PCK1 and PCK2 as candidate diabetes and obesity genes
- 17 April 2007
- journal article
- review article
- Published by Springer Science and Business Media LLC in Cell Biochemistry and Biophysics
- Vol. 48 (2-3), 89-95
- https://doi.org/10.1007/s12013-007-0025-6
Abstract
The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2–3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129–135). The purpose of this review is to further explore these possibilities.Keywords
This publication has 21 references indexed in Scilit:
- Metabolism in the Era of Molecular BiologyPublished by Elsevier BV ,2005
- Impaired Tricarboxylic Acid Cycle Activity in Mouse Livers Lacking Cytosolic Phosphoenolpyruvate CarboxykinasePublished by Elsevier BV ,2004
- Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity geneTrends in Endocrinology & Metabolism, 2004
- Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetesBiochimie, 2003
- Glyceroneogenesis and the Triglyceride/Fatty Acid CyclePublished by Elsevier BV ,2003
- The Key Role of Anaplerosis and Cataplerosis for Citric Acid Cycle FunctionJournal of Biological Chemistry, 2002
- Peroxisome Proliferator-activated Receptor γ and Chicken Ovalbumin Upstream Promoter Transcription Factor II Negatively Regulate the Phosphoenolpyruvate Carboxykinase Promoter via a Common Element*Published by Elsevier BV ,2001
- Adipose Expression of the Phosphoenolpyruvate Carboxykinase Promoter Requires Peroxisome Proliferator-activated Receptor γ and 9-cis-Retinoic Acid Receptor Binding to an Adipocyte-specific Enhancer in VivoPublished by Elsevier BV ,1999
- GLUCONEOGENESIS IN INFANCY AND CHILDHOOD III. Deficiency of the Extramitochondrial Form of Hepatic Phosphoenolpyruvate Carboxykinase in a Case of Persistent Neonatal HypoglycaemiaActa Paediatrica, 1976
- TWO CASES OF PHOSPHOENOLPYRUVATE CARBOXYKINASE DEFICIENCYActa Paediatrica, 1976