A dominant negative peroxisome proliferator-activated receptor-gamma knock-in mouse exhibits features of the metabolic syndrome.
Peroxisome proliferator-activated receptor-gamma (PPARgamma), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPARgamma 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 PPARgamma L466A mutation, shown previously to inhibit wild-type PPARgamma action in vitro. Homozygous PPARgamma L466A knock-in mice die in utero. Heterozygous PPARgamma 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 PPARgamma function and the metabolic syndrome.
Freedman
Bethany D
BD
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Lee
Eun-Jig
EJ
Park
Youngkyu
Y
Jameson
J Larry
JL
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000483:Alleles; D000821:Animal Feed; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure; D015139:Blotting, Southern; D002151:Calorimetry / Q000379:methods; D003433:Crosses, Genetic; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004351:Drug Resistance; D005091:Exons; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D010101:Oxygen Consumption; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D016895:Culture Media, Serum-Free; D017931:DNA Primers; D005227:Fatty Acids; D007328:Insulin; D047495:PPAR gamma; D003847:Deoxyglucose; D005947:Glucose