{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:35:22Z","timestamp":1787502922580,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,15]],"date-time":"2018-09-15T00:00:00Z","timestamp":1536969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent times have seen an increasing move towards harnessing the health-promoting benefits of food and dietary constituents while providing scientific evidence to substantiate their claims. In particular, the potential for bioactive protein hydrolysates and peptides to enhance health in conjunction with conventional pharmaceutical therapy is being investigated. Dairy-derived proteins have been shown to contain bioactive peptide sequences with various purported health benefits, with effects ranging from the digestive system to cardiovascular circulation, the immune system and the central nervous system. Interestingly, the ability of dairy proteins to modulate metabolism and appetite has recently been reported. The ghrelin receptor (GHSR-1a) is a G-protein coupled receptor which plays a key role in the regulation of food intake. Pharmacological manipulation of the growth hormone secretagogue receptor-type 1a (GHSR-1a) receptor has therefore received a lot of attention as a strategy to combat disorders of appetite and body weight, including age-related malnutrition and the progressive muscle wasting syndrome known as cachexia. In this study, a milk protein-derivative is shown to increase GHSR-1a-mediated intracellular calcium signalling in a concentration-dependent manner in vitro. Significant increases in calcium mobilisation were also observed in a cultured neuronal cell line heterologously expressing the GHS-R1a. In addition, both additive and synergistic effects were observed following co-exposure of GHSR-1a to both the hydrolysate and ghrelin. Subsequent in vivo studies monitored standard chow intake in healthy male and female Sprague-Dawley rats after dosing with the casein hydrolysate (CasHyd). Furthermore, the provision of gastro-protected oral delivery to the bioactive in vivo may aid in the progression of in vitro efficacy to in vivo functionality. In summary, this study reports a ghrelin-stimulating bioactive peptide mixture (CasHyd) with potent effects in vitro. It also provides novel and valuable translational data supporting the potential role of CasHyd as an appetite-enhancing bioactive. Further mechanistic studies are required in order to confirm efficacy as a ghrelinergic bioactive in susceptible population groups.<\/jats:p>","DOI":"10.3390\/ijms19092780","type":"journal-article","created":{"date-parts":[[2018,9,17]],"date-time":"2018-09-17T10:42:20Z","timestamp":1537180940000},"page":"2780","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A Dairy-Derived Ghrelinergic Hydrolysate Modulates Food Intake In Vivo"],"prefix":"10.3390","volume":"19","author":[{"given":"Ken","family":"Howick","sequence":"first","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"School of Pharmacy, University College Cork, Cork T12 YT20, Ireland"},{"name":"Food for Health Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shauna E.","family":"Wallace-Fitzsimons","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Kandil","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Food for Health Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Chru\u015bcicka","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mert","family":"Calis","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eoin","family":"Murphy","sequence":"additional","affiliation":[{"name":"Moorepark Food Research Centre, Teagasc, Fermoy, Co. Cork P61 C966, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Moorepark Food Research Centre, Teagasc, Fermoy, Co. Cork P61 C966, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayoa","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Moorepark Food Research Centre, Teagasc, Fermoy, Co. Cork P61 C966, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate M.","family":"Barry","sequence":"additional","affiliation":[{"name":"Moorepark Food Research Centre, Teagasc, Fermoy, Co. Cork P61 C966, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil M.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Moorepark Food Research Centre, Teagasc, Fermoy, Co. Cork P61 C966, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoife M.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Food &amp; Nutritional Sciences, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Cryan","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5433-8398","authenticated-orcid":false,"given":"Brendan T.","family":"Griffin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, University College Cork, Cork T12 YT20, Ireland"},{"name":"Food for Health Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-3797","authenticated-orcid":false,"given":"Harri\u00ebt","family":"Schellekens","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neuroscience, University College Cork, Cork T12 YT20, Ireland"},{"name":"Food for Health Ireland, University College Cork, Cork T12 YT20, Ireland"},{"name":"Alimentary Pharmabiotic Centre (APC) Microbiome Ireland, University College Cork, Cork T12 YT20, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.jff.2015.06.021","article-title":"The scientific evidence for the role of milk protein-derived bioactive peptides in humans: A Review","volume":"17","author":"Nongonierma","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1179\/1476830513Y.0000000099","article-title":"A natural solution for obesity: Bioactives for the prevention and treatment of weight gain. A review","volume":"18","author":"Schellekens","year":"2015","journal-title":"Nutr. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1039\/c1fo10017c","article-title":"The potential role of milk-derived peptides in cardiovascular disease","volume":"2","author":"Phelan","year":"2011","journal-title":"Food Funct."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.idairyj.2014.04.004","article-title":"Milk protein-derived peptides induce 5-HT2C-mediated satiety in vivo","volume":"38","author":"Schellekens","year":"2014","journal-title":"Int. Dairy J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.00356.2016","article-title":"Whey protein effects on energy balance link the intestinal mechanisms of energy absorption with adiposity and hypothalamic neuropeptide gene expression","volume":"313","author":"Nilaweera","year":"2017","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jff.2009.01.007","article-title":"Milk-derived bioactive peptides: From science to applications","volume":"1","author":"Korhonen","year":"2009","journal-title":"J. Funct. Foods"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fox, P.F., and McSweeney, P.L.H. (2003). Milk Protein Hydrolysates and Bioactive Peptides. Advanced Dairy Chemistry\u20141 Proteins: Part A\/Part B, Springer US.","DOI":"10.1007\/978-1-4419-8602-3"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.2174\/1381612033454892","article-title":"Food-derived bioactive peptides\u2014Opportunities for designing future foods","volume":"9","author":"Korhonen","year":"2003","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/45230","article-title":"Ghrelin is a growth-hormone-releasing acylated peptide from stomach","volume":"402","author":"Kojima","year":"1999","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.molmet.2015.03.005","article-title":"Ghrelin","volume":"4","author":"Nogueiras","year":"2015","journal-title":"Mol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Howick, K., Griffin, B., Cryan, J., and Schellekens, H. (2017). From Belly to Brain: Targeting the ghrelin receptor in appetite and food intake regulation. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020273"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.nut.2008.06.013","article-title":"Emergence of ghrelin as a treatment for cachexia syndromes","volume":"24","author":"DeBoer","year":"2008","journal-title":"Nutrition"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Miki, K., Maekura, R., Nagaya, N., Nakazato, M., Kimura, H., Murakami, S., Ohnishi, S., Hiraga, T., Miki, M., and Kitada, S. (2012). Ghrelin treatment of cachectic patients with chronic obstructive pulmonary disease: A multicenter, randomized, double-blind, placebo-controlled trial. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035708"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/S1470-2045(14)71154-4","article-title":"Anamorelin for patients with cancer cachexia: An integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials","volume":"16","author":"Garcia","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S1470-2045(15)00558-6","article-title":"Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): Results from two randomised, double-blind, phase 3 trials","volume":"17","author":"Temel","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.beem.2004.02.004","article-title":"Endocrinology of anorexia of ageing","volume":"18","author":"Chapman","year":"2004","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.maturitas.2013.01.016","article-title":"The anorexia of ageing: Physiopathology, prevalence, associated comorbidity and mortality. A systematic review","volume":"74","author":"Malafarina","year":"2013","journal-title":"Maturitas"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Fujitsuka, N., and Uezono, Y. (2014). Rikkunshito, a ghrelin potentiator, ameliorates anorexia-cachexia syndrome. Front. Pharm., 5.","DOI":"10.3389\/fphar.2014.00271"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"L233","DOI":"10.1152\/ajplung.00096.2013","article-title":"Rikkunshito ameliorates bleomycin-induced acute lung injury in a ghrelin-independent manner","volume":"306","author":"Tsubouchi","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"E373","DOI":"10.1152\/ajpendo.00116.2013","article-title":"New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line","volume":"306","author":"Terawaki","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1021\/jf501425m","article-title":"Teaghrelins, unique acylated flavonoid tetraglycosides in Chin-shin oolong tea, are putative oral agonists of the ghrelin receptor","volume":"62","author":"Lo","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2014.10.063","article-title":"Emoghrelin, a unique emodin derivative in Heshouwu, stimulates growth hormone secretion via activation of the ghrelin receptor","volume":"159","author":"Lo","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Torres-Fuentes, C., Theeuwes, W.F., McMullen, M.K., McMullen, A.K., Dinan, T.G., Cryan, J.F., and Schellekens, H. (2014). Devil\u2019s Claw to suppress appetite\u2014Ghrelin receptor modulation potential of a Harpagophytum procumbens root extract. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0103118"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.ejps.2016.09.003","article-title":"Nutraceuticals: A paradigm of proactive medicine","volume":"96","author":"Santini","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1080\/17512433.2018.1464911","article-title":"Nutraceuticals\u2014Shedding light on the grey area between pharmaceuticals and food","volume":"11","author":"Santini","year":"2018","journal-title":"Expert Rev. Clin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.ijpharm.2017.11.051","article-title":"Sustained-release multiparticulates for oral delivery of a novel peptidic ghrelin agonist: Formulation design and in vitro characterization","volume":"536","author":"Howick","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1074\/jbc.M112.382473","article-title":"Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling","volume":"288","author":"Schellekens","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Schellekens, H., Clarke, G., Jeffery, I.B., Dinan, T.G., and Cryan, J.F. (2012). Dynamic 5-HT2C Receptor Editing in a Mouse Model of Obesity. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0032266"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00535-005-1739-0","article-title":"Molecular characterization and distribution of motilin family receptors in the human gastrointestinal tract","volume":"41","author":"Takeshita","year":"2006","journal-title":"J. Gastroenterol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0378-5173(98)00400-1","article-title":"Gastrointestinal transit of pellets in rats: Effect of size and density","volume":"180","author":"Tuleu","year":"1999","journal-title":"Int. J. Pharm."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.neuropharm.2009.06.024","article-title":"Lean mean fat reducing \u201cghrelin\u201d machine: Hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity","volume":"58","author":"Schellekens","year":"2010","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/35038090","article-title":"Ghrelin induces adiposity in rodents","volume":"407","author":"Tschop","year":"2000","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"5992","DOI":"10.1210\/jcem.86.12.8111","article-title":"Ghrelin enhances appetite and increases food intake in humans","volume":"86","author":"Wren","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.copbio.2007.01.013","article-title":"Food-derived peptides with biological activity: From research to food applications","volume":"18","author":"Hartmann","year":"2007","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.idairyj.2009.11.008","article-title":"Encapsulation for preservation of functionality and targeted delivery of bioactive food components","volume":"20","author":"Faas","year":"2010","journal-title":"Int. Dairy J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.tifs.2016.05.007","article-title":"Oral delivery strategies for nutraceuticals: Delivery vehicles and absorption enhancers","volume":"53","author":"Gleeson","year":"2016","journal-title":"Trends Food Sci. Technol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"301","DOI":"10.4155\/tde.12.152","article-title":"Opportunities for drug-delivery research in nutraceuticals and functional foods?","volume":"4","author":"Brayden","year":"2013","journal-title":"Ther. Deliv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.cofs.2014.09.005","article-title":"Bioactive peptides and protein hydrolysates: Research trends and challenges for application as nutraceuticals and functional food ingredients","volume":"1","year":"2015","journal-title":"Curr. Opin. Food Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"36456","DOI":"10.1038\/srep36456","article-title":"A novel non-peptidic agonist of the ghrelin receptor with orexigenic activity in vivo","volume":"6","author":"Pardo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_40","first-page":"259","article-title":"HIV-based vectors. Preparation and use","volume":"69","author":"Follenzi","year":"2002","journal-title":"Methods Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/S0076-6879(02)46071-5","article-title":"Generation of HIV-1 derived lentiviral vectors","volume":"346","author":"Follenzi","year":"2002","journal-title":"Methods Enzymol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1126\/science.272.5259.263","article-title":"In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector","volume":"272","author":"Naldini","year":"1996","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1002\/1521-2254(200009\/10)2:5<308::AID-JGM131>3.0.CO;2-3","article-title":"Lentiviral vectors: Excellent tools for experimental gene transfer and promising candidates for gene therapy","volume":"2","author":"Vigna","year":"2000","journal-title":"J. Gene Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2780\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:20:47Z","timestamp":1760196047000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2780"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,15]]},"references-count":43,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["ijms19092780"],"URL":"https:\/\/doi.org\/10.3390\/ijms19092780","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,15]]}}}