Skip to main content
SpringerLink
Log in

PCK1 and PCK2 as candidate diabetes and obesity genes

  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Berg, J. M., Tymoczko, J. L., & Stryer, L. (2002). Biochemistry. New York, NY: W. H. Freeman and Company.

    Google Scholar 

  2. Beale, E. G., Hammer, R. E., Antoine, B., & Forest, C. (2004). Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene. Trends in Endocrinology and Metabolism, 15, 129–135.

    Article  PubMed  CAS  Google Scholar 

  3. Utter, M. F., & Kolenbrander, H. M. (1972). Formation of oxalacetate by CO2 fixation of phosphoenolpyruvate. In P. D. Boyer (Ed.), The enzymes (pp. 117–168). New York: Academic Press.

  4. Hanson, R. W., & Reshef, L. (1997). Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annual Review of Biochemistry, 66, 581–611.

    Article  PubMed  CAS  Google Scholar 

  5. Tilghman, S. M., Ballard, F. J., & Hanson, R. W. (1976). Hormonal regulation of phosphoenolpyruvate carboxykinase (GTP) in mammalian tissues. In R. W. Hanson & M. A Mehlman (Eds.), Gluconeogenesis: Its regulation in mammalian species (pp. 47–91). New York: John Wiley & Sons.

  6. Hanson, R. W. (2005). Metabolism in the era of molecular biology. The Journal of Biological Chemistry, 280, 1705–1715.

    Article  PubMed  CAS  Google Scholar 

  7. Beale, E. G., Katzen, C. S., & Granner, D. K. (1981). Regulation of rat liver phosphoenolpyruvate carboxykinase (GTP) messenger ribonucleic acid activity by N6, O2’-dibutyryladenosine 3′,5′-phosphate. Biochemistry, 20, 4878–4883.

    Article  PubMed  CAS  Google Scholar 

  8. Beale, E. G., Hartley, J. L., & Granner, D. K. (1982). N6,O2′-dibutyryl cycle AMP and glucose regulate the amount of messenger RNA coding for hepatic phosphoenolpyruvate carboxykinase (GTP). The Journal of Biological Chemistry, 257, 2022–2028.

    PubMed  CAS  Google Scholar 

  9. Sasaki, K., Cripe, T. P., Koch, S. R., Andreone, T. L., Petersen, D. D., Beale, E. G., & Granner, DK. (1984). Multihormonal regulation of phosphoenolpyruvate carboxykinase gene transcription. The dominant role of insulin. The Journal of Biological Chemistry, 259, 15242–15251.

    PubMed  CAS  Google Scholar 

  10. Chrapkiewicz, N. B., Beale, E. G., & Granner, D. K. (1982). Induction of the messenger ribonucleic acid coding for phosphoenolpyruvate carboxykinase in H4-II-E cells. Evidence for a nuclear effect of cyclic. AMP. The Journal of Biological Chemistry, 257, 14428–14432.

    PubMed  CAS  Google Scholar 

  11. Shrago, E., Shug, A., & Elson, C. (1976). Regulation of cell metabolism by mitochondrial transport systems. In R. W. Hanson & M. A Mehlman (Eds.), Gluconeogenesis: Its regulation in mammalian species (pp. 221–238). New York: John Wiley & Sons.

  12. Reshef, L., Olswang, Y., Cassuto, H., Blum, B., Croniger, C. M., Kalhan, S. C., Tilghman, S. M., & Hanson, R. W. (2003). Glyceroneogenesis and the triglyceride/fatty acid cycle. The Journal of Biological Chemistry, 278, 30413–30416.

    Article  PubMed  CAS  Google Scholar 

  13. Beale, E. G., Hammer, R. E., Antoine, B., & Forest, C. (2002). Glyceroneogenesis comes of age. FASEB Journal, 16, 1695–1696.

    Article  PubMed  CAS  Google Scholar 

  14. Jensen, M. D., Ekberg, K., & Landau, B. R. (2001). Lipid metabolism during fasting. American Journal of Physiology. Endocrinology & Metabology, 281, E789–E793.

    CAS  Google Scholar 

  15. Owen, O. E., Kalhan, S. C., & Hanson, R. W. (2002). The key role of anaplerosis and cataplerosis for citric acid cycle function. The Journal of Biological Chemistry, 277, 30409–30412.

    Article  PubMed  CAS  Google Scholar 

  16. She, P., Shiota, M., Shelton, K. D., Chalkley, R., Postic, C., & Magnuson, M. A. (2000). Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Molecular and Cell Biology, 20, 6508–6517.

    Article  CAS  Google Scholar 

  17. Burgess, S. C., Hausler, N., Merritt, M., Jeffrey, F. M. H., Storey, C., Milde, A., Koshy, S., Lindner, J., Magnuson, M. A, Malloy, C. R, & Sherry, A. D. (2004). Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. The Journal of Biological Chemistry, 279, 48941–48949.

    Article  PubMed  CAS  Google Scholar 

  18. Olswang, Y., Cohen, H., Papo, O., Cassuto, H., Croniger, C. M., Hakimi, P., Tilghman, S. M., Hanson, R. W., Reshef, L. (2002). A mutation in the peroxisome proliferator-activated receptor gamma -binding site in the gene for the cytosolic form of phosphoenolpyruvate carboxykinase reduces adipose tissue size and fat content in mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 625–630.

    Article  PubMed  CAS  Google Scholar 

  19. Devine, J. H., Eubank, D. W., Clouthier, D. E., Tontonoz, P., Spiegelman, B. M., Hammer, R. E., & Beale, E. G. (1999). 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 vivo. The Journal of Biological Chemistry, 274, 13604–13612.

    Article  PubMed  CAS  Google Scholar 

  20. Valera, A., Pujol, A., Pelegrin, M., & Bosch, F. (1994). Transgenic mice overexpressing phosphoenolpyruvate carboxykinase develop non-insulin-dependent diabetes mellitus. Proceedings of the National Academy of Sciences of the United States of America, 91, 9151–9154.

    Article  PubMed  CAS  Google Scholar 

  21. Franckhauser, S., Munoz, S., Pujol, A., Casellas, A., Riu, E., Otaegui, P., Su, B., & Bosch, F. (2002). Increased fatty acid re-esterification by PEPCK overexpression in adipose tissue leads to obesity without insulin resistance. Diabetes, 51, 624–630.

    Article  PubMed  CAS  Google Scholar 

  22. Vidnes, J., & Sovik, O. (1976). Gluconeogenesis in infancy and childhood. III. Deficiency of the extramitochondrial form of hepatic phosphoenolpyruvate carboxykinase in a case of persistent neonatal hypoglycaemia. Acta Paediatrica Scandinavica, 65, 307–312.

    PubMed  CAS  Google Scholar 

  23. Hommes, F. A., Bendien, K., Elema, J. D., Bremer, H. J., & Lombeck, I. (1976). Two cases of phosphoenolpyruvate carboxykinase deficiency. Acta Paediatrica Scandinavica, 65, 233–240.

    PubMed  CAS  Google Scholar 

  24. Duplus, E., Benelli, C., Reis, A. F., Fouque, F., Velho, G., & Forest, C. (2003). Expression of the phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes. Biochimie, 85, 1257–1264.

    Article  PubMed  CAS  Google Scholar 

  25. Eubank, D. W., Duplus, E., Williams, S. C, Forest, C, & Beale, E. G. (2001). Peroxisome proliferator activated receptor γ (PPARγ) and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) negatively regulate the phosphoenolpyruvate carboxykinase promoter via a common element. The Journal of Biological Chemistry, 276, 30561–30569.

    Article  PubMed  CAS  Google Scholar 

  26. Tordjman, J., Chauvet, G., Quette, J., Beale, E. G., Forest, C., & Antoine, B. (2003). Thiazolidinediones block fatty acid release by inducing glyceroneogenesis in fat cells. The Journal of Biological Chemistry, 278, 18785–18790.

    Article  PubMed  CAS  Google Scholar 

  27. Bogacka, I., Xie, H., Bray, G. A., & Smith, S. R. (2004). The effect of pioglitazone on peroxisome proliferator-activated receptor-gamma target genes related to lipid storage in vivo. Diabetes Care, 27, 1660–1667.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Mail Stop 6540, Lubbock, TX, 79430, USA

    Elmus G. Beale & Brandy J. Harvey

  2. INSERM UMR-S 747; Université Paris Descartes, Centre Universitaire - U.F.R. Biomedicale, 45 rue des Saints-Peres, Paris, 75006, France

    Claude Forest

Authors
  1. Elmus G. Beale
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brandy J. Harvey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claude Forest
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elmus G. Beale.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beale, E.G., Harvey, B.J. & Forest, C. PCK1 and PCK2 as candidate diabetes and obesity genes. Cell Biochem Biophys 48, 89–95 (2007). https://doi.org/10.1007/s12013-007-0025-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12013-007-0025-6

Keywords

Search

Navigation