Skip to main content
SpringerLink
Log in

Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Kisspeptin is a neuropeptide that plays an integral role in the regulation of energy intake and reproduction by acting centrally on the hypothalamus–pituitary–gonadal axis. Our current study explores for the first time the effects of a pharmacological treatment of intraperitoneal kisspeptin-10 on murine feeding behavior, respirometry parameters, energy balance, and metabolic hormones.

Methods

Two groups (n = 16) of age- and sex-matched C57BL/6 wild-type adult mice were individually housed in metabolic cages and intraperitoneally injected with either kisspeptin-10 (2 nmol in 200 µl of saline) (10 µM) or vehicle before the beginning of a dark-phase cycle. Microstructure of feeding and drinking behavior, respirometry gases, respiratory quotient (RQ), total energy expenditure (TEE), metabolic hormones, oral glucose tolerance, and lipid profiles were measured.

Results

Intraperitoneal treatment with kisspeptin-10 caused a significant reduction in food intake, meal frequency, meal size, and eating rate. Kisspeptin-10 significantly decreased TEE during both the dark and light phase cycles, while also increasing the RQ during the dark-phase cycle. In addition, mice injected with kisspeptin-10 had significantly higher plasma levels of insulin (343.8 pg/ml vs. 106.4 pg/ml; p = 0.005), leptin (855.5 pg/ml vs. 173.1 pg/ml; p = 0.02), resistin (9411.1 pg/ml vs. 4116.5 pg/ml; p = 0.001), and HDL (147.6 mg/dl vs 97.1 mg/dl; p = 0.04).

Conclusion

A pharmacological dose of kisspeptin-10 significantly altered metabolism by suppressing food intake, meal size, eating rate, and TEE while increasing the RQ. These changes were linked to increased levels of insulin, leptin, resistin, and HDL. The current results suggest that a peripheral kisspeptin treatment could alter metabolism and energy homeostasis by suppressing appetite, food intake, and fat accumulation.

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. Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88:1731–1737.

    CAS  PubMed  Google Scholar 

  2. Uenoyama Y, Pheng V, Tsukamura H, Maeda K-I. The roles of kisspeptin revisited: inside and outside the hypothalamus. J Reprod Dev. 2016;62:537–545.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–1627.

    CAS  PubMed  Google Scholar 

  4. Tng EL. Kisspeptin signalling and its roles in humans. Singap Med J. 2015;56:649–656.

    Google Scholar 

  5. Kirby HR, Maguire JJ, Colledge WH, Davenport AP. International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin receptor nomenclature, distribution, and function. Pharmacol Rev. 2010;62:565–578.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;276:28969–28975.

    CAS  PubMed  Google Scholar 

  7. Stengel A, Wang L, Goebel-Stengel M, Taché Y. Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport. 2011;22:253–257.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 2010;1364:129–138.

    CAS  PubMed  Google Scholar 

  9. Pasquier J, Kamech N, Lafont A-G, Vaudry H, Rousseau K, Dufour S. Molecular evolution of GPCRs: kisspeptin/kisspeptin receptors. J Mol Endocrinol. 2014;52:T101–T117.

    CAS  PubMed  Google Scholar 

  10. Kalamatianos T, Grimshaw SE, Poorun R, Hahn JD, Coen CW. Fasting reduces KiSS-1 expression in the anteroventral periventricular nucleus (AVPV): effects of fasting on the expression of KiSS-1 and neuropeptide Y in the AVPV or arcuate nucleus of female rats. J Neuroendocrinol. 2008;20:1089–1097.

    CAS  PubMed  Google Scholar 

  11. Castellano JM, Navarro VM, Fernández-Fernández R, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology. 2005;146:3917–3925.

    CAS  PubMed  Google Scholar 

  12. Vu JP, Luong L, Parsons WF, et al. Long-term intake of a high-protein diet affects body phenotype, metabolism, and plasma hormones in mice. J Nutr. 2017;147:2243–2251.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Morton GJ, Thatcher BS, Reidelberger RD, et al. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinol Metab. 2012;302:E134–E144.

    CAS  PubMed  Google Scholar 

  14. Wang T, Cui X, Xie L, et al. Kisspeptin receptor GPR54 promotes adipocyte differentiation and fat accumulation in mice. Front Physiol. 2018;9:209.

    PubMed  PubMed Central  Google Scholar 

  15. Wolfe A, Hussain MA. The emerging role(s) for kisspeptin in metabolism in mammals. Front Endocrinol (Lausanne). 2018;9:184.

    Google Scholar 

  16. Tolson KP, Garcia C, Yen S, et al. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J Clin Investig. 2014;124:3075–3079.

    CAS  PubMed  Google Scholar 

  17. Knight WD, Witte MM, Parsons AD, Gierach M, Overton JM. Long-term caloric restriction reduces metabolic rate and heart rate under cool and thermoneutral conditions in FBNF1 rats. Mech Ageing Dev. 2011;132:220–229.

    PubMed  PubMed Central  Google Scholar 

  18. De Bond J-AP, Tolson KP, Nasamran C, Kauffman AS, Smith JT. Unaltered hypothalamic metabolic gene expression in Kiss1r knockout mice despite obesity and reduced energy expenditure. J Neuroendocrinol. 2016;. https://doi.org/10.1111/jne.12430.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8:21–34.

    CAS  PubMed  Google Scholar 

  20. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;18:298–303.

    CAS  PubMed  Google Scholar 

  21. Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Backholer K, Smith JT, Rao A, et al. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology. 2010;151:2233–2243.

    PubMed  Google Scholar 

  23. Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011;173:37–56.

    CAS  PubMed  Google Scholar 

  24. Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR, Anderson GM. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology. 2011;152:1541–1550.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Castellano JM, Navarro VM, Fernández-Fernández R, et al. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes. 2006;55:2602–2610.

    CAS  PubMed  Google Scholar 

  26. Luque RM, Kineman RD, Tena-Sempere M. Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line. Endocrinology. 2007;148:4601–4611.

    CAS  PubMed  Google Scholar 

  27. Zhu HJ, Li SJ, Pan H, et al. The changes of serum leptin and kisspeptin levels in Chinese children and adolescents in different pubertal stages. Int J Endocrinol. 2016;2016:6790794.

    PubMed  PubMed Central  Google Scholar 

  28. Pandit R, Beerens S, Adan RAH. Role of leptin in energy expenditure: the hypothalamic perspective. Am J Physiol Integr Comp Physiol. 2017;312:R938–R947.

    CAS  Google Scholar 

  29. Hukshorn CJ, Saris WHM. Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care. 2004;7:629–633.

    CAS  PubMed  Google Scholar 

  30. Nogueiras R, Novelle MG, Vazquez MJ, Lopez M, Dieguez C. Resistin: regulation of food intake, glucose homeostasis and lipid metabolism. Endocr Dev. 2010;17:175–184.

    CAS  PubMed  Google Scholar 

  31. Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526:26–30.

    CAS  PubMed  Google Scholar 

  32. Cifani C, Durocher Y, Pathak A, et al. Possible common central pathway for resistin and insulin in regulating food intake. Acta Physiol (Oxf). 2009;196:395–400.

    CAS  Google Scholar 

  33. Tovar S, Nogueiras R, Tung LYC, et al. Central administration of resistin promotes short-term satiety in rats. Eur J Endocrinol. 2005;153:R1–R5.

    CAS  PubMed  Google Scholar 

  34. Hauge-Evans AC, Richardson CC, Milne HM, Christie MR, Persaud SJ, Jones PM. A role for kisspeptin in islet function. Diabetologia. 2006;49:2131–2135.

    CAS  PubMed  Google Scholar 

  35. Song W-J, Mondal P, Wolfe A, et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014;19:667–681.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Andreozzi F, Mannino GC, Mancuso E, Spiga R, Perticone F, Sesti G. Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals. PLoS One. 2017;12:e0179834.

    PubMed  PubMed Central  Google Scholar 

  37. Schwetz TA, Reissaus CA, Piston DW. Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10. PLoS One. 2014;9:e113020.

    PubMed  PubMed Central  Google Scholar 

  38. Bowe JE, King AJ, Kinsey-Jones JS, et al. Kisspeptin stimulation of insulin secretion: mechanisms of action in mouse islets and rats. Diabetologia. 2009;52:855–862.

    CAS  PubMed  Google Scholar 

  39. Wu J, Fu W, Huang Y, Ni Y. Effects of kisspeptin-10 on lipid metabolism in cultured chicken hepatocytes. Asian Australas J Anim Sci. 2012;25:1229–1236.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Aydin M, Oktar S, Yonden Z, Ozturk OH, Yilmaz B. Direct and indirect effects of kisspeptin on liver oxidant and antioxidant systems in young male rats. Cell Biochem Funct. 2010;28:293–299.

    CAS  PubMed  Google Scholar 

  41. Lecoultre V, Ravussin E, Redman LM. The fall in leptin concentration is a major determinant of the metabolic adaptation induced by caloric restriction independently of the changes in leptin circadian rhythms. J Clin Endocrinol Metab. 2011;96:E1512–E1516.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jakobsdottir S, van Nieuwpoort IC, van Bunderen CC, et al. Acute and short-term effects of caloric restriction on metabolic profile and brain activation in obese, postmenopausal women. Int J Obes (Lond). 2016;40:1671–1678.

    CAS  Google Scholar 

Download references

Acknowledgments

Grant support NIH T32 DK 07180 (TD).

Author information

Authors and Affiliations

  1. The Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Tien S. Dong

  2. Division of Gastroenterology, Hepatology and Parenteral Nutrition, Department of Medicine and Human Genetics, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    John P. Vu, Suwan Oh, Daniel Sanford & Joseph R. Pisegna

  3. AbbVie, Sunnyvale, CA, USA

    John P. Vu

  4. Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Patrizia Germano

  5. CURE/Digestive Diseases Research Center, Department of Medicine, University of California, Los Angeles, CA, USA

    Patrizia Germano

  6. Division of Pulmonary and Critical Care, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA

    Patrizia Germano

Authors
  1. Tien S. Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John P. Vu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suwan Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Sanford
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph R. Pisegna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Patrizia Germano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tien S. Dong.

Ethics declarations

Conflict of interest

The authors have no potential conflict of interest to disclose.

Ethical approval

All animal research procedures were approved by the Department of Veterans Affair Institutional Animal Care and Use Committee (Protocol #03016-05).

Additional information

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

Dong, T.S., Vu, J.P., Oh, S. et al. Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice. Dig Dis Sci 65, 2254–2263 (2020). https://doi.org/10.1007/s10620-019-05950-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05950-7

Keywords

Search

Navigation