Skip to main content
SpringerLink
Log in

Ghrelin-induced multi-organ damage in mice fed obesogenic diet

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective and design

Ghrelin has a key role in modulating energy metabolism and weight gain. The present study aimed at studying the potential role of ghrelin in the development and/or exacerbation of organ damage in a mouse model of diet-induced obesity.

Objective and design

Adult mice were fed one of two diets for 20 weeks: standard high carbohydrate (HC) or high-fat high-sugar (HFHS). Starting week 17, the animals were given regular intraperitoneal ghrelin (160 µg/kg) or saline injections Abdominal fat, serum creatinine, and glucose levels, as well as kidney, liver and heart weight and pathology were assessed.

Results

Ghrelin-injected mice showed significant organ damage, which was more exacerbated in HFHS-fed animals. While the HFHS diet was associated with significant liver damage, ghrelin administration did not reverse it. Interestingly, ghrelin administration induced moderate kidney damage and significantly affected the heart by increasing perivascular and myocardium fibrosis, steatosis as well as inflammation. Moreover, serum creatinine levels were higher in the animal group injected with ghrelin.

Conclusion

Ghrelin administration was associated with increased functional and structural organ damage, regardless of diet. The present study provides novel evidence of multi-organ physiologic alterations secondary to ghrelin administration.

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. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA. 2004;101:4679–84.

    CAS  PubMed  Google Scholar 

  2. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50:1714–9.

    CAS  PubMed  Google Scholar 

  3. Sato T, Ida T, Nakamura Y, Shiimura Y, Kangawa K, Kojima M. Physiological roles of ghrelin on obesity. Obes Res Clin Pract. 2014;8:e405–13.

    PubMed  Google Scholar 

  4. Scerif M, Goldstone AP, Korbonits M. Ghrelin in obesity and endocrine diseases. Mol Cell Endocrinol. 2011;340:15–25.

    CAS  PubMed  Google Scholar 

  5. Gomez G, Han S, Englander EW, Greeley GH Jr. Influence of a long-term high-fat diet on ghrelin secretion and ghrelin-induced food intake in rats. Regul Pept. 2012;173:60–3.

    CAS  PubMed  Google Scholar 

  6. Handjieva-Darlenska T, Boyadjieva N. The effect of high-fat diet on plasma ghrelin and leptin levels in rats. J Physiol Biochem. 2009;65:157–64.

    CAS  PubMed  Google Scholar 

  7. Reimer MK, Pacini G, Ahren B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology. 2003;144:916–21.

    CAS  PubMed  Google Scholar 

  8. Salehi A, Dornonville de la Cour C, Hakanson R, Lundquist I. Effects of ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regul Pept. 2004;118:143–50.

    CAS  PubMed  Google Scholar 

  9. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–60.

    CAS  PubMed  Google Scholar 

  10. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab. 2000;85:4908–11.

    CAS  PubMed  Google Scholar 

  11. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1483–7.

    CAS  PubMed  Google Scholar 

  12. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115:3573–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3:379–86.

    CAS  PubMed  Google Scholar 

  14. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115:3564–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, et al. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes. 2010;59:2145–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Kemp BA, Howell NL, Gray JT, Keller SR, Nass RM, Padia SH. Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats. Hypertension. 2011;57:633–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kemp BA, Howell NL, Padia SH. Intrarenal ghrelin receptor inhibition ameliorates angiotensin II-dependent hypertension in rats. Am J Physiol Renal Physiol. 2018;315:F1058–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Mosa R, Huang L, Li H, Grist M, LeRoith D, Chen C. Long-term treatment with the ghrelin receptor antagonist [d-Lys3]-GHRP-6 does not improve glucose homeostasis in nonobese diabetic MKR mice. Am J Physiol Regul Integr Comp Physiol. 2018;314:R71–83.

    PubMed  Google Scholar 

  19. Zeeni N, Dagher-Hamalian C, Dimassi H, Faour WH. Cafeteria diet-fed mice is a pertinent model of obesity-induced organ damage: a potential role of inflammation. Inflamm Res. 2015;64:501–12.

    CAS  PubMed  Google Scholar 

  20. Mehra MR, Uber PA, Park MH, Scott RL, Ventura HO, Harris BC, et al. Obesity and suppressed B-type natriuretic peptide levels in heart failure. J Am Coll Cardiol. 2004;43:1590–5.

    CAS  PubMed  Google Scholar 

  21. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci USA. 2000;97:1784–9.

    CAS  PubMed  Google Scholar 

  22. Del Gaudio A, Boschi L, Del Gaudio GA, Mastrangelo L, Munari D. Liver damage in obese patients. Obes Surg. 2002;12:802–4.

    PubMed  Google Scholar 

  23. de Jong PE, Verhave JC, Pinto-Sietsma SJ, Hillege HL, Group PS. Obesity and target organ damage: the kidney. Int J Obes Relat Metab Disord. 2006;26(4):S21–4.

    Google Scholar 

  24. Ciesla DJ, Moore EE, Johnson JL, Burch JM, Cothren CC, Sauaia A. Obesity increases risk of organ failure after severe trauma. J Am Coll Surg. 2006;203:539–45.

    PubMed  Google Scholar 

  25. Li GZ, Jiang W, Zhao J, Pan CS, Cao J, Tang CS, et al. Ghrelin blunted vascular calcification in vivo and in vitro in rats. Regul Pept. 2005;129:167–76.

    CAS  PubMed  Google Scholar 

  26. Xu YP, Zhu JJ, Cheng F, Jiang KW, Gu WZ, Shen Z, et al. Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3 beta/beta-catenin signaling in neonatal rats. J Mol Endocrinol. 2011;47:33–43.

    CAS  PubMed  Google Scholar 

  27. Li G, Xia J, Jia P, Zhao J, Sun Y, Wu C, et al. Plasma levels of acylated ghrelin in children with pulmonary hypertension associated with congenital heart disease. Pediatr Cardiol. 2015;36:1423–8.

    PubMed  Google Scholar 

  28. El Zein N, Abdallah MS, Daher CF, Mroueh M, Stephan J, Bahous SA, et al. Ghrelin modulates intracellular signalling pathways that are critical for podocyte survival. Cell Biochem Funct. 2019;37:245–55.

    PubMed  Google Scholar 

  29. Delhanty PJ, Neggers SJ, van der Lely AJ. Mechanisms in endocrinology: Ghrelin: the differences between acyl- and des-acyl ghrelin. Eur J Endocrinol. 2012;167:601–8.

    CAS  PubMed  Google Scholar 

  30. Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288:E228–35.

    CAS  PubMed  Google Scholar 

  31. Egido EM, Rodriguez-Gallardo J, Silvestre RA, Marco J. Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion. Eur J Endocrinol. 2002;146:241–4.

    CAS  PubMed  Google Scholar 

  32. Reynolds CB, Elias AN, Whisnant CS. Effects of feeding pattern on ghrelin and insulin secretion in pigs. Domest Anim Endocrinol. 2010;39:90–6.

    CAS  PubMed  Google Scholar 

  33. Poher AL, Tschop MH, Muller TD. Ghrelin regulation of glucose metabolism. Peptides. 2018;100:236–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Yang C, Liu J, Liu K, Du B, Shi K, Ding M, et al. Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance. Peptides. 2018;99:27–35.

    PubMed  Google Scholar 

  35. Liang QH, Jiang Y, Zhu X, Cui RR, Liu GY, Liu Y, et al. Ghrelin attenuates the osteoblastic differentiation of vascular smooth muscle cells through the ERK pathway. PLoS ONE. 2012;7:e33126.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang GG, Cai HQ, Li YH, Sui YB, Zhang JS, Chang JR, et al. Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase. Peptides. 2013;48:156–65.

    CAS  PubMed  Google Scholar 

  37. Kuppens RJ, Diene G, Bakker NE, Molinas C, Faye S, Nicolino M, et al. Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome. Endocrine. 2015;50:633–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Harvey RE, Howard VG, Lemus MB, Jois T, Andrews ZB, Sleeman MW. The ghrelin/GOAT system regulates obesity-induced inflammation in male mice. Endocrinology. 2017;158:2179–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Francois M, Barde S, Legrand R, Lucas N, Azhar S, El Dhaybi M, et al. High-fat diet increases ghrelin-expressing cells in stomach, contributing to obesity. Nutrition. 2016;32:709–15.

    CAS  PubMed  Google Scholar 

  40. Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology. 2010;151:4745–55.

    CAS  PubMed  Google Scholar 

  41. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of Diabetes-Induced Liver Damage: the role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016;16:e132–41.

    PubMed  PubMed Central  Google Scholar 

  42. Scheen AJ, Luyckx FH. Obesity and liver disease. Best Pract Res Clin Endocrinol Metab. 2002;16:703–16.

    CAS  PubMed  Google Scholar 

  43. Gressner AM. Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis. Kidney Int Suppl. 1996;54:S39–45.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a joint Grant from the Lebanese American University and from the Lebanese National Council for Scientific Research, Grant nb: 02-01-18.

Author information

Author notes

  1. Carole Dagher-Hamalian and Joseph Stephan have contributed equally to this work.

Authors and Affiliations

  1. Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon

    Carole Dagher-Hamalian, Joseph Stephan, Zeina Harhous, Maya S. Abdallah & Wissam H. Faour

  2. Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon

    Nadine Zeeni & Wassim N. Shebaby

Authors
  1. Carole Dagher-Hamalian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph Stephan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nadine Zeeni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zeina Harhous
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wassim N. Shebaby
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maya S. Abdallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wissam H. Faour
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wissam H. Faour.

Ethics declarations

Conflict of interest

The author(s) declare that they have no competing interests.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dagher-Hamalian, C., Stephan, J., Zeeni, N. et al. Ghrelin-induced multi-organ damage in mice fed obesogenic diet. Inflamm. Res. 69, 1019–1026 (2020). https://doi.org/10.1007/s00011-020-01383-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-020-01383-5

Keywords

Search

Navigation