Skip to main content
Erschienen in: Digestive Diseases and Sciences 8/2020

15.11.2019 | Original Article

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

verfasst von: Tien S. Dong, John P. Vu, Suwan Oh, Daniel Sanford, Joseph R. Pisegna, Patrizia Germano

Erschienen in: Digestive Diseases and Sciences | Ausgabe 8/2020

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat 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.PubMed 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.PubMed
2.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
3.
Zurück zum Zitat Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–1627.PubMed Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614–1627.PubMed
4.
Zurück zum Zitat Tng EL. Kisspeptin signalling and its roles in humans. Singap Med J. 2015;56:649–656. Tng EL. Kisspeptin signalling and its roles in humans. Singap Med J. 2015;56:649–656.
5.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
6.
Zurück zum Zitat 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.PubMed 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.PubMed
7.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
8.
Zurück zum Zitat Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 2010;1364:129–138.PubMed Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 2010;1364:129–138.PubMed
9.
Zurück zum Zitat 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.PubMed 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.PubMed
10.
Zurück zum Zitat 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.PubMed 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.PubMed
11.
Zurück zum Zitat 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.PubMed 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.PubMed
12.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
13.
Zurück zum Zitat 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.PubMed 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.PubMed
14.
Zurück zum Zitat Wang T, Cui X, Xie L, et al. Kisspeptin receptor GPR54 promotes adipocyte differentiation and fat accumulation in mice. Front Physiol. 2018;9:209.PubMedPubMedCentral Wang T, Cui X, Xie L, et al. Kisspeptin receptor GPR54 promotes adipocyte differentiation and fat accumulation in mice. Front Physiol. 2018;9:209.PubMedPubMedCentral
15.
Zurück zum Zitat Wolfe A, Hussain MA. The emerging role(s) for kisspeptin in metabolism in mammals. Front Endocrinol (Lausanne). 2018;9:184. Wolfe A, Hussain MA. The emerging role(s) for kisspeptin in metabolism in mammals. Front Endocrinol (Lausanne). 2018;9:184.
16.
Zurück zum Zitat 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.PubMed 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.PubMed
17.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
19.
Zurück zum Zitat 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.PubMed 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.PubMed
20.
Zurück zum Zitat 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.PubMed 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.PubMed
21.
Zurück zum Zitat Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812.PubMedPubMedCentral Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812.PubMedPubMedCentral
22.
Zurück zum Zitat 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 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
23.
Zurück zum Zitat Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011;173:37–56.PubMed Cravo RM, Margatho LO, Osborne-Lawrence S, et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience. 2011;173:37–56.PubMed
24.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
25.
Zurück zum Zitat 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.PubMed 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.PubMed
26.
Zurück zum Zitat 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.PubMed 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.PubMed
27.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
28.
Zurück zum Zitat 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. 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.
29.
Zurück zum Zitat Hukshorn CJ, Saris WHM. Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care. 2004;7:629–633.PubMed Hukshorn CJ, Saris WHM. Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care. 2004;7:629–633.PubMed
30.
Zurück zum Zitat 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.PubMed 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.PubMed
31.
Zurück zum Zitat Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526:26–30.PubMed Morash BA, Willkinson D, Ur E, Wilkinson M. Resistin expression and regulation in mouse pituitary. FEBS Lett. 2002;526:26–30.PubMed
32.
Zurück zum Zitat 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. 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.
33.
Zurück zum Zitat 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.PubMed 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.PubMed
34.
Zurück zum Zitat 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.PubMed 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.PubMed
35.
Zurück zum Zitat Song W-J, Mondal P, Wolfe A, et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014;19:667–681.PubMedPubMedCentral Song W-J, Mondal P, Wolfe A, et al. Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab. 2014;19:667–681.PubMedPubMedCentral
36.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
37.
Zurück zum Zitat Schwetz TA, Reissaus CA, Piston DW. Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10. PLoS One. 2014;9:e113020.PubMedPubMedCentral Schwetz TA, Reissaus CA, Piston DW. Differential stimulation of insulin secretion by GLP-1 and Kisspeptin-10. PLoS One. 2014;9:e113020.PubMedPubMedCentral
38.
Zurück zum Zitat 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.PubMed 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.PubMed
39.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
40.
Zurück zum Zitat 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.PubMed 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.PubMed
41.
Zurück zum Zitat 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.PubMedPubMedCentral 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.PubMedPubMedCentral
42.
Zurück zum Zitat 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. 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.
Metadaten
Titel
Intraperitoneal Treatment of Kisspeptin Suppresses Appetite and Energy Expenditure and Alters Gastrointestinal Hormones in Mice
verfasst von
Tien S. Dong
John P. Vu
Suwan Oh
Daniel Sanford
Joseph R. Pisegna
Patrizia Germano
Publikationsdatum
15.11.2019
Verlag
Springer US
Erschienen in
Digestive Diseases and Sciences / Ausgabe 8/2020
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-019-05950-7

Weitere Artikel der Ausgabe 8/2020

Digestive Diseases and Sciences 8/2020 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Notfall-TEP der Hüfte ist auch bei 90-Jährigen machbar

26.04.2024 Hüft-TEP Nachrichten

Ob bei einer Notfalloperation nach Schenkelhalsfraktur eine Hemiarthroplastik oder eine totale Endoprothese (TEP) eingebaut wird, sollte nicht allein vom Alter der Patientinnen und Patienten abhängen. Auch über 90-Jährige können von der TEP profitieren.

Niedriger diastolischer Blutdruck erhöht Risiko für schwere kardiovaskuläre Komplikationen

25.04.2024 Hypotonie Nachrichten

Wenn unter einer medikamentösen Hochdrucktherapie der diastolische Blutdruck in den Keller geht, steigt das Risiko für schwere kardiovaskuläre Ereignisse: Darauf deutet eine Sekundäranalyse der SPRINT-Studie hin.

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

25.04.2024 Hypertonie Nachrichten

Beginnen ältere Männer im Pflegeheim eine Antihypertensiva-Therapie, dann ist die Frakturrate in den folgenden 30 Tagen mehr als verdoppelt. Besonders häufig stürzen Demenzkranke und Männer, die erstmals Blutdrucksenker nehmen. Dafür spricht eine Analyse unter US-Veteranen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.