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

Bethany D. Freedman, Eunjig 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

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Peroxisome Proliferator-Activated Receptors
Nutrition
Insulin Resistance
Weight control
Insulin
Hypertension
Adipogenesis
Mutation
Glucose Clamp Technique
Clamping devices
High Fat Diet
Cytoplasmic and Nuclear Receptors
Dyslipidemias
Nonesterified Fatty Acids
Adipocytes
Muscle
Skeletal Muscle
Fats
Diet

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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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.",
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A dominant negative peroxisome proliferator-activated receptor-γ knock-in mouse exhibits features of the metabolic syndrome. / Freedman, Bethany D.; Lee, Eunjig; Park, Youngkyu; Jameson, J. Larry.

In: Journal of Biological Chemistry, Vol. 280, No. 17, 29.04.2005, p. 17118-17125.

Research output: Contribution to journalArticle

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