Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation

Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.

Abstract

PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Body Fluids / drug effects
  • COS Cells
  • Chlorocebus aethiops
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors*
  • Dietary Fats / pharmacology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Ligands
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Models, Molecular
  • Obesity / chemically induced
  • Obesity / metabolism
  • Osteogenesis / drug effects
  • PPAR gamma / agonists
  • PPAR gamma / chemistry
  • PPAR gamma / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Rosiglitazone
  • Thiazolidinediones / adverse effects
  • Thiazolidinediones / pharmacology
  • Transcription, Genetic / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology
  • Weight Gain / drug effects

Substances

  • (S)-4'-((5-((1-(4-nitrophenyl)ethyl)carbamoyl)-1H-indol-1-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid
  • (S)-4'-((5-(1-(4-bromophenyl)ethylcarbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)biphenyl-2-carboxylic acid
  • Biphenyl Compounds
  • Dietary Fats
  • Hypoglycemic Agents
  • Ligands
  • PPAR gamma
  • Thiazolidinediones
  • Tumor Necrosis Factor-alpha
  • Rosiglitazone
  • Phosphoserine
  • 2,4-thiazolidinedione
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse