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.
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.
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).
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, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
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.
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.
Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–1627.
Tng EL. Kisspeptin signalling and its roles in humans. Singap Med J. 2015;56:649–656.
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.
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.
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.
Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 2010;1364:129–138.
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.
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.
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.
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.
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.
Wang T, Cui X, Xie L, et al. Kisspeptin receptor GPR54 promotes adipocyte differentiation and fat accumulation in mice. Front Physiol. 2018;9:209.
Wolfe A, Hussain MA. The emerging role(s) for kisspeptin in metabolism in mammals. Front Endocrinol (Lausanne). 2018;9:184.
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.
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.
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.
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.
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.
Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812.
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.
Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011;173:37–56.
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.
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.
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.
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.
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.
Hukshorn CJ, Saris WHM. Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care. 2004;7:629–633.
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.
Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526:26–30.
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.
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.
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.
Song W-J, Mondal P, Wolfe A, et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014;19:667–681.
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.
Schwetz TA, Reissaus CA, Piston DW. Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10. PLoS One. 2014;9:e113020.
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.
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.
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.
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.
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.
Grant support NIH T32 DK 07180 (TD).
Conflict of interest
The authors have no potential conflict of interest to disclose.
All animal research procedures were approved by the Department of Veterans Affair Institutional Animal Care and Use Committee (Protocol #03016-05).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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