Unimolecular GLP-1/APJ receptor co-agonism improves metabolism and dyslipidaemia as well as normalising hepatic triglyceride and aminotransferase elevation in high-fat-fed mice
- 1Centre for Diabetes, School of Biomedical Sciences, Ulster University, Coleraine, UK
Abstract
Aims/hypothesis: The aim of this study was to determine the applicability of dual activation of glucagon-like peptide-1 (GLP-1) and apelin (APJ) receptors as a next-generation therapeutic option for obesity and diabetes.
Methods: A fully characterised unimolecular dual GLP-1/APJ receptor agonist, namely exendin–linker–apelin (ELA), as well as its acylated long-acting equivalent, ELA-Lys12(γGluPal), were administered once daily to high-fat-fed (HFF) mice for 28 days, with liraglutide used as a positive control. Effects on appetite and body weight, as well as glucose, pyruvate and insulin tolerance, circulating lipids, liver transaminases and triglyceride content, indirect calorimetry measurements and pancreatic morphology were then examined.
Results: ELA, and particularly ELA-Lys12(γGluPal), reduced food intake, circulating glucose and HbA1c concentrations relative to saline-treated HFF control mice. ELA-Lys12(γGluPal) substantially reduced blood glucose concentrations during glucose and pyruvate tolerance tests. These positive effects were largely independent of alterations in circulating insulin. However, circulating triglyceride and LDL-cholesterol concentrations were lowered, accompanied by complete normalisation of hepatic triglyceride and aminotransferase levels in all GLP-1/apelin hybrid-treated HFF mice. Assessment of indirect calorimetry demonstrated restoration of metabolic flexibility in mice treated with ELA-Lys12(γGluPal), despite reductions in energy expenditure. Notably, GLP-1/apelin hybrid treatment did not affect locomotor activity, whereas liraglutide treatment was associated with marked reductions in physical activity. Histological assessment of pancreatic islets revealed that all treatment modalities induced a marked enhancement of beta cell proliferative frequency, and accompanying suppression of apoptotic rates, without major alterations in islet or beta cell areas.
Conclusions/interpretation: Chronic administration of ELA, and especially ELA-Lys12(γGluPal), delivered pronounced metabolic improvements in HFF mice, with the clearest differences from liraglutide treatment evident in circulating lipids and hepatic biomarkers.
Graphical Abstract:
Supplementary Information: The online version contains peer-reviewed but unedited supplementary material available at https://doi.org/10.1007/s00125-026-06863-7.
Related
- Online information seeking behaviour and health outcomes among patients with hypertension, diabetes and dyslipidaemia (the 'three highs'): a scoping review protocol.
- Precision RNAi for fibrodysplasia ossificans progressiva in mice using a combinatorial unimolecular allele selective approach
- Aspartate aminotransferase at large-A case of disappearing macro-aspartate aminotransferase in a child.
- Association of medical visit frequency with cardiovascular events and mortality in patients with dyslipidaemia: a cohort study using a Japanese claims database.
- Association of aspartate aminotransferase to alanine aminotransferase ratio with hypertension in Chinese adults: a cross-sectional study
BibTeX
@article{sridhar2026unimolecular,
title = {{Unimolecular GLP-1/APJ receptor co-agonism improves metabolism and dyslipidaemia as well as normalising hepatic triglyceride and aminotransferase elevation in high-fat-fed mice}},
author = {Ananyaa Sridhar and Ethan S. Palmer and Sarah L. Craig and Neil Tanday and Finbarr P. M. O’Harte and Nigel Irwin},
journal = {Diabetologia},
year = {2026},
month = sep,
doi = {10.1007/s00125-026-06863-7},
url = {https://doi.org/10.1007/s00125-026-06863-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Unimolecular GLP-1/APJ receptor co-agonism improves metabolism and dyslipidaemia as well as normalising hepatic triglyceride and aminotransferase elevation in high-fat-fed mice
AU - Ananyaa Sridhar
AU - Ethan S. Palmer
AU - Sarah L. Craig
AU - Neil Tanday
AU - Finbarr P. M. O’Harte
AU - Nigel Irwin
PY - 2026
DA - 2026/09/18
JO - Diabetologia
DO - 10.1007/s00125-026-06863-7
UR - https://doi.org/10.1007/s00125-026-06863-7
AB - Aims/hypothesis: The aim of this study was to determine the applicability of dual activation of glucagon-like peptide-1 (GLP-1) and apelin (APJ) receptors as a next-generation therapeutic option for obesity and diabetes. Methods: A fully characterised unimolecular dual GLP-1/APJ receptor agonist, namely exendin–linker–apelin (ELA), as well as its acylated long-acting equivalent, ELA-Lys12(γGluPal), were administered once daily to high-fat-fed (HFF) mice for 28 days, with liraglutide used as a positive control. Effects on appetite and body weight, as well as glucose, pyruvate and insulin tolerance, circulating lipids, liver transaminases and triglyceride content, indirect calorimetry measurements and pancreatic morphology were then examined. Results: ELA, and particularly ELA-Lys12(γGluPal), reduced food intake, circulating glucose and HbA1c concentrations relative to saline-treated HFF control mice. ELA-Lys12(γGluPal) substantially reduced blood glucose concentrations during glucose and pyruvate tolerance tests. These positive effects were largely independent of alterations in circulating insulin. However, circulating triglyceride and LDL-cholesterol concentrations were lowered, accompanied by complete normalisation of hepatic triglyceride and aminotransferase levels in all GLP-1/apelin hybrid-treated HFF mice. Assessment of indirect calorimetry demonstrated restoration of metabolic flexibility in mice treated with ELA-Lys12(γGluPal), despite reductions in energy expenditure. Notably, GLP-1/apelin hybrid treatment did not affect locomotor activity, whereas liraglutide treatment was associated with marked reductions in physical activity. Histological assessment of pancreatic islets revealed that all treatment modalities induced a marked enhancement of beta cell proliferative frequency, and accompanying suppression of apoptotic rates, without major alterations in islet or beta cell areas. Conclusions/interpretation: Chronic administration of ELA, and especially ELA-Lys12(γGluPal), delivered pronounced metabolic improvements in HFF mice, with the clearest differences from liraglutide treatment evident in circulating lipids and hepatic biomarkers. Graphical Abstract: Supplementary Information: The online version contains peer-reviewed but unedited supplementary material available at https://doi.org/10.1007/s00125-026-06863-7.
SN - 0012-186X
SN - 1432-0428
ER -