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MICE WITH A TISSUE SPECIFIC DELETION IN THE GENE FOR PHOSPHOENOLPYRUVATE CARBOXYKINASE (PEPCK) ARE INSULIN RESISTANT
Author(s) -
Milllward Carrie Ann,
Heaney Jason D.,
Gornicka Agnieszka,
Croniger Colleen M.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.614.2
Subject(s) - insulin resistance , medicine , endocrinology , phosphoenolpyruvate carboxykinase , glucose homeostasis , adipose tissue , triglyceride , biology , insulin , adiponectin , hyperinsulinemia , white adipose tissue , cholesterol , biochemistry , gene
Obesity has become a world‐wide health problem that is associated with metabolic syndrome, including insulin resistance and the development of type 2 diabetes. The acute elevation of free fatty acid (FFA) levels that occurs in obesity is controlled by the triglyceride/FFA cycle. We have investigated the role of the triglyceride/free fatty acid cycle in the development of insulin resistance using a mouse model with a deletion of the peroxisome proliferator activator response element (PPARE−/−) in the cytosolic form of the phosphoenolpyruvate carboxykinase (PEPCK‐C) gene promoter. This mutation results in ablation of PEPCK‐C gene expression in white adipose tissue leading to insulin resistance and glucose intolerance. We measured the degree of insulin resistance through a hyperinsulinemic‐euglycemic clamp and portal vein injections of insulin. The insulin signaling cascade was severely blunted in the adipose tissue. In addition, the metabolic parameters including triglyceride, free fatty acid, β‐hydroxybutyrate, and cholesterol levels are significantly higher in the PPARE−/− mice compared to the wild type mice. Newborn pups with the deletion of the PPARE site demonstrated altered glucose homeostasis as early as day 14 of birth. The data indicates that the PPARE site in the promoter of the PEPCK‐C gene plays an important role in the regulation of glucose homeostasis and the triglyceride/FFA cycle.