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

Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear hormone receptor family, is a master regulator of adipogenesis. Humans with dominant negative PPAR gamma 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 PPAR gamma L466A mutation, shown previously to inhibit wild-type PPAR gamma action in vitro. Homozygous PPAR gamma L466A knock-in mice die in utero. Heterozygous PPAR gamma 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 PPAR gamma function and the metabolic syndrome.