Skip to main content
Top
Published in: European Journal of Nutrition 3/2024

29-12-2023 | Obesity | Original Contribution

Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner

Authors: María F. Andreoli, Antonela S. Fittipaldi, Daniel Castrogiovanni, Pablo N. De Francesco, Spring Valdivia, Florencia Heredia, Carole Ribet-Travers, Ignacio Mendez, María V. Fasano, Helgi B. Schioth, Suhail A. Doi, Abdella M. Habib, Mario Perello

Published in: European Journal of Nutrition | Issue 3/2024

Login to get access

Abstract

Purpose

The liver-expressed antimicrobial peptide 2 (LEAP2) is a newly recognized peptide hormone that acts via the growth hormone secretagogue receptor (GHSR) blunting the effects of ghrelin and displaying ghrelin-independent actions. Since the implications of LEAP2 are beginning to be elucidated, we investigated if plasma LEAP2 concentration varies with feeding status or sex and whether it is associated with glucose metabolism and appetite sensations.

Methods

We performed a single test meal study, in which plasma concentrations of LEAP2, ghrelin, insulin and glucose as well as visual analogue scales for hunger, desire to eat, prospective food consumption, fullness were assessed before and 60 min after breakfast in 44 participants (n = 21 females) with normal weight (NW) or overweight/obesity (OW/OB).

Results

Pre-prandial plasma LEAP2 concentration was ~ 1.6-fold higher whereas ghrelin was ~ 2.0-fold lower in individuals with OW/OB (p < 0.001) independently of sex. After adjusting for body mass index (BMI) and sex, pre-prandial plasma LEAP2 concentration displayed a direct relationship with BMI (β: 0.09; 95%CI: 0.05, 0.13; p < 0.001), fat mass (β: 0.05; 95%CI: 0.01, 0.09; p = 0.010) and glycemia (β: 0.24; 95%CI: 0.05, 0.43; p = 0.021), whereas plasma ghrelin concentration displayed an inverse relationship with BMI and fat mass but not with glycemia. Postprandial plasma LEAP2 concentration increased ~ 58% in females with OW/OB (p = 0.045) but not in females with NW or in males. Pre-prandial plasma LEAP2 concentration displayed an inverse relationship with hunger score (β: − 11.16; 95% CI: − 18.52, − 3.79; p = 0.004), in a BMI-, sex- and ghrelin-independent manner.

Conclusions

LEAP2 emerges as a key hormone implicated in the regulation of metabolism and appetite in humans.

Trial registration

The study was retrospectively registered in clinicaltrials.gov (April 2023). ClinicalTrials.gov Identifier: NCT05815641.
Appendix
Available only for authorised users
Literature
1.
go back to reference Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273(5277):974–977. https://doi.org/10.1126/science.273.5277.974CrossRefPubMed Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273(5277):974–977. https://​doi.​org/​10.​1126/​science.​273.​5277.​974CrossRefPubMed
9.
go back to reference M’Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, Mary S, Denoyelle S, Dutertre S, Peraldi-Roux S, Neasta J, Oiry C, Baneres JL, Marie J, Perello M, Fehrentz JA (2019) N-Terminal Liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. J Med Chem 62(2):965–973. https://doi.org/10.1021/acs.jmedchem.8b01644CrossRefPubMed M’Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, Mary S, Denoyelle S, Dutertre S, Peraldi-Roux S, Neasta J, Oiry C, Baneres JL, Marie J, Perello M, Fehrentz JA (2019) N-Terminal Liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. J Med Chem 62(2):965–973. https://​doi.​org/​10.​1021/​acs.​jmedchem.​8b01644CrossRefPubMed
12.
go back to reference Cornejo MP, Castrogiovanni D, Schioth HB, Reynaldo M, Marie J, Fehrentz JA, Perello M (2019) Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model. J Neuroendocrinol 31(10):e12785. https://doi.org/10.1111/jne.12785CrossRefPubMed Cornejo MP, Castrogiovanni D, Schioth HB, Reynaldo M, Marie J, Fehrentz JA, Perello M (2019) Growth hormone secretagogue receptor signalling affects high-fat intake independently of plasma levels of ghrelin and LEAP2, in a 4-day binge eating model. J Neuroendocrinol 31(10):e12785. https://​doi.​org/​10.​1111/​jne.​12785CrossRefPubMed
13.
go back to reference Andreoli MF, De Francesco PN, Perello M (2018) Gastrointestinal hormones controlling energy homeostasis and their potential role in obesity. In: Nillni E (ed) Textbook of energy balance, neuropeptide hormones, and neuroendocrine function. Springer, Cham Andreoli MF, De Francesco PN, Perello M (2018) Gastrointestinal hormones controlling energy homeostasis and their potential role in obesity. In: Nillni E (ed) Textbook of energy balance, neuropeptide hormones, and neuroendocrine function. Springer, Cham
16.
go back to reference Fernandez G, Cabral A, De Francesco PN, Uriarte M, Reynaldo M, Castrogiovanni D, Zubiria G, Giovambattista A, Cantel S, Denoyelle S, Fehrentz JA, Tolle V, Schioth HB, Perello M (2022) GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner. Cell Mol Life Sci CMLS 79(5):277. https://doi.org/10.1007/s00018-022-04302-5CrossRefPubMed Fernandez G, Cabral A, De Francesco PN, Uriarte M, Reynaldo M, Castrogiovanni D, Zubiria G, Giovambattista A, Cantel S, Denoyelle S, Fehrentz JA, Tolle V, Schioth HB, Perello M (2022) GHSR controls food deprivation-induced activation of CRF neurons of the hypothalamic paraventricular nucleus in a LEAP2-dependent manner. Cell Mol Life Sci CMLS 79(5):277. https://​doi.​org/​10.​1007/​s00018-022-04302-5CrossRefPubMed
21.
go back to reference Hagemann CA, Zhang C, Hansen HH, Jorsal T, Rigbolt KTG, Madsen MR, Bergmann NC, Heimburger SMN, Falkenhahn M, Theis S, Breitschopf K, Holm S, Hedegaard MA, Christensen MB, Vilsboll T, Holst B, Vrang N, Jelsing J, Knop FK (2021) Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment. J Clin Endocrinol Metab 106(2):e966–e981. https://doi.org/10.1210/clinem/dgaa803CrossRefPubMed Hagemann CA, Zhang C, Hansen HH, Jorsal T, Rigbolt KTG, Madsen MR, Bergmann NC, Heimburger SMN, Falkenhahn M, Theis S, Breitschopf K, Holm S, Hedegaard MA, Christensen MB, Vilsboll T, Holst B, Vrang N, Jelsing J, Knop FK (2021) Identification and metabolic profiling of a novel human gut-derived LEAP2 fragment. J Clin Endocrinol Metab 106(2):e966–e981. https://​doi.​org/​10.​1210/​clinem/​dgaa803CrossRefPubMed
22.
go back to reference Fittipaldi AS, Hernandez J, Castrogiovanni D, Lufrano D, De Francesco PN, Garrido V, Vitaux P, Fasano MV, Fehrentz JA, Fernandez A, Andreoli MF, Perello M (2020) Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance. Eur J Endocrinol 182(2):165–175. https://doi.org/10.1530/EJE-19-0684CrossRefPubMed Fittipaldi AS, Hernandez J, Castrogiovanni D, Lufrano D, De Francesco PN, Garrido V, Vitaux P, Fasano MV, Fehrentz JA, Fernandez A, Andreoli MF, Perello M (2020) Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance. Eur J Endocrinol 182(2):165–175. https://​doi.​org/​10.​1530/​EJE-19-0684CrossRefPubMed
28.
go back to reference Obesity: preventing and managing the global epidemic. Report of a WHO consultation (2000). World Health Organization technical report series 894:i-xii, 1–253 Obesity: preventing and managing the global epidemic. Report of a WHO consultation (2000). World Health Organization technical report series 894:i-xii, 1–253
34.
go back to reference Stubbs RJ, Hughes DA, Johnstone AM, Rowley E, Reid C, Elia M, Stratton R, Delargy H, King N, Blundell JE (2000) The use of visual analogue scales to assess motivation to eat in human subjects: a review of their reliability and validity with an evaluation of new hand-held computerized systems for temporal tracking of appetite ratings. Br J Nutr 84(4):405–415. https://doi.org/10.1017/s0007114500001719CrossRefPubMed Stubbs RJ, Hughes DA, Johnstone AM, Rowley E, Reid C, Elia M, Stratton R, Delargy H, King N, Blundell JE (2000) The use of visual analogue scales to assess motivation to eat in human subjects: a review of their reliability and validity with an evaluation of new hand-held computerized systems for temporal tracking of appetite ratings. Br J Nutr 84(4):405–415. https://​doi.​org/​10.​1017/​s000711450000171​9CrossRefPubMed
38.
go back to reference Basulto J, Roura À, Calbet D (2008) Valoración de las sensaciones de apetito, hambre y saciedad mediante la utilización de sustitutivos de comidas (barritas). Ensayo aleatorizado, abierto y cruzado. Revista Española de Nutrición Humana y Dietética 12(2):47–55 Basulto J, Roura À, Calbet D (2008) Valoración de las sensaciones de apetito, hambre y saciedad mediante la utilización de sustitutivos de comidas (barritas). Ensayo aleatorizado, abierto y cruzado. Revista Española de Nutrición Humana y Dietética 12(2):47–55
Metadata
Title
Pre-prandial plasma liver-expressed antimicrobial peptide 2 (LEAP2) concentration in humans is inversely associated with hunger sensation in a ghrelin independent manner
Authors
María F. Andreoli
Antonela S. Fittipaldi
Daniel Castrogiovanni
Pablo N. De Francesco
Spring Valdivia
Florencia Heredia
Carole Ribet-Travers
Ignacio Mendez
María V. Fasano
Helgi B. Schioth
Suhail A. Doi
Abdella M. Habib
Mario Perello
Publication date
29-12-2023
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nutrition / Issue 3/2024
Print ISSN: 1436-6207
Electronic ISSN: 1436-6215
DOI
https://doi.org/10.1007/s00394-023-03304-8

Other articles of this Issue 3/2024

European Journal of Nutrition 3/2024 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Webinar | 06-02-2024 | 20:00 (CET)

Mastering chronic pancreatitis pain: A multidisciplinary approach and practical solutions

Severe pain is the most common symptom of chronic pancreatitis. In this webinar, experts share the latest insights in pain management for chronic pancreatitis patients. Experts from a range of disciplines discuss pertinent cases and provide practical suggestions for use within clinical practice.

Sponsored by: Viatris

Developed by: Springer Healthcare