PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance

Mol Cell. 1999 Oct;4(4):597-609. doi: 10.1016/s1097-2765(00)80210-5.


Agonist-induced activation of peroxisome proliferator-activated receptor gamma (PPAR gamma) is known to cause adipocyte differentiation and insulin sensitivity. The biological role of PPAR gamma was investigated by gene targeting. Homozygous PPAR gamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Quite unexpectedly, heterozygous PPAR gamma-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. These phenotypes were abrogated by PPAR gamma agonist treatment. Heterozygous PPAR gamma-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. This study reveals a hitherto unpredicted role for PPAR gamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPAR gamma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Body Weight / genetics
  • Cell Differentiation / genetics
  • Cell Size / genetics*
  • Diet
  • Eating
  • Energy Metabolism
  • Fats / pharmacology*
  • Fetal Viability / genetics
  • Hypoglycemic Agents / pharmacology
  • Insulin Resistance / genetics*
  • Leptin / metabolism
  • Mice
  • Mice, Knockout
  • Myocardium / pathology
  • Pioglitazone
  • Placenta / pathology
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / agonists
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Blood Glucose
  • Fats
  • Hypoglycemic Agents
  • Leptin
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Pioglitazone