The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor γ (PPARγ) Deficiency and PPARγ Agonist Improve Insulin Resistance

Toshimasa Yamauchi, Junji Kamon, Hironori Waki, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Tomohiro Ide, Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Hiroshi Miki, Atsuko Tsuchida, Yasuo Akanuma, Ryozo Nagai, Satoshi Kimura, Takashi Kadowaki*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

593 Scopus citations

Abstract

Peroxisome proliferator-activated receptor (PPAR) γ is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARγ and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARγ by PPARγ agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARγ activity by heterozygous PPARγ deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARγ deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARγ deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor α, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARγ deficiency and PPARγ agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.

Original languageEnglish
Pages (from-to)41245-41254
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number44
DOIs
StatePublished - 2001/11/02

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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