Acute effect of a cod protein hydrolysate on postprandial acylated ghrelin concentration and sensations associated with appetite in healthy subjects: a double-blind crossover trial

  • Hanna Fjeldheim Dale Haukeland University Hospital
  • Caroline Jensen Centre for Nutrition, Department of Clinical Medicine, University of Bergen, Bergen, Norway
  • Trygve Hausken
  • Einar Lied
  • Jan Gunnar Hatlebakk
  • Ingeborg Brønstad
  • Dag Arne Lihaug Hoff
  • Gülen Arslan Lied
Keywords: hunger, overweight, marine peptides, gastric hormones, nutrition supplement


Background: Fish protein hydrolysates are suggested to contain bioactive sequences capable of affecting metabolic pathways involved in the regulation of glucose metabolism and body weight when consumed in low doses. Modulation of the appetite-regulating hormone ghrelin may explain suppression of insulin secretion and weight loss observed in previous studies with fish protein hydrolysates.

Objective: This study aimed to assess the effect of a single, low dose of cod protein hydrolysate (CPH) before a breakfast meal on postprandial acylated ghrelin concentration and sensations associated with appetite in healthy subjects.

Design: In this explorative trial with a crossover design, 41 healthy individuals (15 males and 26 females, age 51 ± 6 years) completed 2 study days separated by 4–7 days of washout. On both study days, a test drink containing 20 mg CPH or casein (control) per kg body weight was given immediately before a standardized breakfast meal. Acylated ghrelin concentrations were measured before test drink/breakfast (baseline) and at time 0, 20, 40, 80, and 180 min postprandially. Sensations associated with appetite were measured by a Visual Analog Scale (100 mm) at baseline and 0, 20, 40, and 180 min postprandially.

Results: Statistically, no difference was observed between CPH and control for postprandial acylated ghrelin concentrations (mean difference geometric mean: 1.05 pg/mL, 95% confidence interval [CI]: 0.97–1.13, P = 0.266), or between the total area under the curve (tAUC) for acylated ghrelin after CPH (tAUC = 17518 pg/mL × min, 95% CI: 0–47941) and control (tAUC = 17272 pg/mL × min, 95% CI: 0–48048, P = 0.991). No differences were found between CPH and control for sensation of appetite, according to tAUC of postprandial scores for satiety (P = 0.794) and the feeling of fullness (P = 0.996).

Conclusion: We did not find an effect of a single dose of CPH on postprandial concentrations of acylated ghrelin or sensations related to feeling of hunger, compared to control. Further studies should aim to evaluate the effect of a supplement with CPH given daily over a period of time.


Download data is not yet available.


  1. Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav 2006; 89(1): 71–84. doi: 10.1016/j.physbeh.2006.05.022

  2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402(6762): 656–60. doi: 10.1038/45230

  3. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50(8): 1714–9. doi: 10.2337/diabetes.50.8.1714

  4. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409(6817): 194–8. doi: 10.1038/35051587

  5. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001; 86(10): 5083–6. doi: 10.1210/jcem.86.10.8098

  6. Tong J, Davis HW, Gastaldelli A, D'Alessio D. Ghrelin impairs prandial glucose tolerance and insulin secretion in healthy humans despite increasing GLP-1. J Clin Endocrinol Metab 2016; 101(6): 2405–14. doi: 10.1210/jc.2015-4154

  7. Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ. Hyperphagic effects of brainstem ghrelin administration. Diabetes 2003; 52(9): 2260–5. doi: 10.2337/diabetes.52.9.2260

  8. Meyer C. Final answer: ghrelin can suppress insulin secretion in humans, but is it clinically relevant? Diabetes 2010; 59(11): 2726–8. doi: 10.2337/db10-1088

  9. Castaneda TR, Tong J, Datta R, Culler M, Tschop MH. Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 2010; 31(1): 44–60. doi: 10.1016/j.yfrne.2009.10.008

  10. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, et al. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 2010; 59(9): 2145–51. doi: 10.2337/db10-0504

  11. Tremblay F, Lavigne C, Jacques H, Marette A. Role of dietary proteins and amino acids in the pathogenesis of insulin resistance. Annu Rev Nutr 2007; 27: 293–310. doi: 10.1146/annurev.nutr.25.050304.092545

  12. Vikoren LA, Nygard OK, Lied E, Rostrup E, Gudbrandsen OA. A randomised study on the effects of fish protein supplement on glucose tolerance, lipids and body composition in overweight adults. Br J Nutr 2013; 109(4): 648–57. doi: 10.1017/S0007114512001717

  13. Vildmyren I, Cao HJV, Haug LB, Valand IU, Eng O, Oterhals A, et al. Daily intake of protein from cod residual material lowers serum concentrations of nonesterified fatty acids in overweight healthy adults: a randomized double-blind pilot study. Mar Drugs 2018; 16(6): E197. doi: 10.3390/md16060197

  14. Dale HF, Jensen C, Hausken T, Lied E, Hatlebakk JG, Brønstad I, et al. Effect of a cod protein hydrolysate on postprandial glucose metabolism in healthy subjects: a double-blind cross-over trial. J Nutr Sci 2018; 7: e33. doi: 10.1017/jns.2018.23

  15. Drotningsvik A, Mjos SA, Pampanin DM, Slizyte R, Carvajal A, Remman T, et al. Dietary fish protein hydrolysates containing bioactive motifs affect serum and adipose tissue fatty acid compositions, serum lipids, postprandial glucose regulation and growth in obese Zucker fa/fa rats. Br J Nutr 2016; 116(8): 1336–45. doi: 10.1017/S0007114516003548

  16. Liaset B, Madsen L, Hao Q, Criales G, Mellgren G, Marschall HU, et al. Fish protein hydrolysate elevates plasma bile acids and reduces visceral adipose tissue mass in rats. Biochim Biophys Acta 2009; 1791(4): 254–62. doi: 10.1016/j.bbalip.2009.01.016

  17. Zaïr Y, Duclos E, Housez B, Vergara C, Cazaubiel M, Soisson F. Evaluation of the satiating properties of a fish protein hydrolysate among overweight women: a pilot study. Nutr Food Sci 2014; 44(5): 389–99. doi:10.1108/NFS-06-2013-0075

  18. Nobile V, Duclos E, Michelotti A, Bizzaro G, Negro M, Soisson F. Supplementation with a fish protein hydrolysate (Micromesistius poutassou): effects on body weight, body composition, and CCK/GLP-1 secretion. Food Nutr Res 2016; 60: 29857. doi: 10.3402/fnr.v60.29857

  19. Ministers NCo. Nordic Nutrition Recommendations 2012: integrating nutrition and physical activity. Copenhagen: Nordic Council of Ministers; 2014; 1–627. doi: 10.6027/Nord2014-002

  20. Le Gouic AV, Harnedy PA, FitzGerald RJ. Bioactive peptides from fish protein by-products. In: Mérillon J-M, Ramawat KG, eds. Bioactive molecules in food. Cham: Springer International Publishing; 2018, pp. 1–35. doi: 10.1007/978-3-319-54528-8_29-1

  21. Kane SV, Sandborn WJ, Rufo PA, Zholudev A, Boone J, Lyerly D, et al. Fecal lactoferrin is a sensitive and specific marker in identifying intestinal inflammation. Am J Gastroenterol 2003; 98(6): 1309–14. doi: 10.1111/j.1572-0241.2003.07458.x

  22. Lavigne C, Tremblay F, Asselin G, Jacques H, Marette A. Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats. Am J Physiol Endocrinol Metab 2001; 281(1): E62–71. doi: 10.1152/ajpendo.2001.281.1.E62

  23. Ouellet V, Marois J, Weisnagel SJ, Jacques H. Dietary cod protein improves insulin sensitivity in insulin-resistant men and women: a randomized controlled trial. Diabetes Care 2007; 30(11): 2816–21. doi: 10.2337/dc07-0273

  24. Erdmann J, Topsch R, Lippl F, Gussmann P, Schusdziarra V. Postprandial response of plasma ghrelin levels to various test meals in relation to food intake, plasma insulin, and glucose. J Clin Endocrinol Metab 2004; 89(6): 3048–54. doi: 10.1210/jc.2003-031610

  25. Heppner KM, Tong J. Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions. Eur J Endocrinol 2014; 171(1): R21–32. doi: 10.1530/EJE-14-0183

  26. Blom WA, Lluch A, Stafleu A, Vinoy S, Holst JJ, Schaafsma G, et al. Effect of a high-protein breakfast on the postprandial ghrelin response. Am J Clin Nutr 2006; 83(2): 211–20. doi: 10.1093/ajcn/83.2.211

  27. Foster-Schubert KE, Overduin J, Prudom CE, Liu J, Callahan HS, Gaylinn BD, et al. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J Clin Endocrinol Metab 2008; 93(5): 1971–9. doi: 10.1210/jc.2007-2289

  28. Leidy HJ, Mattes RD, Campbell WW. Effects of acute and chronic protein intake on metabolism, appetite, and ghrelin during weight loss. Obesity (Silver Spring, Md) 2007; 15(5): 1215–25. doi: 10.1038/oby.2007.143

  29. Tannous dit El Khoury D, Obeid O, Azar ST, Hwalla N. Variations in postprandial ghrelin status following ingestion of high-carbohydrate, high-fat, and high-protein meals in males. Ann Nutr Metab 2006; 50(3): 260–9. doi: 10.1159/000091684

  30. Giezenaar C, Lange K, Hausken T, Jones KL, Horowitz M, Chapman I, et al. Acute effects of substitution, and addition, of carbohydrates and fat to protein on gastric emptying, blood glucose, gut hormones, appetite, and energy intake. Nutrients 2018; 10(10): E1451. doi: 10.3390/nu10101451

  31. Giezenaar C, Luscombe-Marsh ND, Hutchison AT, Lange K, Hausken T, Jones KL, et al. Effect of gender on the acute effects of whey protein ingestion on energy intake, appetite, gastric emptying and gut hormone responses in healthy young adults. Nutr Diabetes 2018; 8(1): 40. doi: 10.1038/s41387-018-0048-7

  32. Smeets AJ, Soenen S, Luscombe-Marsh ND, Ueland O, Westerterp-Plantenga MS. Energy expenditure, satiety, and plasma ghrelin, glucagon-like peptide 1, and peptide tyrosine-tyrosine concentrations following a single high-protein lunch. J Nutr 2008; 138(4): 698–702. doi: 10.1093/jn/138.4.698

  33. Hutchison AT, Piscitelli D, Horowitz M, Jones KL, Clifton PM, Standfield S, et al. Acute load-dependent effects of oral whey protein on gastric emptying, gut hormone release, glycemia, appetite, and energy intake in healthy men. Am J Clin Nutr 2015; 102(6): 1574–84. doi: 10.3945/ajcn.115.117556

  34. Uhe AM, Collier GR, O'Dea K. A comparison of the effects of beef, chicken and fish protein on satiety and amino acid profiles in lean male subjects. J Nutr 1992; 122(3): 467–72. doi: 10.1093/jn/122.3.467

  35. Nielsen LV, Nyby S, Klingenberg L, Juul-Hindsgaul N, Rudnicki J, Ritz C, et al. Meals based on cod or veal in combination with high or low glycemic index carbohydrates did not affect diet-induced thermogenesis, appetite sensations, or subsequent energy intake differently. Appetite 2018; 130: 199–208. doi: 10.1016/j.appet.2018.08.006

  36. Borzoei S, Neovius M, Barkeling B, Teixeira-Pinto A, Rossner S. A comparison of effects of fish and beef protein on satiety in normal weight men. Eur J Clin Nutr 2006; 60(7): 897–902. doi: 10.1038/sj.ejcn.1602397

  37. Cudennec B, Fouchereau-Peron M, Ferry F, Duclos E, Ravallec R. In vitro and in vivo evidence for a satiating effect of fish protein hydrolysate obtained from blue whiting (Micromesistius poutassou) muscle. J Funct Foods 2012; 4(1): 271–7. doi: 10.1016/j.jff.2011.12.003

  38. Schmedes M, Bendtsen LQ, Gomes S, Liaset B, Holst JJ, Ritz C, et al. The effect of casein, hydrolyzed casein and whey proteins on urinary and postprandial plasma metabolites in overweight and moderately obese human subjects. J Sci Food Agric 2018; 98(15): 5598–5605. doi: 10.1002/jsfa.9103

  39. Blundell J, de Graaf C, Hulshof T, Jebb S, Livingstone B, Lluch A, et al. Appetite control: methodological aspects of the evaluation of foods. Obes Rev 2010; 11(3): 251–70. doi: 10.1111/j.1467-789X.2010.00714.x

  40. Parker BA, Sturm K, MacIntosh CG, Feinle C, Horowitz M, Chapman IM. Relation between food intake and visual analogue scale ratings of appetite and other sensations in healthy older and young subjects. Eur J Clin Nutr 2004; 58(2): 212–8. doi: 10.1038/sj.ejcn.1601768

  41. Grosse J, Heffron H, Burling K, Akhter Hossain M, Habib AM, Rogers GJ, et al. Insulin-like peptide 5 is an orexigenic gastrointestinal hormone. Proc Natl Acad Sci USA 2014; 111(30): 11133–8. doi: 10.1073/pnas.1411413111

How to Cite
Dale H, Jensen C, Hausken T, Lied E, Hatlebakk J, Brønstad I, Hoff DA, Lied G. Acute effect of a cod protein hydrolysate on postprandial acylated ghrelin concentration and sensations associated with appetite in healthy subjects: a double-blind crossover trial. fnr [Internet]. 2019Oct.22 [cited 2019Nov.21];630. Available from:
Original Articles