Genetic GHSR deficiency and LEAP2 treatment enhance the glucose-lowering effects of liraglutide in male mice in a metabolic state-dependent manner
Abstract
Aims Liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers glycemia and is used to treat type 2 diabetes (T2D) and obesity. Activation of the growth hormone secretagogue receptor (GHSR) increases glycemia. We aimed to determine whether GHSR inhibition enhances the glucose-lowering effects of liraglutide. Materials and methods We investigated the acute glucose-lowering effects of liraglutide in mice with genetic GHSR deletion or pharmacological GHSR blockade under fed, fasting, and postprandial conditions. We also examined the potential cellular basis of this interaction in murine islets using transcriptomic and immunolabeling approaches and in human pancreatic tissue using a publicly available transcriptomic dataset. Key findings Liraglutide similarly reduced glycemia in ad libitum-fed GHSR-null and control mice. Following food deprivation, liraglutide more effectively attenuated postprandial increases in glycemia in male, but not female, GHSR-null mice than in control mice. Liraglutide reduced glycemia in fasted GHSR-null male mice but not in WT males. In male mice, pretreatment with a LEAP2 (liver-expressed antimicrobial peptide 2) analog, an endogenous GHSR antagonist and inverse agonist, enhanced the glucose-lowering effects of liraglutide under postprandial and fasting conditions. GHSR and GLP-1R showed limited co-expression in murine islets. In human islets, their co-expression was also limited and enriched in δ-cells, but was also detected in β-cells, where the proportion of GHSR + /GLP-1R + cells was higher in donors with T2D. Significance GHSR inhibition enhances liraglutide's glucose-lowering effects in a sex-dependent manner, highlighting GHSR as a potential target to improve GLP-1R agonist efficacy.
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BibTeX
@article{cassano2026genetic,
title = {{Genetic GHSR deficiency and LEAP2 treatment enhance the glucose-lowering effects of liraglutide in male mice in a metabolic state-dependent manner}},
author = {Daniela A Cassano and Gimena Fernandez and María P Cornejo and Sepideh Sheybani-Deloui and Julieta Aguggia and Sonia Cantel and Jean-Alain Fehrentz and Abdella M Habib and Laura Rolland and Magalie A Ravier and María F Andreoli and Jeffrey M Zigman and Helgi B Schiöth and Mario Perello},
journal = {Life Sciences},
year = {2026},
month = oct,
doi = {10.1016/j.lfs.2026.124754},
url = {https://hal.science/hal-05842667v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Genetic GHSR deficiency and LEAP2 treatment enhance the glucose-lowering effects of liraglutide in male mice in a metabolic state-dependent manner
AU - Daniela A Cassano
AU - Gimena Fernandez
AU - María P Cornejo
AU - Sepideh Sheybani-Deloui
AU - Julieta Aguggia
AU - Sonia Cantel
AU - Jean-Alain Fehrentz
AU - Abdella M Habib
AU - Laura Rolland
AU - Magalie A Ravier
AU - María F Andreoli
AU - Jeffrey M Zigman
AU - Helgi B Schiöth
AU - Mario Perello
PY - 2026
DA - 2026/10/28
JO - Life Sciences
DO - 10.1016/j.lfs.2026.124754
UR - https://hal.science/hal-05842667v1
AB - Aims Liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist that lowers glycemia and is used to treat type 2 diabetes (T2D) and obesity. Activation of the growth hormone secretagogue receptor (GHSR) increases glycemia. We aimed to determine whether GHSR inhibition enhances the glucose-lowering effects of liraglutide. Materials and methods We investigated the acute glucose-lowering effects of liraglutide in mice with genetic GHSR deletion or pharmacological GHSR blockade under fed, fasting, and postprandial conditions. We also examined the potential cellular basis of this interaction in murine islets using transcriptomic and immunolabeling approaches and in human pancreatic tissue using a publicly available transcriptomic dataset. Key findings Liraglutide similarly reduced glycemia in ad libitum-fed GHSR-null and control mice. Following food deprivation, liraglutide more effectively attenuated postprandial increases in glycemia in male, but not female, GHSR-null mice than in control mice. Liraglutide reduced glycemia in fasted GHSR-null male mice but not in WT males. In male mice, pretreatment with a LEAP2 (liver-expressed antimicrobial peptide 2) analog, an endogenous GHSR antagonist and inverse agonist, enhanced the glucose-lowering effects of liraglutide under postprandial and fasting conditions. GHSR and GLP-1R showed limited co-expression in murine islets. In human islets, their co-expression was also limited and enriched in δ-cells, but was also detected in β-cells, where the proportion of GHSR + /GLP-1R + cells was higher in donors with T2D. Significance GHSR inhibition enhances liraglutide's glucose-lowering effects in a sex-dependent manner, highlighting GHSR as a potential target to improve GLP-1R agonist efficacy.
SN - 0024-3205
ER -