A dominant negative peroxisome proliferator-activated receptor-γ knock-in mouse exhibits features of the metabolic syndrome

Bethany D. Freedman, Eun Jig Lee, Youngkyu Park, J. Larry Jameson

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPARγ mutations have features of the metabolic syndrome (severe insulin resistance, dyslipidemia, and hypertension). We created a knock-in mouse model containing a potent dominant negative PPARγ L466A mutation, shown previously to inhibit wild-type PPARγ action in vitro. Homozygous PPARγ L466A knock-in mice die in utero. Heterozygous PPARγ L466A knock-in (PPARKI) mice exhibit hypoplastic adipocytes, hypoadiponectinemia, increased serum-free fatty acids, and hepatic steatosis. When subjected to high fat diet feeding, PPARKI mice gain significantly less weight than controls. Hyperinsulinemic-euglycemic clamp studies in PPARKI mice revealed insulin resistance and reduced glucose uptake into skeletal muscle. Female PPARKI mice exhibit hypertension independent of diet. The PPARKI mouse provides a novel model for studying the relationship between impaired PPARγ function and the metabolic syndrome.

Original languageEnglish
Pages (from-to)17118-17125
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number17
DOIs
Publication statusPublished - 2005 Apr 29

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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