein Binding; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D007004:Hypoglycemic Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D005947:Glucose; D003545:Cysteine; C068268:N-acetyl-S-farnesylcysteine; D000111:Acetylcysteine