A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity

Mol Cell. 2001 Oct;8(4):737-47. doi: 10.1016/s1097-2765(01)00353-7.

Abstract

FMOC-L-Leucine (F-L-Leu) is a chemically distinct PPARgamma ligand. Two molecules of F-L-Leu bind to the ligand binding domain of a single PPARgamma molecule, making its mode of receptor interaction distinct from that of other nuclear receptor ligands. F-L-Leu induces a particular allosteric configuration of PPARgamma, resulting in differential cofactor recruitment and translating in distinct pharmacological properties. F-L-Leu activates PPARgamma with a lower potency, but a similar maximal efficacy, than rosiglitazone. The particular PPARgamma configuration induced by F-L-Leu leads to a modified pattern of target gene activation. F-L-Leu improves insulin sensitivity in normal, diet-induced glucose-intolerant, and in diabetic db/db mice, yet it has a lower adipogenic activity. These biological effects suggest that F-L-Leu is a selective PPARgamma modulator that activates some (insulin sensitization), but not all (adipogenesis), PPARgamma-signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / physiology*
  • Amino Acids / chemistry
  • Amino Acids / metabolism
  • Amino Acids / pharmacology*
  • Animals
  • Binding Sites
  • Blood Glucose / metabolism
  • Body Weight
  • Cell Differentiation
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fluorenes / chemistry
  • Fluorenes / metabolism
  • Fluorenes / pharmacology*
  • Gene Expression Regulation / physiology
  • Genes, Reporter
  • Hypoglycemic Agents / pharmacology
  • Insulin Resistance / physiology
  • Leucine / chemistry*
  • Leucine / metabolism
  • Ligands
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Rosiglitazone
  • Spectrometry, Mass, Electrospray Ionization
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptional Activation
  • Tyrosine / chemistry
  • Tyrosine / metabolism

Substances

  • Amino Acids
  • Blood Glucose
  • Fluorenes
  • Hypoglycemic Agents
  • Ligands
  • N(alpha)-fluorenylmethyloxycarbonylamino acids
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Fusion Proteins
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone
  • Tyrosine
  • Leucine