Skip to main content

Advertisement

SpringerLink
Log in

Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Uroguanylin (UGN) is a 16 amino acid peptide produced mainly by intestinal epithelial cells. Nutrients intake increases circulating levels of prouroguanylin that is processed and converted to UGN to activate the guanylyl cyclase 2C receptor (GUCY2C). Given that the UGN-GUCY2C system has been proposed as a novel gut-brain endocrine axis regulating energy balance, the aim of the present study was to investigate the regulation of UGN protein levels in duodenum and circulating levels in lean and obese mice under different nutritional conditions and its potential interaction with leptin.

Methods

Swiss, C57BL/6 wild-type and ob/ob male adult mice under different nutritional conditions were used: fed ad libitum standard diet (control); 48 h fasting (fasted); 48 h fasting followed by 24 h of feeding (refed); and fed high-fat diet (45 %) during 10 weeks. In addition, peripheral leptin administration was performed. Intestinal uroguanylin expression was studied by Western blot analysis; plasma levels were measured by ELISA.

Results

Food deprivation significantly reduced plasma UGN levels, which were correlated with the lower protein levels of UGN in duodenum. These effects were reverted after refeeding and leptin challenge. Consistently, in ob/ob mice UGN expression was decreased, whereas leptin treatment up-regulated UGN levels in duodenum in these genetically modified mice compared to WT. Diet-induced obese mice displayed increased UGN levels in intestine and plasma in comparison with lean mice.

Conclusions

Our findings suggest that UGN levels are correlated with energy balance status and that the regulation of UGN by nutritional status is leptin-dependent.

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

Similar content being viewed by others

References

  1. Lancha A, Fruhbeck G, Gomez-Ambrosi J (2012) Peripheral signalling involved in energy homeostasis control. Nutr Res Rev 25:223–248. doi:10.1017/S0954422412000145

    Article  CAS  Google Scholar 

  2. Dhillo WS, Bloom SR (2004) Gastrointestinal hormones and regulation of food intake. Horm Metab Res 36:846–851. doi 10.1055/s-2004-826174

  3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660. doi:10.1038/45230

    Article  CAS  Google Scholar 

  4. Heppner KM, Chaudhary N, Muller TD, Kirchner H, Habegger KM, Ottaway N, Smiley DL, Dimarchi R, Hofmann SM, Woods SC, Sivertsen B, Holst B, Pfluger PT, Perez-Tilve D, Tschop MH (2012) Acylation type determines ghrelin’s effects on energy homeostasis in rodents. Endocrinology 153:4687–4695. doi:10.1210/en.2012-1194

    Article  CAS  Google Scholar 

  5. Gahete MD, Rincon-Fernandez D, Villa-Osaba A, Hormaechea-Agulla D, Ibanez-Costa A, Martinez-Fuentes AJ, Gracia-Navarro F, Castano JP, Luque RM (2014) Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight. J Endocrinol 220:R1–R24. doi:10.1530/JOE-13-0391

    Article  CAS  Google Scholar 

  6. Kirchner H, Heppner KM, Holland J, Kabra D, Tschop MH, Pfluger PT (2013) Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background. PLoS ONE 8:e61822. doi:10.1371/journal.pone.0061822

    Article  CAS  Google Scholar 

  7. Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407:908–913. doi:10.1038/35038090

    Article  CAS  Google Scholar 

  8. Hamra FK, Forte LR, Eber SL, Pidhorodeckyj NV, Krause WJ, Freeman RH, Chin DT, Tompkins JA, Fok KF, Smith CE et al (1993) Uroguanylin: structure and activity of a second endogenous peptide that stimulates intestinal guanylate cyclase. Proc Natl Acad Sci USA 90:10464–10468

    Article  CAS  Google Scholar 

  9. Seeley RJ, Tschop MH (2011) Uroguanylin: how the gut got another satiety hormone. J Clin Investig 121:3384–3386. doi:10.1172/JCI58297

    Article  CAS  Google Scholar 

  10. Carrithers SL, Barber MT, Biswas S, Parkinson SJ, Park PK, Goldstein SD, Waldman SA (1996) Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues. Proc Natl Acad Sci USA 93:14827–14832

    Article  CAS  Google Scholar 

  11. Carrithers SL, Parkinson SJ, Goldstein S, Park P, Robertson DC, Waldman SA (1994) Escherichia coli heat-stable toxin receptors in human colonic tumors. Gastroenterology 107:1653–1661

    CAS  Google Scholar 

  12. Swenson ES, Mann EA, Jump ML, Witte DP, Giannella RA (1996) The guanylin/STa receptor is expressed in crypts and apical epithelium throughout the mouse intestine. Biochem Biophys Res Commun 225:1009–1014. doi:10.1006/bbrc.1996.1286

    Article  CAS  Google Scholar 

  13. Kim GW, Lin JE, Waldman SA (2013) GUCY2C: at the intersection of obesity and cancer. Trends Endocrinol Metabol 24:165–173. doi:10.1016/j.tem.2013.01.001

    Article  CAS  Google Scholar 

  14. London RM, Krause WJ, Fan X, Eber SL, Forte LR (1997) Signal transduction pathways via guanylin and uroguanylin in stomach and intestine. Am J Physiol 273:G93–G105

    CAS  Google Scholar 

  15. Perkins A, Goy MF, Li Z (1997) Uroguanylin is expressed by enterochromaffin cells in the rat gastrointestinal tract. Gastroenterology 113:1007–1014

    Article  CAS  Google Scholar 

  16. Nakazato M, Yamaguchi H, Date Y, Miyazato M, Kangawa K, Goy MF, Chino N, Matsukura S (1998) Tissue distribution, cellular source, and structural analysis of rat immunoreactive uroguanylin. Endocrinology 139:5247–5254. doi:10.1210/endo.139.12.6347

    CAS  Google Scholar 

  17. Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS, Hyslop T, Schulz S, Waldman SA (2011) A uroguanylin-GUCY2C endocrine axis regulates feeding in mice. J Clin Investig 121:3578–3588. doi:10.1172/JCI57925

    Article  CAS  Google Scholar 

  18. Imbernon M, Sanchez-Rebordelo E, Gallego R, Gandara M, Lear P, Lopez M, Dieguez C, Nogueiras R (2014) Hypothalamic KLF4 mediates leptin’s effects on food intake via AgRP. Mol Metabol 3:441–451. doi:10.1016/j.molmet.2014.04.001

    Article  CAS  Google Scholar 

  19. Perez-Sieira S, Lopez M, Nogueiras R, Tovar S (2014) Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency. Sci Rep 4:4264. doi:10.1038/srep04264

    Article  CAS  Google Scholar 

  20. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1:1311–1314

    Article  CAS  Google Scholar 

  21. Begg DP, Steinbrecher KA, Mul JD, Chambers AP, Kohli R, Haller A, Cohen MB, Woods SC, Seeley RJ (2014) Effect of guanylate cyclase-C activity on energy and glucose homeostasis. Diabetes. doi:10.2337/db14-0160

    Google Scholar 

  22. Schulz S, Chrisman TD, Garbers DL (1992) Cloning and expression of guanylin. Its existence in various mammalian tissues. J Biol Chem 267:16019–16021

    CAS  Google Scholar 

  23. Miyazato M, Nakazato M, Matsukura S, Kangawa K, Matsuo H (1996) Uroguanylin gene expression in the alimentary tract and extra-gastrointestinal tissues. FEBS Lett 398:170–174

    Article  CAS  Google Scholar 

  24. Williams LM (2012) Hypothalamic dysfunction in obesity. Proc Nutr Soc 71:521–533. doi:10.1017/S002966511200078X

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work has been supported by grants from Instituto de Salud Carlos III (PS09/02075 and PI1202021); Xunta de Galicia (10 PXIB 918 273PR), Fundación Mutua Madrileña. Ministerio de Economia y Competitividad (RN: BFU2012-35255), Xunta de Galicia (RN: EM 2012/039 and 2012-CP069), Fondo de Investigaciones Sanitarias (LS: I3SNS-SERGAS/ISCIII), CF is funded by IDIS (Instituto de Investigación Sanitaria de Santiago de Compostela) and SB-F by Xunta de Galicia. Centro de Investigacion Biomedica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn) is a iniciative of the Instituto de Salud Carlos III (ISCIII) of Spain which is supported by FEDER funds (CB06/03). The research leading to these results has also received funding from the European Community’s Seventh Framework Programme under the following Grant: CD: FP7/2007-2013: No. 245009: NeuroFAST and ERC StG-2011-OBESITY53-281408 to R.N.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Author information

Authors and Affiliations

  1. Grupo Fisiopatología Endocrina, Laboratorio 14, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain

    C. Folgueira, S. Barja-Fernandez & L. M. Seoane

  2. CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

    C. Folgueira, E. Sanchez-Rebordelo, S. Barja-Fernandez, S. Tovar, F. F. Casanueva, C. Dieguez, R. Nogueiras & L. M. Seoane

  3. Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

    C. Folgueira, E. Sanchez-Rebordelo, S. Tovar, C. Dieguez & R. Nogueiras

  4. Pediatric Department, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

    S. Barja-Fernandez & R. Leis

  5. Laboratorio de Endocrinología Molecular y Celular, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Universidad de Santiago de Compostela (USC), Santiago de Compostela, Spain

    F. F. Casanueva

Authors
  1. C. Folgueira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Sanchez-Rebordelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. Barja-Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Leis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Tovar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. F. Casanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. Dieguez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Nogueiras
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. M. Seoane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to R. Nogueiras or L. M. Seoane.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Folgueira, C., Sanchez-Rebordelo, E., Barja-Fernandez, S. et al. Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner. Eur J Nutr 55, 529–536 (2016). https://doi.org/10.1007/s00394-015-0869-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-015-0869-2

Keywords

Search

Navigation