Skip to main content
SpringerLink
Log in

Anti-ghrelin Therapeutic Vaccine: A Novel Approach for Obesity Treatment

  • Chapter
  • First Online:
Molecular Vaccines

Abstract

Obesity is currently a major public health problem, due to the worldwide increasing rates of the disease and burden of the associated co-morbilities, such as, type 2 diabetes, cardiovascular disease and cancer. Despite its increasing clinical relevance, there are still very few tools to treat obesity. The cornerstones for obesity treatment are still diet and exercise; anti-obesity drugs, which cause anorexia or malabsorption of nutrients, can be used as adjuvant therapy, however achieve only a modest weight loss and often short-term due to weight regain. For severe obesity the only proven effective therapy is bariatric surgery, an invasive procedure that carries inherent risks and is only recommended for selected patients.

Ghrelin is the only known hormone that stimulates food intake. In physiological conditions, ghrelin levels rise with fasting and decrease after meals. Most obese individuals have low fasting ghrelin levels that rise after food restriction and weigh loss, an explanation for the difficulty of weight loss maintenance. In contrast, in spite of major weight loss, the increase in ghrelin levels is prevented by some bariatric surgery techniques, which could contribute to sustain weight loss.

As ghrelin is the only known orexigenic hormone, it has been hypothesized that blocking reactive ghrelin increase could induce a sustained weight control.

Previous attempts to neutralize ghrelin orexigenic effects included passive immunizations by the inoculation of monoclonal anti-ghrelin antibodies and mixtures of monoclonal antibodies targeting different ghrelin haptens, which were able to decrease ghrelin-mediated and deprivation-induced food intake, while promoted an increase in energy expenditure, but had the limitation of having only acute effects; use of ghrelin receptor antagonists that demonstrated to improve glucose tolerance, suppress appetite and promote weight loss; and active immunization against ghrelin using keyhole limpet hemocyanin and bovine serum albumin as carrier proteins, which required the use of adjuvants that may be responsible for inflammatory responses and have limited use in humans.

A novel molecular approach is the use of an anti-ghrelin vaccine using Virus-like Particles as immunogenic carrier, which appears to be well-tolerated, decrease food intake and increase energy expenditure in both normal weight and diet-induced obese (DIO) mice. Vaccinated DIO mice also display a significant decrease of NPY gene expression in the basal hypothalamus reflecting a decrease in central orexigenic drive. All together, data suggests that this novel therapeutic anti-ghrelin vaccine is safe, has a positive impact on energy homeostasis and may be a useful tool for obesity treatment.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. do Carmo, I., et al.: Overweight and obesity in Portugal: national prevalence in 2003–2005. Obes. Rev. 9, 11–19 (2008). doi:10.1111/j.1467-789X.2007.00422.x. OBR422 [pii]

    PubMed  CAS  Google Scholar 

  2. WHO: Obesity and overweight fact sheet Nº311. http://www.who.int/mediacentre/factsheets/fs311/en/print.html (2006). Accessed 3 July 2009

  3. Ogden, C.L., Carroll, M.D., Kit, B.K., Flegal, K.M.: Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 307, 483–490 (2012). doi:10.1001/jama.2012.40. jama.2012.40 [pii]

    Article  PubMed  Google Scholar 

  4. Pi-Sunyer, F.X.: The obesity epidemic: pathophysiology and consequences of obesity. Obes. Res. 10(Suppl 2), 97S–104S (2002). doi:10.1038/oby.2002.202

    Article  PubMed  Google Scholar 

  5. Finkelstein, E.A., Trogdon, J.G., Cohen, J.W., Dietz, W.: Annual medical spending attributable to obesity: payer-and service-specific estimates. Health Aff. 28, w822–w831 (2009). doi:10.1377/hlthaff.28.5.w822

    Article  Google Scholar 

  6. Rappange, D.R., Brouwer, W.B., Brouwer, W.B., Hoogenveen, R.T., Van Baal, P.H.: Healthcare costs and obesity prevention: drug costs and other sector-specific consequences. Pharmacoeconomics 27, 1031–1044 (2009). doi:10.2165/11319900-000000000-00000

    Article  PubMed  Google Scholar 

  7. Wolf, A.M., Colditz, G.A.: Current estimates of the economic cost of obesity in the United States. Obes. Res. 6, 97–106 (1998)

    Article  PubMed  CAS  Google Scholar 

  8. Peeters, A., et al.: Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann. Intern. Med. 138, 24–32 (2003). doi:200301070-00008 [pii]

    Article  PubMed  Google Scholar 

  9. WHO: Diet, nutrition and the prevention of chronic diseases. http://www.who.int/mediacentre/news/releases/2003/pr20/en/ (2003). Accessed 3 July 2009

  10. NHLBI Obesity Education Initiative Expert Panel on the Identification, Evaluation, and Treatment of Obesity in Adults (US). Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda (MD): National Heart, Lung, and Blood Institute; Sep 1998 Available from: http://www.ncbi.nlm.nih.gov/books/NBK2003/

  11. Puska, P., Nishida, C., Porter, D., World Health Organization: Obesity and overweight. http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/print.html (2006). Accessed 3 July 2009

  12. Bray, G.A.: Lifestyle and pharmacological approaches to weight loss: efficacy and safety. J. Clin. Endocrinol. Metab. 93, S81–S88 (2008). doi:10.1210/jc.2008-1294. jc.2008-1294 [pii]

    Article  PubMed  CAS  Google Scholar 

  13. Fujioka, K.: Management of obesity as a chronic disease: nonpharmacologic, pharmacologic, and surgical options. Obes. Res. 10(Suppl 2), 116S–123S (2002). doi:10.1038/oby.2002.204

    Article  PubMed  Google Scholar 

  14. Avenell, A., et al.: Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol. Assess. 8(iii–iv), 1–182 (2004). doi:99-02-02 [pii]

    Google Scholar 

  15. Rucker, D., Padwal, R., Li, S.K., Curioni, C., Lau, D.C.: Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ 335, 1194–1199 (2007). doi:10.1136/bmj.39385.413113.25. bmj.39385.413113.25 [pii]

    Article  PubMed  CAS  Google Scholar 

  16. Bays, H.E.: Lorcaserin: drug profile and illustrative model of the regulatory challenges of weight-loss drug development. Expert Rev. Cardiovasc. Ther. 9, 265–277 (2011). doi:10.1586/erc.10.22

    Article  PubMed  CAS  Google Scholar 

  17. Bays, H.E., Gadde, K.M.: Phentermine/topiramate for weight reduction and treatment of adverse metabolic consequences in obesity. Drugs Today (Barc.) 47, 903–914 (2011). doi:10.1358/dot.2011.47.12.1718738. 1718738 [pii]

    CAS  Google Scholar 

  18. Snow, V., Barry, P., Fitterman, N., Qaseem, A., Weiss, K.: Pharmacologic and surgical management of obesity in primary care: a clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 142, 525–531 (2005). doi:142/7/525 [pii]

    Article  PubMed  Google Scholar 

  19. Bult, M.J., van Dalen, T., Muller, A.F.: Surgical treatment of obesity. Eur. J. Endocrinol. 158, 135–145 (2008). doi:10.1530/EJE-07-0145. 158/2/135 [pii]

    Article  PubMed  CAS  Google Scholar 

  20. NIH: The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. National Institutes of Health, National Heart, Lung, and Blood Institute, and North American Association for the Study of Obesity, Bethesda (2000) (NIH Publication Number 00-4084)

    Google Scholar 

  21. Fisher, B.L., Schauer, P.: Medical and surgical options in the treatment of severe obesity. Am. J. Surg. 184, 9S–16S (2002). doi:S000296100201173X [pii]

    Article  PubMed  Google Scholar 

  22. Schneider, B.E., Mun, E.C.: Surgical management of morbid obesity. Diabetes Care 28, 475–480 (2005). doi:28/2/475 [pii]

    Article  PubMed  Google Scholar 

  23. Picot, J., et al.: The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation. Health Technol. Assess. 13, 1–190, 215–357, iii–iv (2009). doi:10.3310/hta13410

  24. Christou, N. V. et al.: Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Ann. Surg. 240, 416–423; discussion 423–414, (2004). doi:00000658-200409000-00003 [pii]

    Google Scholar 

  25. Buchwald, H., Williams, S.E.: Bariatric surgery worldwide. Obes. Surg. 14, 1157–1164 (2003). doi:10.1381/0960892042387057 (2004)

    Article  Google Scholar 

  26. Field, B.C., Chaudhri, O.B., Bloom, S.R.: Obesity treatment: novel peripheral targets. Br. J. Clin. Pharmacol. 68, 830–843 (2009). doi:10.1111/j.1365-2125.2009.03522.x. BCP3522 [pii]

    Article  PubMed  CAS  Google Scholar 

  27. Schwartz, M.W., Woods, S.C., Porte Jr., D., Seeley, R.J., Baskin, D.G.: Central nervous system control of food intake. Nature 404, 661–671 (2000). doi:10.1038/35007534

    PubMed  CAS  Google Scholar 

  28. De Vriese, C., Delporte, C.: Ghrelin: a new peptide regulating growth hormone release and food intake. Int. J. Biochem. Cell Biol. 40, 1420–1424 (2008). doi:10.1016/j.biocel.2007.04.020. S1357-2725(07)00138-0 [pii]

    Article  PubMed  Google Scholar 

  29. Kojima, M., et al.: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999). doi:10.1038/45230

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Cone, R.D., et al.: The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 25(Suppl 5), S63–S67 (2001). doi:10.1038/sj.ijo.0801913

    Article  PubMed  CAS  Google Scholar 

  32. Millington, G.W.: The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr. Metab. (Lond.) 4, 18 (2007). doi:10.1186/1743-7075-4-18. 1743-7075-4-18 [pii]

    Article  Google Scholar 

  33. Williams, G., Harrold, J.A., Cutler, D.J.: The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. Proc. Nutr. Soc. 59, 385–396 (2000). doi:S0029665100000434 [pii]

    Article  PubMed  CAS  Google Scholar 

  34. Cummings, D.E., et al.: Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623–1630 (2002). doi:10.1056/NEJMoa012908346/21/1623 [pii]

    Article  PubMed  Google Scholar 

  35. English, P.J., Ghatei, M.A., Malik, I.A., Bloom, S.R., Wilding, J.P.: Food fails to suppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. 87, 2984 (2002)

    Article  PubMed  CAS  Google Scholar 

  36. Stock, S., et al.: Ghrelin, peptide YY, glucose-dependent insulinotropic polypeptide, and hunger responses to a mixed meal in anorexic, obese, and control female adolescents. J. Clin. Endocrinol. Metab. 90, 2161–2168 (2005). doi:10.1210/jc.2004-1251. jc.2004-1251 [pii]

    Article  PubMed  CAS  Google Scholar 

  37. Hansen, T.K., et al.: Weight loss increases circulating levels of ghrelin in human obesity. Clin. Endocrinol. (Oxf) 56, 203–206 (2002). doi:1456 [pii]

    Article  CAS  Google Scholar 

  38. Janas-Kozik, M., Krupka-Matuszczyk, I., Malinowska-Kolodziej, I., Lewin-Kowalik, J.: Total ghrelin plasma level in patients with the restrictive type of anorexia nervosa. Regul. Pept. 140, 43–46 (2007). doi:10.1016/j.regpep.2006.11.005. S0167-0115(06)00223-0 [pii]

    Article  PubMed  CAS  Google Scholar 

  39. Goldstone, A.P., et al.: Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance. J. Clin. Endocrinol. Metab. 89, 1718–1726 (2004)

    Article  PubMed  CAS  Google Scholar 

  40. Monteiro, M.P., et al.: Increase in ghrelin levels after weight loss in obese Zucker rats is prevented by gastric banding. Obes. Surg. 17, 1599–1607 (2007). doi:10.1007/s11695-007-9324-7

    Article  PubMed  Google Scholar 

  41. Lu, S.C., et al.: An acyl-ghrelin-specific neutralizing antibody inhibits the acute ghrelin-mediated orexigenic effects in mice. Mol. Pharmacol. 75, 901–907 (2009). doi:10.1124/mol.108.052852. mol.108.052852 [pii]

    Article  PubMed  CAS  Google Scholar 

  42. Zakhari, J.S., Zorrilla, E.P., Zhou, B., Mayorov, A.V., Janda, K.D.: Oligoclonal antibody targeting ghrelin increases energy expenditure and reduces food intake in fasted mice. Mol. Pharm. 9, 281–289 (2012). doi:10.1021/mp200376c

    Article  PubMed  CAS  Google Scholar 

  43. Esler, W.P., et al.: Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 148, 5175–5185 (2007). doi:10.1210/en.2007-0239. en.2007-0239 [pii]

    Article  PubMed  CAS  Google Scholar 

  44. Zorrilla, E.P., et al.: Vaccination against weight gain. Proc. Natl. Acad. Sci. U. S. A. 103, 13226–13231 (2006). doi:10.1073/pnas.0605376103. 0605376103 [pii]

    Article  PubMed  CAS  Google Scholar 

  45. Vizcarra, J.A., Kirby, J.D., Kim, S.K., Galyean, M.L.: Active immunization against ghrelin decreases weight gain and alters plasma concentrations of growth hormone in growing pigs. Domest. Anim. Endocrinol. 33, 176–189 (2007). doi:10.1016/j.domaniend.2006.05.005. S0739-7240(06)00112-3 [pii]

    Article  PubMed  CAS  Google Scholar 

  46. Jennings, G.T., Bachmann, M.F.: Immunodrugs: therapeutic VLP-based vaccines for chronic diseases. Annu. Rev. Pharmacol. Toxicol. 49, 303–326 (2009). doi:10.1146/annurev-pharmtox-061008-103129

    Article  PubMed  CAS  Google Scholar 

  47. Brown, M.J.: Therapeutic potential of vaccines in the management of hypertension. Drugs 68, 2557–2560 (2008). doi:68182 [pii]

    Article  PubMed  CAS  Google Scholar 

  48. Hewat, E.A., Booth, T.F., Wade, R.H., Roy, P.: 3-D reconstruction of bluetongue virus tubules using cryoelectron microscopy. J. Struct. Biol. 108, 35–48 (1992). doi:1047-8477(92)90005-U[pii]

    Article  PubMed  CAS  Google Scholar 

  49. Ghosh, M.K., Borca, M.V., Roy, P.: Virus-derived tubular structure displaying foreign sequences on the surface elicit CD4+ Th cell and protective humoral responses. Virology 302, 383–392 (2002). doi:S004268220291648X [pii]

    Article  PubMed  CAS  Google Scholar 

  50. Andrade, S., Carreira, M., Ribeiro, A.: Development of an Anti-Ghrelin Vaccine for Obesity Treatment Endocr. Rev. 32, P2-305 (2011). (The Endocrine Society).

    Google Scholar 

  51. Moayyedi, P.: The epidemiology of obesity and gastrointestinal and other diseases: an overview. Dig. Dis. Sci. 53, 2293–2299 (2008). doi:10.1007/s10620-008-0410-z

    Article  PubMed  Google Scholar 

  52. Kojima, M., Kangawa, K.: Ghrelin: structure and function. Physiol. Rev. 85, 495–522 (2005). doi:10.1152/physrev.00012.2004. 85/2/495 [pii]

    Article  PubMed  CAS  Google Scholar 

  53. Mayorov, A.V., et al.: Catalytic antibody degradation of ghrelin increases whole-body metabolic rate and reduces refeeding in fasting mice. Proc. Natl. Acad. Sci. U. S. A. 105, 17487–17492 (2008). doi:10.1073/pnas.0711808105

    Article  PubMed  CAS  Google Scholar 

  54. Lechner, F., et al.: Virus-like particles as a modular system for novel vaccines. Intervirology 45, 212–217 (2002). doi:10.1159/000067912int45212 [pii]

    Article  PubMed  Google Scholar 

  55. Mikhailov, M., Monastyrskaya, K., Bakker, T., Roy, P.: A new form of particulate single and multiple immunogen delivery system based on recombinant bluetongue virus-derived tubules. Virology 217, 323–331 (1996). doi:10.1006/viro.1996.0119. S0042-6822(96)90119-1 [pii]

    Article  PubMed  CAS  Google Scholar 

  56. Dornonville de la Cour, C., et al.: Ghrelin treatment reverses the reduction in weight gain and body fat in gastrectomised mice. Gut 54, 907–913 (2005). doi:10.1136/gut.2004.058578

    Article  PubMed  CAS  Google Scholar 

  57. Wortley, K.E., et al.: Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc. Natl. Acad. Sci. U. S. A. 101, 8227–8232 (2004). doi:10.1073/pnas.04027631010402763101 [pii]

    Article  PubMed  CAS  Google Scholar 

  58. Kellokoski, E., et al.: Ghrelin vaccination decreases plasma MCP-1 level in LDLR(–/–)-mice. Peptides 30, 2292–2300 (2009). doi:10.1016/j.peptides.2009.09.008. S0196-9781(09)00366-0 [pii]

    Article  PubMed  CAS  Google Scholar 

  59. Kalra, S.P., Dube, M.G., Sahu, A., Phelps, C.P., Kalra, P.S.: Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. U. S. A. 88, 10931–10935 (1991)

    Article  PubMed  CAS  Google Scholar 

  60. De Smet, B., et al.: Energy homeostasis and gastric emptying in ghrelin knockout mice. J. Pharmacol. Exp. Ther. 316, 431–439 (2006). doi:10.1124/jpet.105.091504. jpet.105.091504 [pii]

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

UMIB is funded by grants from FCT POCTI/FEDER Fcomp-01-0124-FEDER-015893 and Project Grant EXPL/BIM-MET/0618/2012. Portugal.

Author information

Authors and Affiliations

  1. Department of Anatomy and UMIB (Unit for Multidisciplinary Biomedical Research) of ICBAS, University of Porto, Porto, Portugal

    Sara Andrade MBSc & Mariana P. Monteiro MD, PhD

  2. CIBER de Fisiopatologia Obesidad y Nutricion (CB06/03), Instituto Salud Carlos III, Santiago de Compostela, Spain

    Marcos Carreira PhD & Felipe F. Casanueva MD, PhD

  3. Department of Medicine, USC University Hospital Complex, University of Santiago de Compostela, Santiago de Compostela, Spain

    Felipe F. Casanueva MD, PhD

  4. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, UK

    Polly Roy PhD

Authors
  1. Sara Andrade MBSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marcos Carreira PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felipe F. Casanueva MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Polly Roy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariana P. Monteiro MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariana P. Monteiro MD, PhD .

Editor information

Editors and Affiliations

  1. Institute for Molecular Vaccines, Heidelberg, Germany

    Matthias Giese

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Andrade, S., Carreira, M., Casanueva, F.F., Roy, P., Monteiro, M.P. (2014). Anti-ghrelin Therapeutic Vaccine: A Novel Approach for Obesity Treatment. In: Giese, M. (eds) Molecular Vaccines. Springer, Cham. https://doi.org/10.1007/978-3-319-00978-0_2

Download citation

Publish with us

Policies and ethics

Search

Navigation