Skip to main content

Advertisement

SpringerLink
Log in

Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance

  • Article
  • Published:
Diabetologia Aims and scope Submit manuscript

Abstract

Aims/hypothesis

Pantothenate kinase (PANK) is the first enzyme in CoA biosynthesis. Pank1-deficient mice have 40% lower liver CoA and fasting hypoglycaemia, which results from reduced gluconeogenesis. Single-nucleotide polymorphisms in the human PANK1 gene are associated with insulin levels, suggesting a link between CoA and insulin homeostasis. We determined whether Pank1 deficiency (1) modified insulin levels, (2) ameliorated hyperglycaemia and hyperinsulinaemia, and (3) improved acute glucose and insulin tolerance of leptin (Lep)-deficient mice.

Methods

Serum insulin and responses to glucose and insulin tolerance tests were determined in Pank1-deficient mice. Levels of CoA and regulating enzymes were measured in liver and skeletal muscle of Lep-deficient mice. Double Pank1/Lep-deficient mice were analysed for the diabetes-related phenotype and global metabolism.

Results

Pank1-deficient mice had lower serum insulin and improved glucose tolerance and insulin sensitivity compared with wild-type mice. Hepatic and muscle CoA was abnormally high in Lep-deficient mice. Pank1 deletion reduced hepatic CoA but not muscle CoA, reduced serum glucose and insulin, but did not normalise body weight or improve acute glucose tolerance or protein kinase B phosphorylation in Lep-deficient animals. Pank1/Lep double-deficient mice exhibited reduced whole-body metabolism of fatty acids and amino acids and had a greater reliance on carbohydrate use for energy production.

Conclusions/interpretation

The results indicate that Pank1 deficiency drives a whole-body metabolic adaptation that improves aspects of the diabetic phenotype and uncouples hyperglycaemia and hyperinsulinaemia from obesity in leptin-deficient mice.

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
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AKT:

Protein kinase B

ITT:

Insulin tolerance test

NUDT7:

Nudix hydrolase 7

PANK:

Pantothenate kinase

RER:

Respiratory exchange ratio

\( \dot{V}{\mathrm{CO}}_2 \) :

Rate of CO2 production

\( \dot{V}{\mathrm{O}}_2 \) :

Rate of O2 consumption

References

  1. Perriello G, Pampanelli S, del Sindaco P et al (1997) Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM. Diabetes 46:1010–1016

    Article  CAS  PubMed  Google Scholar 

  2. Caton PW, Nayuni NK, Kieswich J, Khan NQ, Yaqoob MM, Corder R (2010) Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol 205:97–106

    Article  CAS  PubMed  Google Scholar 

  3. Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283

    Article  CAS  PubMed  Google Scholar 

  4. Leonardi R, Rehg JE, Rock CO, Jackowski S (2010) Pantothenate kinase 1 is required to support the metabolic transition from the fed to the fasted state. PLoS ONE 5:e11107

    Article  PubMed Central  PubMed  Google Scholar 

  5. Leonardi R, Zhang Y-M, Rock CO, Jackowski S (2005) Coenzyme A: back in action. Prog Lipid Res 44:125–153

    Article  CAS  PubMed  Google Scholar 

  6. Gasmi L, McLennan AG (2001) The mouse Nudt7 gene encodes a peroxisomal nudix hydrolase specific for coenzyme A and its derivatives. Biochem J 357:33–38

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Reilly SJ, Tillander V, Ofman R, Alexson SE, Hunt MC (2008) The nudix hydrolase 7 is an acyl-CoA diphosphatase involved in regulating peroxisomal coenzyme A homeostasis. J Biochem 144:655–663

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Y-M, Rock CO, Jackowski S (2005) Feedback regulation of murine pantothenate kinase 3 by coenzyme A and coenzyme A thioesters. J Biol Chem 280:32594–32601

    Article  CAS  PubMed  Google Scholar 

  9. Garcia M, Leonardi R, Zhang YM, Rehg JE, Jackowski S (2012) Germline deletion of pantothenate kinases 1 and 2 reveals the key roles for CoA in postnatal metabolism. PLoS ONE 7:e40871

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Rock CO, Karim MA, Zhang Y-M, Jackowski S (2002) The murine Pank1 gene encodes two differentially regulated pantothenate kinase isozymes. Gene 291:35–43

    Article  CAS  PubMed  Google Scholar 

  11. Leonardi R, Rock CO, Jackowski S, Zhang Y-M (2007) Activation of human mitochondrial pantothenate kinase 2 by palmitoylcarnitine. Proc Natl Acad Sci U S A 104:1494–1499

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Leonardi R, Zhang YM, Lykidis A, Rock CO, Jackowski S (2007) Localization and regulation of mouse pantothenate kinase 2. FEBS Lett 581:4639–4644

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Rock CO, Calder RB, Karim MA, Jackowski S (2000) Pantothenate kinase regulation of the intracellular concentration of coenzyme A. J Biol Chem 275:1377–1383

    Article  CAS  PubMed  Google Scholar 

  14. Leonardi R, Zhang Y-M, Yun M-K et al (2010) Modulation of pantothenate kinase 3 activity by small molecules that interact with the substrate/allosteric regulatory domain. Chem Biol 17:892–902

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Alfonso-Pecchio A, Garcia M, Leonardi R, Jackowski S (2012) Compartmentalization of mammalian pantothenate kinases. PLoS ONE 7:e49509

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Gerdes S, Lerma-Ortiz C, Frelin O et al (2012) Plant B vitamin pathways and their compartmentation: a guide for the perplexed. J Exp Bot 63:5379–5395

    Article  CAS  PubMed  Google Scholar 

  17. Zallot R, Agrimi G, Lerma-Ortiz C et al (2013) Identification of mitochondrial coenzyme a transporters from maize and Arabidopsis. Plant Physiol 162:581–588

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Prohl C, Pelzer W, Diekert K et al (2001) The yeast mitochondrial carrier Leu5p and its human homologue Graves' disease protein are required for accumulation of coenzyme A in the matrix. Mol Cell Biol 21:1089–1097

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Fiermonte G, Paradies E, Todisco S, Marobbio CM, Palmieri F (2009) A novel member of solute carrier family 25 (SLC25A42) is a transporter of coenzyme A and adenosine 3′,5′-diphosphate in human mitochondria. J Biol Chem 284:18152–18159

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Zhang YM, Chohnan S, Virga KG et al (2007) Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis. Chem Biol 14:291–302

    Article  PubMed Central  PubMed  Google Scholar 

  21. Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, Hayflick SJ (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat Genet 28:345–349

    Article  CAS  PubMed  Google Scholar 

  22. Sabatti C, Service SK, Hartikainen AL et al (2009) Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 41:35–46

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kennedy AJ, Ellacott KL, King VL, Hasty AH (2010) Mouse models of the metabolic syndrome. Dis Model Mech 3:156–166

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature (London) 372:425–432

    Article  CAS  Google Scholar 

  25. Lindstrom P (2007) The physiology of obese-hyperglycemic mice [ob/ob mice]. Sci World J 7:666–685

    Article  Google Scholar 

  26. Steiner AA, Petenusci SO, Brentegani LG, Branco LG (2000) The importance of glucose for the freezing tolerance/intolerance of the anuran amphibians Rana catesbeiana and Bufo paracnemis. Rev Bras Biol 60:321–328

    Article  CAS  PubMed  Google Scholar 

  27. Minkler PE, Kerner J, Ingalls ST, Hoppel CL (2008) Novel isolation procedure for short-, medium-, and long-chain acyl-coenzyme A esters from tissue. Anal Biochem 376:275–276

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Shimada K, Mitamura K (1994) Derivatization of thiol-containing compounds. J Chromatogr B Biomed Appl 659:227–241

    Article  CAS  PubMed  Google Scholar 

  29. Schneider WC (1945) Phosphorus compounds in animal tissues; extraction and estimation of desoxypentose nucleic acid and of pentose nucleic acid. J Biol Chem 161:293–303

    CAS  PubMed  Google Scholar 

  30. Yu XX, Drackley JK, Odle J, Lin X (1997) Response of hepatic mitochondrial and peroxisomal β-oxidation to increasing palmitate concentrations in piglets. Biol Neonate 72:284–292

    Article  CAS  PubMed  Google Scholar 

  31. Demaugre F, Leroux JP, Cartier P (1978) The effects of pyruvate concentration, dichloroacetate and alpha-cyano-4-hydroxycinnamate on gluconeogenesis, ketogenesis and [3-hydroxybutyrate]/[3-oxobutyrate] ratios in isolated rat hepatocytes. Biochem J 172:91–96

    CAS  PubMed Central  PubMed  Google Scholar 

  32. KirscHbAum N, Clemons R, Marino KA, Sheedy G, Nguyen ML, Smith CM (1990) Pantothenate kinase activity in livers of genetically diabetic mice (db/db) and hormonally treated cultured rat hepatocytes. J Nutr 120:1376–1386

    CAS  PubMed  Google Scholar 

  33. Mutel E, Gautier-Stein A, Abdul-Wahed A et al (2011) Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon. Diabetes 60:3121–3131

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Houten SM, Herrema H, Te BH et al (2013) Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. Hum Mol Genet 22:5249–5261

    Article  CAS  PubMed  Google Scholar 

  35. Haymond MW, Miles JM (1982) Branched chain amino acids as a major source of alanine nitrogen in man. Diabetes 31:86–89

    Article  CAS  PubMed  Google Scholar 

  36. Newgard CB, An J, Bain JR et al (2009) A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:311–326

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Tai ES, Tan ML, Stevens RD et al (2010) Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia 53:757–767

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Storlien L, Oakes ND, Kelley DE (2004) Metabolic flexibility. Proc Nutr Soc 63:363–368

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Pate, L. Richmond, K. Miller, J. Wang, K. Wells and M. Frank (Department of Infectious Diseases, St Jude Children’s Hospital), the Veterinary Pathology Core Facility at St Jude Children’s Hospital and the Protein Core of the University of California at Davis for their expert technical assistance.

Funding

The research was funded by NIH GM062896 (to SJ) and ALSAC.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

RL, SJ and COR were responsible for conception and design of the study. RL performed and supervised the experiments to obtain the data. RL and SJ were responsible for analysis and interpretation of the data, and wrote the manuscript. COR contributed to discussion and reviewed/edited the manuscript. All authors gave final approval. SJ is responsible for the integrity of the work as a whole.

Author information

Author notes

  1. Roberta Leonardi

    Present address: Department of Biochemistry, School of Medicine, West Virginia University, Morgantown, WV, USA

Authors and Affiliations

  1. Department of Infectious Diseases, St Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA

    Roberta Leonardi, Charles O. Rock & Suzanne Jackowski

Authors
  1. Roberta Leonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charles O. Rock
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suzanne Jackowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suzanne Jackowski.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM Fig. 1

(PDF 56 kb)

ESM Fig. 2

(PDF 45 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leonardi, R., Rock, C.O. & Jackowski, S. Pank1 deletion in leptin-deficient mice reduces hyperglycaemia and hyperinsulinaemia and modifies global metabolism without affecting insulin resistance. Diabetologia 57, 1466–1475 (2014). https://doi.org/10.1007/s00125-014-3245-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00125-014-3245-5

Keywords

Search

Navigation