title: Phosphoenolpyruvate carboxykinase (Pck1) helps regulate the triglyceride/fatty acid cycle and development of insulin resistance in mice.
abstract: The aim of this study was to investigate the role of the cytosolic form of phosphoenolpyruvate carboxykinase (Pck1) in the development of insulin resistance. Previous studies have shown that the roles of Pck1 in white adipose tissue (WAT) in glyceroneogenesis and reesterification of free fatty acids (FFA) to generate triglyceride are vital for the prevention of diabetes. We hypothesized that insulin resistance develops when dysregulation of Pck1 occurs in the triglyceride/fatty acid cycle, which regulates lipid synthesis and transport between adipose tissue and the liver. We examined this by analyzing mice with a deletion of the PPARgamma binding site in the promoter of Pck1 (PPARE(-/-)). This mutation reduced the fasting Pck1 mRNA expression in WAT in brown adipose tissue (BAT). To analyze insulin resistance, we performed hyperinsulinemic-euglycemic glucose clamp analyses. PPARE(-/-) mice were profoundly insulin resistant and had more FFA and glycerol released during the hyperinsulinemic-euglycemic clamp compared with wild-type mice (WT). Finally, we analyzed insulin secretion in isolated islets. We found a 2-fold increase in insulin secretion in the PPARE(-/-) mice at 16.7 mM glucose. Thus, the PPARE site in the Pck1 promoter is essential for maintenance of lipid metabolism and glucose homeostasis and disease prevention.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Millward
authors.forename: David
authors.initials: D
authors.lastname: Desantis
authors.forename: Chang-Wen
authors.initials: CW
authors.lastname: Hsieh
authors.forename: Jason D
authors.initials: JD
authors.lastname: Heaney
authors.forename: Sorana
authors.initials: S
authors.lastname: Pisano
authors.forename: Yael
authors.initials: Y
authors.lastname: Olswang
authors.forename: Lea
authors.initials: L
authors.lastname: Reshef
authors.forename: Michelle
authors.initials: M
authors.lastname: Beidelschies
authors.forename: Michelle
authors.initials: M
authors.lastname: Puchowicz
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D008066:Lipolysis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009132:Muscles / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D047495:PPAR gamma; D012333:RNA, Messenger; D014280:Triglycerides; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose